Nicotine-Use/Smoking Is Associated with the Efficacy of Naltrexone in the Treatment of Alcohol Dependence.

BACKGROUND: The opioid antagonist naltrexone is not efficacious for every alcohol treatment seeker. However, various individual factors, such as genetic differences and nicotine-use/smoking status, have been suggested as predictors of naltrexone response. In a randomized clinical trial, we previously reported that nicotine-use/smoking status might be a stronger predictor of naltrexone efficacy than OPRM1 A118G single nucleotide polymorphism (SNP) genotype. In this report, we further characterize the nicotine-users in that trial, examine other drinking outcomes, examine the influence of smoking change on naltrexone effects on drinking, and validate the result in smokers with disialo carbohydrate-deficient transferrin (%dCDT) change as an independent biomarker of response. METHODS: Individuals (n = 146) meeting DSM-IV criteria for alcohol dependence who were genotyped for the OPRM1 A118G SNP and who did, or did not, use nicotine/cigarettes were randomized, in a balanced fashion, to naltrexone (50 mg/d) or placebo and provided medical management (MM) over a 16-week clinical trial. Alcohol use and smoking during the trial were assessed and analyzed. RESULTS: Nicotine-use/smoking status significantly interacted with medication in reducing percent heavy drinking days (PHDD) during the trial (p = 0.003), such that nicotine-users/smokers showed significantly lower PHDD on naltrexone versus placebo (p = 0.0001, Cohen's d = 0.89), while nonusers showed no significant difference between naltrexone and placebo (p = 0.95, Cohen's d = 0.02). Similar effects were shown for drinks per day and percent days drinking. The superiority of naltrexone over placebo on PHDD reduction in nicotine-users/smokers was confirmed with %dCDT (Cohen's d range 0.3 to 0.9 over the study). Naltrexone did not significantly change cigarette use in smokers, and change in use did not influence naltrexone's effect on PHDD. CONCLUSIONS: These data confirm past findings that naltrexone is more efficacious in those who use nicotine/cigarettes. Compared to previous work on the OPRM1 A118G SNP, it appears that nicotine-use might be a more salient predictor of naltrexone treatment response. While naltrexone did not change cigarette use during the study, and smoking change was not related to alcohol reduction, it should be noted that participants were not seeking smoking cessation and MM did not address this issue.

Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status.

This corrects the article DOI: 10.1038/npp.2017.74.

Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status.

Naltrexone reduces drinking among individuals with alcohol use disorders (AUDs), but it is not effective for everyone. Variability in its effects on reward-related brain activation, genetic variation, and/or cigarette smoking may account for this mixed response profile. This randomized clinical trial tested the effects of naltrexone on drinking and alcohol cue-elicited brain activation, evaluated whether OPRM1 A118G genotype or smoking moderated these effects, and explored whether the effects of medication on cue-elicited activation predicted subsequent drinking. One hundred and fifty-two treatment-seeking individuals with alcohol dependence, half preselected to carry at least one A118G G (Asp) allele, were randomized to naltrexone (50 mg) or placebo for 16 weeks and administered an fMRI alcohol cue reactivity task at baseline and after 2 weeks of treatment. Naltrexone, relative to placebo, significantly reduced alcohol cue-elicited activation of the right ventral striatum (VS) between baseline and week 2 and reduced heavy drinking over 16 weeks. OPRM1 genotype did not significantly moderate these effects, but G-allele carriers who received naltrexone had an accelerated return to heavy drinking after medication was stopped. Smoking moderated the effects of medication on drinking, such that naltrexone was superior to placebo only among smokers. The degree of reduction in right VS activation between scans interacted with medication in predicting subsequent drinking, such that individuals with greater reduction in activation who received naltrexone, but not placebo, experienced the least heavy drinking during the following 14 weeks. These data replicate previous findings that naltrexone reduces heavy drinking and reward-related brain activation among treatment-seeking individuals with AUDs, and indicate that smoking and the magnitude of reduction in cue-elicited brain activation may predict treatment response.

Identifying chronic heavy alcohol use in emergency general surgery patients: a pilot study.

BACKGROUND: Chronic heavy alcohol (CHA) use has been associated with perioperative complications. Emergency general surgery (EGS) patients are not routinely screened for CHA. If screened, it is usually for hazardous use of alcohol, using a survey such as the Alcohol Use Disorders Identification Test (AUDIT). This study screened EGS patients for CHA use using serum carbohydrate-deficient transferrin (%dCDT) level, a biomarker that has been validated as an indicator for CHA use, as well as the AUDIT. The purpose of this study was to determine the percent of EGS patients with CHA (as indicated by elevated %dCDT), and the relationship between %dCDT and AUDIT. Secondary aims included comparing the characteristics of EGS patients with and without CHA use, and evaluating the association of CHA use with negative clinical outcomes. METHODS: EGS patients aged 21 and older admitted to the general surgery inpatient service of a tertiary hospital from July 2014 to June 2016 were invited to participate in this study. %dCDT levels above 1.7% were considered positive for CHA use, as were AUDIT scores ≥8. RESULTS: 195 EGS patients were screened for inclusion and 91 (46.7%) agreed to participate. 14 (15.4%) were positive for hazardous alcohol use on AUDIT and 5 (5.5%) were positive for CHA by %dCDT. Positive predictive value of AUDIT for CHA was 21.4%. There was no correlation between positive scores on AUDIT and %dCDT. DISCUSSION: Identifying at risk patients early on in their hospital course may allow clinicians to institute treatments to mitigate and/or circumvent complications in such patients. This pilot study determined that 17.6% of participating EGS patients were positive for some type of alcohol misuse, but only 5.5% had CHA. Further research is needed to determine whether routine use of %dCDT would be beneficial in reducing perioperative complications in this patient population. LEVEL OF EVIDENCE: III (diagnostic test).

Varenicline effects on drinking, craving and neural reward processing among non-treatment-seeking alcohol-dependent individuals.

RATIONALE: The α4ß2 nicotinic acetylcholine receptor partial agonist varenicline has been reported to reduce drinking among both heavy-drinking smokers and primary alcoholics, and this effect may be related to varenicline-mediated reduction of alcohol craving. Among smokers, varenicline has been reported to modulate cigarette cue-elicited brain activation in several reward-related areas. OBJECTIVES: This pilot study tested varenicline's effects on drinking, alcohol craving, and alcohol cue-elicited activation of reward-related brain areas among non-treatment-seeking alcohol-dependent individuals. METHODS: Thirty-five such individuals (mean age = 30, 57 % male, 76 % heavy drinking days in the past month, 15 smokers) were randomized to either varenicline (titrated to 2 mg) or placebo for 14 days, and were administered an alcohol cue reactivity fMRI task on day 14. A priori regions of interest (ROIs) were bilateral and medial orbitofrontal cortex (OFC), right ventral striatum (VS), and medial prefrontal cortex (mPFC). RESULTS: Despite good medication adherence, varenicline did not reduce heavy drinking days or other drinking parameters. It did, however, increase self-reported control over alcohol-related thoughts and reduced cue-elicited activation bilaterally in the OFC, but not in other brain areas. CONCLUSIONS: These data indicate that varenicline reduces alcohol craving and some of the neural substrates of alcohol cue reactivity. However, varenicline effects on drinking mediated by cue-elicited brain activation and craving might be best observed among treatment-seekers motivated to reduce their alcohol consumption.

Childhood adversity increases risk for nicotine dependence and interacts with α5 nicotinic acetylcholine receptor genotype specifically in males.

The relative importance of specific genetic and environmental factors in regulating nicotine dependence (ND) risk, including the effects on specific forms of childhood adversity on smoking risk, have been understudied. Genome-wide association studies and rodent models have demonstrated that the α5 nicotinic acetylcholine receptor gene (CHRNA5) is important in regulating nicotine intake. Childhood adversity increases the methylation level of the CHRNA5 promoter region in European Americans (EAs), an effect that was observed only in males (Zhang et al, submitted for publication). In view of this potential sex difference in the effects of early life experience on smoking, we investigated the presence of a sex-specific gene-by-environment effect of this marker on ND risk. A nonsynonymous SNP in CHRNA5 previously associated to ND and several related traits, rs16969968, was genotyped in 2206 EAs (1301 men and 905 women). The main and interactive effects of childhood adversity and rs16969968 genotype on diagnosis of ND and ND defined by dichotomized Fagerstrom test for ND (FTND) scores were explored. Men and women were analyzed separately to test for sex differences. Childhood adversity significantly increased ND risk in both sexes, and the effect in women was twice than that in men. Significant interactive effects of childhood adversity and rs16969968 genotype were observed in men (ND: OR=1.80, 95% CI=1.18-2.73, P=0.0044; FTND: OR=1.79, 95% CI=1.11-2.88, P=0.012). No interaction was found in women. This study provides evidence of a sex-specific gene × environment effect of CHRNA5 and childhood adversity on the risk for ND.

Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence.

BACKGROUND: Several studies report association of alpha-4 nicotinic acetylcholine receptors (encoded by CHRNA4) with nicotine dependence (ND). A meta-analysis of genomewide linkage studies for ND implicated a single chromosomal region, which includes CHRNA4, as genome-wide significant. METHODS: After establishing that common variants are unlikely to completely account for this linkage, we investigated the distribution of CHRNA4 rare variants by sequencing the coding exons and flanking intronic regions of CHRNA4 in 209 European American (EA) ND cases and 183 EA control subjects. Because most of the rare variants that we detected (and all nonsynonymous changes) were in Exon 5, we sequenced Exon 5 in an additional 1000 ND cases and 1000 non-ND comparison subjects, both of which included equal numbers of EAs and African Americans. RESULTS: Comparison subjects had a higher frequency of rare nonsynonymous variants in the Exon 5 region (encoding the large intercellular loop of the α4 subunit; Fisher's Exact Test p = .009; association test p = .009, odds ratio = .43; weighted-sum method p = .014), indicating a protective effect against ND. Considering data from the two stages combined and only nonsynonymous variants predicted to alter protein function, the association was stronger (Fisher's Exact Test p = .005; association test p = .008, odds ratio = .29; weighted-sum method p = .005). Single-photon emission computed tomography imaging results were consistent with functionality. CONCLUSIONS: CHRNA4 functional rare variants may reduce ND risk. This is the first demonstration that rare functional variants at a candidate locus protect against substance dependence to our knowledge, suggesting a novel mechanism of substance dependence heritability that is potentially of general importance.

Liver disease and HPLC quantification of disialotransferrin for heavy alcohol use: a case series.

BACKGROUND: It had previously been suggested that individuals with cirrhosis may have a pattern of transferrin glycosylation that interferes with the interpretation of carbohydrate-deficient transferrin (CDT) testing for heavy alcohol use. The goal of this case series was to evaluate the prevalence of liver disease among individuals with poor resolution of transferrin glycoforms by high performance liquid chromatography. METHODS: We reviewed the electronic medical records of 35 consecutive patients with poor chromatographic resolution of disialotransferrin from trisialotransferrin and recorded information on diagnosed liver disease, liver function testing, and other factors. RESULTS: Thirty of the 35 subjects with poor chromatographic resolution of the transferrin glycoforms had sufficient data in the medical record for some estimation of liver function. Of these 30 subjects, 25 had previously diagnosed liver pathology. Of the remaining 5 subjects, 2 had liver imaging results suggestive of benign tumor; the remaining 3 had mildly elevated bilirubin and aminotransferase activity, and low albumin. CONCLUSIONS: Liver abnormalities, but not necessarily cirrhosis, are common in individuals with poor chromatographic separation of transferrin glycoforms, which might lead to false-positive results on CDT testing. However, the chromatographic-based assay can detect this issue, minimizing the reporting of false positives, but not necessarily assisting in valid detection of heavy drinking.

COMT genotype influences the effect of alcohol on blood pressure: results from the COMBINE study.

BACKGROUND: Heavy drinking can cause chronic hypertension, possibly due to effects on the autonomic nervous system. Catechol- O-methyltransferase (COMT) inactivates catecholamines, and a G to A substitution in codon 108 in the soluble COMT mRNA (or codon 158 in the membrane-bound form) substitutes methionine for valine and alters enzyme activity. METHODS: We evaluated the association of COMT genotype at this locus with blood pressure (BP) in 839 alcohol-dependent individuals before and during participation in an alcoholism treatment trial. Hierarchical linear models were used to account for within-subject correlation on repeated BP measurements, and findings were adjusted for age, gender, ethnicity, alcohol use, body mass index, current smoking, hypertension history, and study site. RESULTS: Relative to those with the val-val genotype, those with the met-met genotype had higher adjusted systolic (+4.9 mm Hg, P < 0.01) and diastolic (+3.2 mm Hg, P < 0.01) BP at baseline. Those with the val-met genotype did not significantly differ from the val-val genotype. Changes in BP between baseline and 4 weeks of alcohol treatment also differed by genotype. Relative to the val-val genotype, the met-met genotype had a greater reduction in adjusted systolic pressure (-3.9 mm Hg, P < 0.01) and diastolic pressure (-2.8 mm Hg, P < 0.01). Corresponding relative reductions for the val-met genotype were -2.2 mm Hg systolic (P = 0.070) and -1.5 mm Hg diastolic (P < 0.05). CONCLUSION: Findings suggest that alcohol-induced BP elevation may be related to the effects of catecholamines and their genetically determined inactivation.

What role does measuring medication compliance play in evaluating the efficacy of naltrexone?

BACKGROUND: Compliance with medication in pharmacotherapy trials of alcoholism has been shown to be equal to, or more, important than in other areas of medicine. Research has suggested that naltrexone's effectiveness can be greatly influenced by the compliance of participants in clinical trials. Presently, we compare 2 compliance measurement methods [urine riboflavin and medication event monitoring system (MEMS)] used simultaneously to evaluate naltrexone's efficacy and the impact of compliance on the size of observable treatment effects. METHODS: One hundred and thirty-seven of 160 randomized alcoholic patients completed 12-weeks (84 days) of naltrexone or placebo and cognitive behavioral therapy (CBT) or motivational enhancement therapy (MET). Urine riboflavin was determined during study weeks 2, 6, and 12. The MEMS provided a detailed computerized record of when a participant opened their medication bottle throughout the trial. Baseline predictors of MEMS (80% openings) and urine riboflavin (>or=1,500 ng/mL by fluorimetry) compliance were examined. The effects of the treatments in the compliant participants defined by one, the other, or both methods were compared and contrasted with a previously reported intent-to-treat analysis where compliance was not taken into account. RESULTS: Age was predictive of compliance. 105 participants were deemed compliant via urine riboflavin criteria, 87 via MEMS, and 77 when both criteria were met, with no significant differences between treatment groups. The most compliant participants showed a significant medication by therapy interaction. Those treated with naltrexone/CBT showed more abstinence days (p<0.03), less heavy drinking days (p<0.03) and less total drinks (p<0.03) than the other groups. The effect size of this interaction increased from about 0.2 in the intent-to-treat analysis, to about 0.4 to 0.5 in the compliant group analyses, with little difference between compliance measurement methods. CONCLUSIONS: Compliance measurement does appear to influence the evaluation of the efficacy of naltrexone within the context of CBT. Treatment effect sizes approximately doubled in the most compliant individuals. Measuring compliance by either of 2 distinct methods provides approximately similar results. As compliance with naltrexone within the context of CBT has such a large impact of treatment outcome, methods of enhancing compliance during treatment should be given the utmost attention.

Alcohol biomarker screening in medical and surgical settings.

This article highlights the proceedings of a symposium presented at the 28th Annual Meeting of the Research Society on Alcoholism in Santa Barbara, CA, on June 28, 2005, organized and chaired by Peter Miller. The presentations included (1) Screening for Alcohol Use Disorders in Surgical and Trauma Patients, presented by Claudia Spies; (2) Are Serum Levels of %CDT and GGT Related to Severity of Liver Biopsy Inflammation, Fibrosis, and Steatohepatitis in Patients with Hepatitis C? by Martin Javors; (3) Biochemical Alcohol Screening in the Treatment of Hypertension, presented by Peter Miller; and (4) The Cost-Effectiveness of a New Biomarker, CDT, in a Primary Care Sample, by Michael Fleming. Presentations were discussed by Raymond Anton.

A review of genetic, biological, pharmacological, and clinical factors that affect carbohydrate-deficient transferrin levels.

BACKGROUND: Carbohydrate-deficient transferrin (CDT) is an alcohol biomarker recently approved by the U.S. Food and Drug Administration. This test is increasingly being used to detect and monitor alcohol use in a variety of health care, legal, and industrial settings. The goal of this study is to review the genetic, biological, pharmacological, and clinical factors that may affect CDT levels. METHODS: A review of the literature identified 95 research articles that met the authors' criteria and reported potential interactions of a variety of factors on percent and total CDT levels. The review established 12 categories of variables that may affect CDT levels. These categories include (1) alcohol use, (2) genetic factors, (3) race, (4) gender, (5) age, (6) liver disease, (7) iron levels, (8) tobacco use, (9) medication such as estrogen and anticonvulsants, (10) metabolic factors such as body mass index and total body water, (11) chronic medical conditions such as rheumatoid arthritis, and (12) surgical patients. RESULTS: There is evidence that %CDT levels are affected by alcohol use, end-stage liver disease, and genetic variants. In addition to these three factors, total CDT levels (CDTect) are also affected by factors that raise transferrin levels such as iron deficiency, chronic illnesses, and menopausal status. Other potential factors such as tobacco and age appear to be confounded by alcohol use. The roles of female gender, low body mass index, chronic inflammatory diseases, and medication on CDT levels require further study. False negatives are associated with female gender, episodic lower level alcohol use, and acute trauma with blood loss. CONCLUSIONS: This review suggests that a number of factors are associated with false-positive CDTect and %CDT levels. CDT offers great promise to assist physicians in the care of patients to detect and monitor heavy alcohol use.

Biochemical alcohol screening in primary health care.

Alcohol biomarkers such as carbohydrate-deficient transferrin (CDT) and gamma-glutamyltransferase (GGT) have significant potential for enhancing the quality of medical treatment in primary health care settings. Recent studies demonstrate that these laboratory tests can help the general practitioner in several ways. First, CDT and GGT can detect current heavy drinking in primary care patients with a fair degree of sensitivity (approximately 60% to 70%), with CDT being more specific (approximately 90%). When combined with self-report tests, they can provide a clinically useful alcohol screening battery. Second, elevated CDT and GGT levels have been correlated with specific alcohol-sensitive diseases (e.g., hypertension) and, as such, can serve as risk indicators for those diseases. Third, alcohol biomarkers have proven to be useful in monitoring the effectiveness of brief alcohol interventions with medical patients. Unfortunately, preliminary findings indicate that physicians have little knowledge of current biomarker research as applied to primary health care. Translational studies are needed on methods to facilitate knowledge and use of alcohol biomarkers by general practitioners.

Depression and coronary artery atherosclerosis and reactivity in female cynomolgus monkeys.

OBJECTIVE: Depression and coronary heart disease (CHD) are comorbid conditions, and it is thought that depression may increase the risk of CHD. However, the evidence for the latter relationship is sparse and difficult to collect. Cynomolgus monkeys (Macaca fascicularis) have been used effectively as animal models of CHD risk and depression. Here we report the results of a comparison of physiological characteristics, coronary artery reactivity, and atherosclerosis in 16 depressed and 26 nondepressed female cynomolgus monkeys. METHODS: Forty-two females were housed in single cages for 3 months and in their final social groups for 26 months, during which time they consumed an atherogenic diet. RESULTS: During the 26-month social grouping period, 16 of the females displayed behavioral depression, defined as a slumped or collapsed body posture accompanied by a relative lack of responsiveness to environmental stimuli. These depressed monkeys had higher heart rates throughout the study, even during the single-caging period, suggesting a priori differences in the autonomic function of females that displayed behavioral depression relative to those that did not. Hypothalamic-pituitary-adrenal function was impaired in all females during the single-caging period and during new group formation. By 26 months in the final social groups, females that never displayed depression were more sensitive to glucocorticoid negative feedback in a dexamethasone suppression test than females that displayed behavioral depression. Depressed females had poorer quality ovarian function than their nondepressed counterparts. There was no difference between depressed and nondepressed females in coronary artery atherosclerosis extent or cineangiographically determined coronary vasomotor responses to infused vasoactive substances (vascular reactivity). CONCLUSION: Depression did not appear to be associated with CHD risk in these female monkeys.