Robert M. Swift

An Evaluation of μ-Opioid Receptor (OPRM1) as a Predictor of Naltrexone Response in the Treatment of Alcohol Dependence: Results From the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study

CONTEXT Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict naltrexone response. OBJECTIVE To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone. DESIGN Pharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004. SETTING Eleven academic sites in the COMBINE Study. PARTICIPANTS Recently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA. INTERVENTIONS Alcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI). MAIN OUTCOME MEASURES Time trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome. RESULTS Alcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P = .07) and a decreased percentage of heavy drinking days (P = .04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P = .005). No gene x medication interactions were observed in those treated with both MM and CBI. CONCLUSIONS These results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 genotyping in alcoholic individuals might be useful to assist in selecting treatment options. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00006206.

Research to practice: adoption of naltrexone in alcoholism treatment.

Naltrexone, a prescription medication, was approved in December 1994 as an adjunct to counseling in treatment of alcoholism and alcohol abuse, representing the first new medication for alcoholism in several decades. Initial controlled trials indicated that it is effective in preventing relapse, while later trials show mixed results. Although many physicians and others treating alcoholism have found naltrexone to be very helpful in treatment, it is still a technology that has not been used widely. In this study, we examine which clinicians have adopted naltrexone into practice for what reasons, and what clinical and nonclinical factors acted as barriers to its use. In our mail survey of alcoholism treatment clinicians, 80% of physicians and 45% of nonphysicians report prescribing or recommending naltrexone at least rarely, but only 15% of physicians, even among addiction specialists, prescribe naltrexone often. The strongest barriers to adoption of naltrexone were financing and inadequate knowledge about the medication, followed by lack of sufficient evidence regarding effectiveness. Clinicians were most likely to adopt naltrexone if they were affiliated with treatment programs that actively promoted its use. We conclude that in order for a new substance abuse treatment medication to be widely adopted in clinical practice, information about it must be properly directed, clinicians must be convinced of its effectiveness, it must be adequately financed, and the treatment organizations in which clinicians work must promote its use.

Alcohol demand, delayed reward discounting, and craving in relation to drinking and alcohol use disorders

A behavioral economic approach to alcohol use disorders (AUDs) emphasizes both individual and environmental determinants of alcohol use. The current study examined individual differences in alcohol demand (i.e., motivation for alcohol under escalating conditions of price) and delayed reward discounting (i.e., preference for immediate small rewards compared to delayed larger rewards) in 61 heavy drinkers (62% with an AUD). In addition, based on theoretical accounts that emphasize the role of craving in reward valuation and preferences for immediate rewards, craving for alcohol was also examined in relation to these behavioral economic variables and the alcohol-related variables. Intensity of alcohol demand and delayed reward discounting were significantly associated with AUD symptoms, but not with quantitative measures of alcohol use, and were also moderately correlated with each other. Likewise, craving was significantly associated with AUD symptoms, but not with alcohol use, and was also significantly correlated with both intensity of demand and delayed reward discounting. These findings further emphasize the relevance of behavioral economic indices of motivation to AUDs and the potential importance of craving for alcohol in this relationship.

The DRD4 VNTR Polymorphism Moderates Craving After Alcohol Consumption

Recent research has suggested that alterations in mesolimbic dopamine neurotransmission are central to the development and expression of craving for alcohol. Because the D4 dopamine receptor gene, variable numbers of tandem repeats (DRD4 VNTR) polymorphism putatively expresses functional differences in dopamine receptors, the present study tested whether this polymorphism influences the effects of a priming dose of alcohol on craving. Participants consumed 3 alcoholic drinks or 3 control drinks and completed measures of craving after each drink. Participants who were homozygous or heterozygous for the 7 (or longer) repeat allele were classified as DRD4 L, whereas the other participants were classified as DRD4 S. Results suggested that DRD4 L participants demonstrated significantly higher craving after consumption of alcohol as compared with the control beverage.

Typologies of Alcohol Dependence. From Jellinek to Genetics and Beyond

The goal of typology research is to identify subtypes of alcohol dependent (AD) patients sharing fundamental characteristics and try to match each subtype, with the most precise treatment strategy. This review provides a comprehensive history of the literature on alcohol dependent subtypes starting from the earliest attempt made by Jellinek. The binary models identified most closely with Cloninger and Babor as well as the successively more complex classifications are discussed. Typology classification potentially useful in guiding the treatment of AD patients, especially in the case of the serotonergic medications. Contrasting data suggests that other factors could influence the response to a medication and/or that more complex typologies should be identified. In summary, typology models may assist in the ascertainment criteria for clinical trials performed in behavioral and pharmacotherapeutic interventions. Greater emphasis, however, must be made to more clearly delineate this field of research, while moving toward more standardized typologies.

Olanzapine reduces craving for alcohol: a DRD4 VNTR polymorphism by pharmacotherapy interaction.

Separate investigations have suggested that olanzapine, a D4 antagonist, decreases craving after a priming dose of alcohol and that the DRD4 variable number of tandem repeats (VNTR) polymorphism influences the expression of craving after a priming dose of alcohol. The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving based on individual differences in DRD4 VNTR in a sample of heavy social drinkers. Participants were randomly assigned to receive olanzapine (5 mg) or a control medication (cyproheptadine, 4 mg) prior to consuming three alcoholic drinks. Participants completed subjective measures of craving and euphoria after each drink. Participants who were homozygous or heterozygous for the 7 (or longer) repeat allele of the DRD4 VNTR were classified as DRD4 L, while the other participants were classified as DRD4 S. The findings indicated that olanzapine reduces craving for alcohol at baseline for both DRD4 S and DRD4 L individuals, but only reduces craving after exposure to alcohol cues and after a priming dose of alcohol for DRD4 L individuals.

Personality factors moderate subjective and psychophysiological responses to d-amphetamine in humans.

The aim of the present study was to examine the relationship between measures of novelty and sensation seeking and both psychophysiological and subjective measures of stimulation after a pharmacological challenge with an indirect dopamine agonist, d-amphetamine. Prepulse inhibition (PPI) of the startle reflex and subjective responses were assessed after the challenge. The results indicated that the Novelty Seeking scale of the Tridimensional Personality Questionnaire (TPQ; M. Zuckerman, 1994). TPQ was a significant predictor of lower PPI and greater subjective stimulation. The Disinhibition scale of the Sensation Seeking Scale (SSS; M. Zuckerman, S. B. G. Eysenck, & M. J. Eysenck, 1978) moderated the effects of amphetamine on stimulation and elation, whereas the Boredom Susceptibility and Experience Seeking subscales of the SSS moderated subjective stimulation. These findings indicate that higher scores on novelty and sensation seeking correspond to heightened sensitivity to the effects of a stimulant medication.

A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence

Abstract: The opiate antagonist nalmefene has been shown in 2 single-site studies to reduce alcohol consumption and relapse drinking in alcohol-dependent individuals. This safety and preliminary multisite efficacy study evaluated 3 doses of nalmefene (5, 20, or 40 mg) in a double-blind comparison to placebo over a 12-week treatment period in 270 recently abstinent outpatient alcohol-dependent individuals. Participants concomitantly received 4 sessions of a motivational enhancement therapy (with a medication compliance component) delivered from trained counselors. Although more subjects in the active medication groups terminated the study early secondary to adverse events, the rates did not differ significantly from that of placebo. The 20-mg/d group experienced more insomnia, dizziness, and confusion, while the 5-mg group also had more dizziness and the 40-mg group had more nausea than the placebo group. Most of these symptoms were mild and improved over time. Although all subjects had a reduction in heavy drinking days, craving, γ-glutamyl transferase, and carbohydrate-deficient transferrin concentrations over the course of the study, there was no difference between the active medication and placebo groups on these measures. The time to first heavy drinking day was also not significantly different between the placebo and the active treatment groups. This relatively small multisite trial showed that nalmefene was reasonably well tolerated in recently abstinent alcoholics. However, possibly because of variation among the sites or the comparatively small sample size, there was no evidence of superior efficacy outcomes with nalmefene treatment.

The Effect of Olanzapine on Craving and Alcohol Consumption

Previous studies have indicated that olanzapine decreases craving after a priming dose of alcohol, that craving after a priming dose of alcohol is greater among individuals with the seven-repeat allele of the DRD4 variable number of tandem repeats (VNTR) polymorphism, and that the effect of olanzapine (a D2/D4 antagonist) is more pronounced among individuals with this allele. The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving and differentially effective as a treatment for alcohol dependence over the course of a 12-week, randomized, placebo-controlled trial among individuals with and without the seven-repeat allele. Participants who met DSM IV criteria for alcohol dependence were randomly assigned to receive olanzapine (5 mg) or a placebo over the course of the trial. After 2 weeks of treatment, participants completed a cue reactivity assessment. The results suggested that participants who were homozygous or heterozygous for the seven (or longer)-repeat allele of the DRD4 VNTR responded to olanzapine with reductions in cue-elicited craving as well as reductions in alcohol consumption over the course of the 12-week trial, whereas individuals with the shorter alleles did not respond favorably to olanzapine.

Effect of d-amphetamine on prepulse inhibition of the startle reflex in humans

Rationale: Prepulse inhibition of the startle reflex (PPI) is attenuated in animals after administration of d-amphetamine and other drugs that stimulate mesolimbic dopamine activity. Objective: The aim of the present study was to evaluate the effects of d-amphetamine (20 mg) on a variety of psychophysiological and subjective measures, including PPI, in humans. Method: Thirty-six participants (18 women) participated in a double-blind, placebo controlled, repeated measures study. In one session, participants received d-amphetamine (20 mg) orally, and in the other session, participants received an identical appearing placebo. Participants were assessed at 60, 90, and 120 min after ingestion with a 5-min block of startle trials (six control trials and six prepulse trials) followed by subjective measures of stimulation and mood. Results: d-Amphetamine increased subjective measures of stimulation and euphoria, attenuated PPI, and increased heart rate, relative to placebo treatment. Conclusions: The effect of d-amphetamine on the subjective measures was substantial and consistent over time, while the effect on PPI was only observed at 90 min after ingestion, and the effect on heart rate was limited to 90 and 120 min after ingestion.