Bankole A. Johnson

Oral topiramate for treatment of alcohol dependence: a randomised controlled trial

BACKGROUND Topiramate, a sulphamate fructopyranose derivative, might antagonise alcohols rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function. We aimed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence. METHODS We did a double-blind randomised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence. Of these 150 individuals, 75 were assigned to receive topiramate (escalating dose of 25-300 mg per day) and 75 had placebo as an adjunct to weekly standardised medication compliance management. Primary efficacy variables were: self-reported drinking (drinks per day, drinks per drinking day, percentage of heavy drinking days, percentage of days abstinent) and plasma gamma-glutamyl transferase, an objective index of alcohol consumption. The secondary efficacy variable was self-reported craving. FINDINGS At study end, participants on topiramate, compared with those on placebo, had 2.88 (95% CI -4.50 to -1.27) fewer drinks per day (p=0.0006), 3.10 (-4.88 to -1.31) fewer drinks per drinking day (p=0.0009), 27.6% fewer heavy drinking days (p=0.0003), 26.2% more days abstinent (p=0.0003), and a log plasma gamma-glutamyl transferase ratio of 0.07 (-0.11 to -0.02) less (p=0.0046). Topiramate-induced differences in craving were also significantly greater than those of placebo, of similar magnitude to the self-reported drinking changes, and highly correlated with them. INTERPRETATION Topiramate (up to 300 mg per day) is more efficacious than placebo as an adjunct to standardised medication compliance management in treatment of alcohol dependence.

A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of methamphetamine dependence

Methamphetamine dependence is an increasing public health problem in the United States. No efficacious medication for methamphetamine dependence has been developed. As ondansetron, a 5-HT3 receptor antagonist and modulator of cortico-mesolimbic dopamine function, has been shown to reduce some of the rewarding effects of d-amphetamine in animal and human laboratory studies, we decided to test whether it would be superior to placebo at reducing methamphetamine use. In a preliminary, multi-site, randomized, double-blind, 8-wk controlled trial, 150 methamphetamine-dependent men and women received ondansetron (0.25 mg, 1 mg, or 4 mg b.i.d.) or placebo. Participants were assessed on several measures of methamphetamine use including urine methamphetamine level up to three times per week. As a psychosocial adjunct to the medication condition, cognitive behavioural therapy also was administered three times per week. Ondansetron was well tolerated and was less likely than placebo to be associated with serious adverse events. Nevertheless, none of the ondansetron doses was superior to placebo at decreasing any of the measures of methamphetamine use, withdrawal, craving, or clinical severity of methamphetamine dependence. Our preliminary results do not support the utility of ondansetron, at the doses tested, as a treatment for methamphetamine dependence. These findings should be viewed in light of the possibility that a less intensive cognitive behavioural therapy regimen might have yielded more positive results in this initial phase II trial exploring for the efficacy of ondansetron.

Medication treatment of different types of alcoholism.

Alcoholism remains a serious cause of morbidity and mortality despite progress through neurobiological research in identifying new pharmacological strategies for its treatment. Drugs that affect neural pathways that modulate the activity of the cortico-mesolimbic dopamine system have been shown to alter drinking behavior, presumably because this dopaminergic system is closely associated with rewarding behavior. Ondansetron, naltrexone, topiramate, and baclofen are examples. Subtyping alcoholism in adults into an early-onset type, with chronic symptoms and a strong biological predisposition to the disease, and a late-onset type, typically brought on by psychosocial triggers and associated with mood symptoms, may help in the selection of optimal therapy. Emerging adults with binge drinking patterns also might be aided by selective treatments. Although preliminary work on the pharmacogenetics of alcoholism and its treatment has been promising, the assignment to treatment still depends on clinical assessment. Brief behavioral interventions that encourage the patient to set goals for a reduction in heavy drinking or abstinence also are part of optimal therapy.

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.

Percentage of Subjects With No Heavy Drinking Days: Evaluation as an Efficacy Endpoint for Alcohol Clinical Trials

BACKGROUND Percent subjects with no heavy drinking days (PSNHDDs), an efficacy end point recommended by the Food and Drug Administration, considers abstinent individuals or those engaging in low-risk drinking behavior as successful responders to treatment. As PSNHDD has been used infrequently in previous alcohol clinical trials, we evaluated the utility and validity of the PSNHDD outcome measure in 2 large alcohol clinical trials. METHODS Data sets from 2 alcohol trials, COMBINE and a multisite topiramate trial, were used to analyze PSNHDDs and other traditional end points for the topiramate, naltrexone, acamprosate, and placebo groups. Effect sizes of PSNHDDs were determined for each month of active treatment and by varying grace periods-early periods in the trial where outcome is not considered in the analysis-and were compared with that of other traditional outcome measures. Long-term outcomes were compared for groups that had no heavy drinking days versus those that had heavy drinking days during active treatment. RESULTS PSNHDD effect sizes were significant for both topiramate (0.34 and 0.25 at months 2 and 3, respectively) and naltrexone (0.24 and 0.26 at months 3 and 4, respectively). Given a 2-month grace period for naltrexone, the effect size of PSNHDDs was comparable to the effect sizes using traditional outcome measures. With a 1-month grace period for topiramate, it was greater than the majority of traditional outcome measures. Little is gained by allowing up to 1, 2, or 3 heavy drinking days as an end point. Subjects with no HDDs during treatment fared better than those with some HDDs on drinking outcomes and alcohol-related consequences during a 1-year follow-up. CONCLUSIONS PSNHDD appears to be a clinically informative end point measure, especially when used with a grace period, and is as sensitive as most traditional outcome measures in detecting differences between the medication and placebo groups. Nonetheless, these findings should be replicated in other clinical data sets, particularly with medications that work via different mechanisms.

Role of the serotonergic system in the neurobiology of alcoholism: implications for treatment.

Preclinical studies have contributed greatly to our understanding of the neurochemical pathways associated with the development and maintenance of alcohol-seeking behaviour. These studies have demonstrated the important role of serotonin pathways, particularly as they relate to dopaminergic function, which mediates alcohol-induced reward associated with its abuse liability. Naturally, this has led to the study of serotonergic agents as treatments for alcoholism.SSRIs do not appear to be effective treatment for a heterogeneous alcoholic group. However, they may be useful as treatment for late-onset alcoholics, or alcoholism complicated by comorbid major depression. Buspirone, a serotonin 5-HT1a partial agonist, does not appear to be an effective treatment for alcoholics without comorbid disease. Buspirone may, however, have some utility for treating alcoholics with comorbid anxiety disorder. The 5-HT2 antagonist ritanserin, at pharmacologically relevant clinical doses, does not appear to be an effective treatment for alcoholism. Ondansetron, a 5-HT3 antagonist, is an efficacious and promising medication for the treatment of early-onset alcoholism. Preliminary evidence suggests that combining the mu antagonist naltrexone with the 5-HT3 antagonist ondansetron promises to be more effective for treating alcoholism than either alone.The differential treatment effect of SSRIs and ondansetron among various subtypes of alcoholic is intriguing. Future research is needed to understand more clearly the molecular genetic differences and the interactions of such differences with the environment that typify a particular alcoholic subtype. Such an understanding could enable us to make comfortable predictions as to which alcoholic subtype might respond best to a particular serotonergic agent, which could then be provided.

A Pilot Evaluation of the Safety and Tolerability of Repeat Dose Administration of Long‐Acting Injectable Naltrexone (Vivitrex®) in Patients With Alcohol Dependence

BACKGROUND : Oral naltrexone is currently used as part of a treatment regimen for alcohol-dependent patients, but its clinical utility is hampered by poor patient adherence. A long-acting injectable naltrexone formulation (Vivitrex) was designed to facilitate patient adherence by providing an extended duration of therapeutic naltrexone over 1 month, thereby eliminating the need for daily dosing. METHODS : A multicenter, randomized, double-blind, placebo-controlled pilot study was conducted to evaluate the safety and tolerability of intramuscular repeat dose administration of this extended-release naltrexone formulation in DSM-IV alcohol-dependent patients. Thirty patients were randomized to treatment with injectable naltrexone (400 mg; n = 25) or a matching placebo injection (n = 5) and were dosed once every 28 days over 4 months. Psychosocial treatment was offered to patients in both treatment groups. Outcome measures related to drinking activity and trough plasma concentrations of naltrexone and its primary metabolite, 6-beta-naltrexol, were evaluated. RESULTS : Injectable naltrexone was generally safe and well tolerated. Reported adverse events were mild to moderate and resolved without intervention; only two patients discontinued due to adverse events. The most common adverse events (nausea and headache) occurred at a similar rate for patients in both treatment groups. Pharmacokinetic analysis confirmed that therapeutic levels of naltrexone were delivered throughout the four 1-month treatment cycles. CONCLUSIONS : The results of this pilot study provide the basis and methods for a larger, more definitive trial to determine the utility of this long-acting injectable naltrexone formulation in the treatment of alcohol-dependent patients.

Genetics of Alcoholism Using Intermediate Phenotypes

This article represents the proceedings of a symposium at the 2002 meeting of the Research Society on Alcoholism in San Francisco, CA. It was organized by Mary-Anne Enoch and David Goldman and chaired by David Goldman. The presentations were (1) Two functional polymorphisms and their intermediate phenotypes in complex behaviors: COMT/executive cognition and anxiety and HTT/anxiety, by David Goldman; (2) Role of the EEG in determining genetic risk for alcoholism and anxiety disorders, by Mary-Anne Enoch; (3) The response to alcohol as an intermediate phenotype for alcoholism, by Marc A. Schuckit; and (4) Pharmacogenomic approaches to alcoholism treatment: toward a hypothesis, by Bankole A. Johnson.

Progress in the development of topiramate for treating alcohol dependence: From a hypothesis to a proof-of-concept study

Advances in neuroscientific knowledge have evoked interest in developing effective medications for the treatment of alcohol dependence. Pharmacological approaches that involve the use of relatively specific medications at a particular neuronal target to modulate corticomesolimbic dopamine neuronal activity, the critical pathway for expression of the reinforcing effects of abused drugs, have yielded modest efficacy in the treatment of alcohol dependence. A new approach is needed. Because corticomesolimbic dopamine neurons interact with a variety of neurotransmitters that modulate its effects in the nucleus accumbens, it might be possible to more reliably control these dopaminergic effects with a medication that acted contemporaneously on more than one neuromodulator of dopamine function. Additionally, because alcohol use results in neuronal adaptations due to sensitization, the chances of effective therapy might be bolstered by administering a medication that also has utility with mitigating its chronic effects. My proposed conceptual framework suggests that a medication that facilitates inhibitory gamma-aminobutyric acid-A input and antagonizes excitatory glutaminergic afferents to the nucleus accumbens would have pharmacotherapeutic potential in treating the alcohol dependence syndrome because these effects would act contemporaneously to suppress corticomesolimbic dopamine release. Through similar effects, topiramate might also aid chronic drinkers to wean themselves off alcohol and might ameliorate the symptoms of alcohol withdrawal. This commentary highlights the scientific concepts and clinical evidence for the development of topiramate in the treatment of alcohol dependence.

Dose-ranging Kinetics and Behavioral Pharmacology of Naltrexone and Acamprosate, Both Alone and Combined, in Alcohol-dependent Subjects

We examined kinetic and dynamic factors to determine the pharmacological and behavioral safety and tolerability of low versus high doses of an opiate antagonist, naltrexone (50 mg/day vs. 100 mg/day), and acamprosate (2 g/day vs. 3 g/day), a functional N-methyl-D-aspartate receptor antagonist, both independently and combined, among non-treatmentseeking, alcohol-dependent individuals. This double-blind, double-dummy, placebo-controlled, randomized, 23-day, four-way crossover study involved 23 subjects assigned to one of four groups. Placebo washout (phase I) preceded phase II, where subjects received low-dose or high-dose naltrexone or acamprosate. In phases III and IV, the alternative medication type at its lower and higher doses, respectively, was administered with continuation of the phase II medication. Predetermined behavioral, performance, and pharmacological criteria determined significant pathological change from baseline (phase I). Case records were reviewed. Criterion-significant increases in symptoms from baseline with monotherapy included nervousness and fatigue with 3 g acamprosate and somnolence and headache with 50 mg and 100 mg naltrexone, respectively. Combined treatment at various doses evinced anger, depression, somnolence, nervousness, diarrhea, and headache. Notably, for all but one subject who dropped out, increased symptoms did not produce any remarkable clinical deterioration. Naltrexone administration significantly increased plasma acetylhomotaurine (i.e., acamprosate) levels, presumably by prolonging gastric emptying. The level of neither plasma acetylhomotaurine nor plasma 6-β naltrexol (i.e., naltrexone’s metabolite) predicted adverse-event frequency. Naltrexone and acamprosate, both alone and in combination at the tested doses, were behaviorally and pharmacologically safe. Adverse events were infrequent, were of moderate intensity, and resolved with reassurance and symptomatic treatment. More side effects were noted with the combination of medications than with either medication alone. Naltrexone administration significantly increased plasma acamprosate levels.