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Of poor substance

For centuries alcoholism has ravaged lives, yet we are still searching for an effective treatment

Of poor substanceAlcohol is the oldest and most widely used drug worldwide, and it is by far the most abused. The consequences of alcoholism extend beyond the physical and mental effects on the drinker. Families are destroyed, relationships are ruined and livelihoods are lost, not to mention the lives that are cut short. For susceptible individuals, it can be a gradual but slippery slope from recreational use, to hazardous use or abuse, to full-blown alcoholism.

According to the World Health Organisation (WHO), in the US alone, alcoholism affects around 12.5 million people; that's 4 per cent of the population. It might not sound like much, but alcoholism is a danger to society. The WHO estimates that worldwide, excessive alcohol use causes approximately 20-30 per cent of all cases of liver cancer, oesophageal cancer, cirrhosis of the liver, epilepsy, homicide and car accidents.

Alcoholism or alcohol dependence is a primary, chronic disease characterised by a strong craving for alcohol, the inability to control drinking, continued consumption despite adverse consequences, the need to increase the amount consumed to feel the effects and physical illness when drinking stops.

Alcohol primarily affects the GABAA receptor. Via GABA, this ligand-gated chloride ion channel mediates the majority of inhibitory neurotransmissions, ie, it inhibits the firing of new action potentials. Alcohol increases activation of the GABAA receptor, which promotes central nervous system depression. Continuous, heavy alcohol consumption desensitises these receptors and down-regulates their expression. As a result of the decreased functioning of these receptors, the cessation of alcohol consumption leads to the neuropsychiatric excitability and autonomic disturbances typical of the withdrawal state.

Development efforts over the last several decades have focused on GABA receptor agonism as a main target in the treatment of alcoholism. The opioid receptors are also implicated in the reward, tolerance and withdrawal of alcohol, among other drugs of abuse. Recent drug development efforts have partly shifted to this target. Glutamate receptor antagonists have even more recently become a focus of development efforts. These receptors are responsible for the glutamate-mediated post-synaptic excitation of neurons. Chronic exposure to alcohol up-regulates the expression of the NMDA subtype of glutamate receptors, leading to enhanced susceptibility to glutamate-induced neurotoxicity.

Treatment for alcoholism can include behavioural interventions (such as counselling, cognitive therapy or psychotherapy), drug therapy or combinations thereof. The first FDA-approved drug therapy for alcoholism was disulfiram. Approved in 1951, disulfiram is unique in that it relies on "psychological threat" to treat the patient. The patient is motivated to abstain from drinking in order to avoid disulfiram-alcohol reactions. Disulfiram prevents the elimination of acetaldehyde, which is the cause of many hangover symptoms. This results in severe discomfort when alcohol is ingested; at a moderate level of intensity, the disulfiram-alcohol reaction leads to nausea, tachycardia, palpitations, hyperventilation, hypotension and dyspnoea. These effects often result in poor patient compliance, raising questions about the drug's practicality, and are a major reason that disulfiram has demonstrated inconsistent results in helping patients to abstain from alcohol. Calcium carbamide has a similar mode of action as disulfiram, but is only available outside of the US.

Treatment history
Over three decades passed before another drug therapy for alcoholism became available. Acamprosate was first approved in Europe in the late 1980s, but was not approved in the US until 2004. Acamprosate is a synthetic GABAminergic compound, ie, a GABA agonist and glutamate antagonist. Acamprosate is not known to have a direct effect on acute alcohol withdrawal, but is thought to reduce the cravings. Though acamprosate proved superior to placebo in maintaining abstinence by six and 12 months in several clinical trials, the large COMBINE study was unable to demonstrate efficacy for acamprosate versus placebo. Acamprosate must be dosed three times daily, a factor which may negatively impact on patient compliance.

Oral naltrexone was launched in the US in 1995. Naltrexone is a competitive antagonist at μ- and κ-opioid receptors, and to a lesser extent at δ-opioid receptors. The COMBINE study proved the usefulness of naltrexone in an ordinary, primary care setting. A major drawback of naltrexone is that it may be associated with intolerable nausea and hepatotoxicity. In 2006, controlled-release naltrexone for intramuscular injection was approved in the US, with approval in Russia following in 2008. This product has been filed for approval in the EU. The main advantage of this formulation is that it only requires once-monthly dosing. A clinical trial demonstrated that a single dose of injectable controlled-release naltrexone maintained therapeutic levels for a month, the dose required being less than one-fifth the total monthly oral dose.

Tianeptine was approved in some countries in Europe in 2007 for the treatment of the symptoms of alcohol withdrawal. A selective serotonin reuptake enhancer, this drug is widely used outside the US as an antidepressant and anxiolytic. In addition to modulating the serotonergic system, tianeptine is thought to relieve the symptoms of alcohol withdrawal by acting on the NMDA receptors. Clinical trials have demonstrated the efficacy of tianeptine in treating patients with major depression or dysthymic disorder following alcohol withdrawal. The low incidences of anticholinergic effects, sedation and cardiotoxicity make tianeptine particularly attractive in the treatment of patients with post-alcohol withdrawal depression, as this patient subgroup is known to have increased sensitivity to the adverse effects of psychotropic agents.


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What's in the pipeline?
Nalmefene is an opioid receptor antagonist undergoing phase III development in the EU. Nalmefene is structurally similar to naltrexone, and similarly, it has no agonist activity and no abuse potential. However, in clinical trials to date, nalmefene treatment has not been associated with the intolerable nausea and hepatotoxicity sometimes seen in patients treated with naltrexone. Also, the longer half-life of nalmefene may endow it with more sustained opioid antagonist effects than naltrexone. In a 12-week phase III trial in 105 patients in the US, significantly fewer patients treated with nalmefene than patients treated with placebo relapsed to heavy drinking. One-third of nalmefene recipients, however, did relapse. Among those who relapsed, those receiving nalmefene had significantly fewer heavy drinking episodes than those receiving placebo. Treatment groups did not differ in the percentage of abstinent days. In a 28-week phase III trial in 400 patients in Finland, nalmefene treatment reduced the number of heavy drinking days almost by half without psycho-therapy, while heavy drinking days were decreased by about one-third in the placebo group, a significant difference.

Quetiapine is widely used in the treatment of bipolar depression, bipolar disorders, depression, manic episodes and schizophrenia, and is undergoing phase II development for the treatment of alcoholism in the US and Europe. Quetiapine and its active metabolite, norquetiapine, appear to act on the three principal neurotransmitter systems associated with depression and psychosis: norepinephrine, serotonin and dopamine. In the norepinephrine system, norquetiapine acts as a potent inhibitor of the norepinephrine reuptake transporters, while quetiapine antagonises the α2 adrenergic receptors. In the serotonin system, both quetiapine and nor-quetiapine act as antagonists at serotonin2A receptors and partial agonists at serotonin1A receptors. In the dopamine system, quetiapine acts as an antagonist of D2 receptors. Additionally, norquetiapine targets the norepinephrine transporter. In a 12-week phase II trial in 62 patients with alcoholism conducted in Spain, the addition of quetiapine to naltrexone therapy did not demonstrate any efficacy advantage compared with the addition of placebo.

Topiramate is an anticonvulsant that is used widely in the treatment of epilepsy and migraine, and is undergoing phase II development in the US for the treatment of alcoholism. It is hypothesised that topiramate may decrease alcohol reinforcement and the propensity to drink by reducing cortico-mesolimbic dopamine release through two primary mechanisms. These include the facilitation of GABA function at some GABAA receptor subtypes, and the antagonism of glutamate activity at AMPA and kainate receptors. Early results are promising. Among 371 patients in a phase II trial, topiramate was significantly more efficacious than placebo in all outcome measures from baseline to week 14. Outcome measures included percentage of self-reported heavy drinking days, percentage of self-reported days abstinent and drinks per drinking day, and laboratory measures of alcohol consumption. It appears that the drug's mood stabilising effects occur at lower dosages than those required for an anticonvulsant effect.

OpRA II is an opioid receptor antagonist about which very little has been disclosed. Phase II development is underway in the US. ALKS 33 is an opioid receptor antagonist undergoing phase II development in the US. Early clinical data show the drug is rapidly absorbed, with a pharmacokinetic profile that supports once-daily dosing. Preclinical studies suggest ALKS 33 is not readily metabolised by the liver, a unique advantage over existing oral therapies for addiction. ORG 25935 is a glycine transporter 1 inhibitor undergoing phase II trials in Australia and Europe for the prevention of relapse in alcoholism.

Where to from here?
Alcohol affects multiple neurotransmitter systems, making it unlikely that a single therapeutic agent will consistently produce a robust treatment effect as the clinical trials of various marketed and experimental agents have demonstrated. Treatment approaches also need to take into account the individual symptoms of alcoholism, namely craving, tolerance, physical dependence and withdrawal. Successful treatment may require a multimodal approach comprising multiple therapeutic agents and behavioural interventions.

The Author
Pipeline was written by Anita Ballantyne of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight. For further information on Adis services, please contact Kuljeet Sohanpal on +44 (0)207 981 0714.

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30th March 2010


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