HCl ABT 418

Figure 8 Continued hypotension, syncope, anxiety, weakness, vertigo, blurred vision, and confusion. Mild reactions are usually followed by sound sleep and complete recovery. However, symptoms may progress to respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, seizures, and death.

Disulfiram is a medication with a significant risk for serious toxicity, both in the absence and presence of alcohol, and its usefulness is also limited by the high degree of patient compliance that is required.

In recent years, other medications for alcohol dependence have been approved by the FDA. Naltrexone is a m opioid receptor antagonist that partially attenuates the rewarding effects of alcohol. Initial clinical trials indicated that naltrexone prevents relapse to heavy drinking, and reduces alcohol craving, days of drinking per week, and the relapse rate among those who drank. Thus, naltrexone reduces, but does not generally eliminate, drinking. The fact that several clinical trials did not report positive findings and that this medications is not widely used by clinicians may reflect its modest effectiveness.55

Acamprosate (calcium acetylhomotaurinate) was recently approved by the FDA for the maintenance of abstinence from alcohol in patients with alcohol dependence that are abstinent at treatment initiation. The mechanism of action is still under investigation. However, some evidence indicates that acamprosate acts to normalize the glutamate system, and possibly the GABA system as well, whose normal function is disrupted by chronic alcoholism. Treatment with acamprosate is moderately effective, helping to significantly reduce relapse.55 A number of other medications are under investigation for alcohol dependence (see Table 6). Nicotine Addiction

Nicotine replacement (patches, gum) and sustained release bupropion are the only FDA-approved treatments for nicotine dependence. Nicotine, administered in a manner to produce steady and sustained nicotine blood levels, helps decrease withdrawal symptoms and doubles the initial success rate for quitting smoking. Unfortunately, a substantial number of patients ultimately relapse,58 illustrating the chronic relapsing nature of nicotine dependence and other addictive disorders. FDA-approved formulations of nicotine include: the transdermal nicotine patch, and the nicotine polacrilex gum and lozenge that are available over the counter. The nicotine nasal spray and inhaler are available via prescription. The rationale and use of nicotine replacement therapy is reviewed by Henningfield.58

Bupropion is an antidepressant that also helps to reduce nicotine withdrawal symptoms. The usual course of treatment is for 6 months, resulting in about a 30% quit rate at the 1-year follow-up. Bupropion and its metabolite hydroxybupropion59 are active as inhibitors of DA and NE uptake, as well as being weak antagonists of the a4b2 neuronal nicotinic receptor. These actions probably explain its ability to help patients stop smoking. Other medications that are considered effective for smoking cessation include the a2 agonist clonidine, and the tricyclic antidepressant nortriptyline.55 The relatively low success rate of current treatments for nicotine dependence illustrates the need for additional pharmacological adjuncts to smoking cessation treatment programs. Table 6 provides a list of some additional medications that are currently under investigation for this purpose. Heroin (Opioid) Addiction

The mainstay treatment for opioid dependence is agonist substitution therapy with long-duration opioid agonists such as methadone, levomethadyl acetate (LAAM), or buprenorphine. Without methadone treatment, most patients relapse to drug use again, supporting the hypothesis that heroin addicts suffer from a dysregulated endorphin system, which is normalized by treatment with a m receptor agonist, and that long-term treatment is necessary. Methadone treatment reduces criminal behavior and diseases such as hepatitis that occur as a result of intravenous drug use.7'60

LAAM is a long-acting methadone analog that can be dosed at 48- or 72-h intervals, allowing take-home doses. Unfortunately, LAAM can increase the cardiac QT interval, which can cause a number of serious or fatal cardiac adverse effects, such as torsades depointes and cardiac arrest. When this became known from postmarketing reports, LAAM was removed from the EU market and is considered to be a second-line medication in the USA.

Buprenorphine is a partial m opioid receptor agonist and a potent k receptor antagonist.61 For take-home doses, buprenorphine is combined with naloxone. Since naloxone is not bioactive after oral administration, but is after intravenous administration, this combination serves to prevent diversion of the medication to intravenous use. When dispensed in a clinic, buprenorphine does not have to be coadministered with naloxone. Since buprenorphine is a partial m agonist, it is less useful than methadone in heroin addicts who require higher doses of methadone (80-150 mg day " 1).7

Naltrexone has been available since the 1970s as a treatment for heroin addiction. The rationale for its use is to block the effects of heroin by virtue of its long-lasting antagonist action at m opioid receptors. Naltrexone is quite effective in this regard; however, compliance with this treatment among heroin addicts is quite poor. The underlying

Table 6 Medications for addictive disorders under clinical investigation

Clinical indication


Biological targets

Alcohol dependence

Cocaine dependence

Nicotine dependence





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