A

ALCOHOLISM AND DRUG DEPENDENCE, DRUG DELIVERY TO TREAT

Brown University and the VA Medical Center Providence, Rhode Island KEY WORDS

Addictive disorders Alcoholism Buprenorphine Clonidine Disulfiram Drug abuse Naltrexone Nicotine Opioids
OUTLINE

removal of the drug from the body and the treatment of physiological withdrawal signs and symptoms that may occur with drug discontinuation. Rehabilitation provides the patient with strategies and techniques to avoid psychoactive substances, to develop better methods of coping with stress and distress, and to improve self-esteem and selfefficacy. Medications are frequently used as a component of both detoxification treatment and rehabilitation treatment, along with psychosocial therapies, such as counseling and self-help groups (e.g., Alcoholics Anonymous). Pharmacotherapies can treat alcohol and drug dependence through several mechanisms that may reduce some of the impetus for drug use. These mechanisms and the medications that may operate through these mechanisms are depicted in Table 1. Controlled drug delivery systems are particularly applicable to the treatment of addictive disorders. Several advantages of controlled drug delivery systems are as follows: They mimic the pharmacokinetics of the abused drug, including the rise and fall of plasma drug concentrations. They facilitate the attainment of constant plasma concentrations of drug to prevent intoxication symptoms caused by high plasma concentrations and to prevent the development of withdrawal caused by low plasma drug concentrations. They improve therapeutic medication bioavailability. They improve therapeutic medication compliance in drug and alcohol treatment. For a medication used as a substitution treatment, a controlled delivery system can be used to mimic the pharmacokinetics of the abused drug, without the dangers asTable 1. Medications Used for Addiction Treatment
Medication property Substitution treatment with a cross-tolerant medication Example Methadone maintenance treatment for opioid dependence; transdermal nicotine or nicotine gum for smoking cessation Transdermal clonidine in opioid detoxification and withdrawal Depot naltrexone for opioid dependence Depot disulfiram treatment in alcoholism Depot naltrexone in alcohol dependence

Addictive Disorders and Their Treatment Treatment for Nicotine Dependence (Smoking) Nicotine Replacement Other Medications for Smoking Cessation Treatments for Opioid Dependence Opioid Detoxification: Clonidine Opioid Maintenance Treatments for Alcohol Dependence Disulfiram Naltrexone Summary Bibliography
ADDICTIVE DISORDERS AND THEIR TREATMENT

Addictive disorders, including alcoholism, drug dependence, and nicotine dependence, afflict over 30% of Americans (1) and are associated with considerable morbidity, mortality, social problems, and health care costs (2,3). Addiction is characterized by impaired control over drinking or drug use, increased tolerance to the effects of alcohol and drugs, preoccupation with alcohol and drugs, and use despite adverse consequences (4). One way to reduce the impact of addictive disorders is through effective drug and alcohol treatment. Treatment consists of medical, psychological, and social interventions to reduce or eliminate the harmful effects of substances on the individual, his or her family and associates, and others in society. The treatment consists of two components: detoxification and rehabilitation. Detoxification refers to the

Administration of agents to block the signs and symptoms of withdrawal Administration of a medication to block drug intoxication Aversive therapy Administration of a medication to suppress craving

sociated with the usual mode of administration. For example, several methods of controlled administration of nicotine can keep plasma nicotine levels high enough to prevent nicotine withdrawal, without the inherent dangers of smoking. Two of these nicotine delivery methods can actually induce the rise and fall of plasma nicotine levels that occurs with smoking. Patients with addictive disorders are frequently noncompliant with medications and may either overuse or underuse therapeutic medications. Controlled drug delivery systems offer methods for controlling drug use and plasma concentrations to improve compliance. This chapter discusses use of controlled drug delivery in the treatment of addictive disorders, the putative mechanisms of action of the medications, and the evidence for their efficacy. TREATMENT FOR NICOTINE DEPENDENCE (SMOKING) The treatment of nicotine dependence provides several examples of the therapeutic use of controlled medication delivery systems in treatment. Nicotine is an alkaloid drug present in the leaves of the tobacco plant, Nicotiana tabacumy used for centuries by Native Americans in rituals and folk medicine. Today, nicotine has become one of the most commonly used psychoactive drugs. Over 50 million persons in the U.S. are daily users of cigarettes (one-third of adults), and 10 million use another form of tobacco (5). Although the overall number of Americans who smoke has declined, the numbers of young women who smoke, and the use of other tobacco products such as smokeless tobacco, has increased. Tobacco use is increasing in developing countries. The medical consequences of nicotine use are common and constitute a significant public health problem. These include coronary artery disease, vascular disease, respiratory disease, and cancer, particularly of the lung, oral cavity, and pharynx. Many deleterious effects of tobacco are not due to nicotine, but are due to other toxic and carcinogenic compounds present in tobacco extract or smoke. To maximize the absorption of nicotine, tobacco products are usually smoked in pipes, cigars, or cigarettes, or instilled intranasally or orally as snuff or smokeless tobacco. Following absorption from the lungs or buccal mucosa, nicotine levels peak rapidly and then decline with a half-life of 30 to 60 minutes. Nicotine has several effects on the peripheral autonomic and central nervous systems. It is an agonist at nicotinic cholinergic receptors in parasympathetic and sympathetic autonomic ganglia. Nicotine produces salivation, increases gastric motility and acid secretion, and releases catecholamines, resulting in cardiac stimulation and peripheral vasoconstriction. Nicotine is a central-nervous-system stimulant, producing increased alertness, increased attention and concentration, and appetite suppression. The fact that tobacco use can prevent weight gain makes the drug especially attractive to young women. Repeated use of nicotine produces tolerance and dependence. The degree of dependence is considerable, as over 70% of dependent individuals relapse within one year of stopping use. Cessation of nicotine use in dependent indi-

viduals is followed by a withdrawal syndrome characterized by increased irritability, decreased attention and concentration, an intense craving for and preoccupation with nicotine, anxiety, and depression (6,7). Withdrawal symptoms begin within several hours of cessation of use or reduction in dosage, and typically last about a week. Increased appetite with weight gain occurs in the weeks and months following cessation of chronic nicotine use. The treatment of nicotine dependence consists of reducing or stopping use of tobacco use and minimizing nicotine withdrawal symptoms. Brief education and advice on smoking cessation provided by physicians has been shown to be effective in helping patients stop smoking, and it is now recommended that all physicians provide their patients with smoking cessation tools (8,9). The most successful treatment programs use cognitive-behavioral techniques to educate patients about the health hazards of tobacco and provide the patient with behavioral methods of coping with urges. Such programs can achieve 25-45% abstinence rates at 6 to 12 months. Although some programs use gradual reduction in tobacco use over days to weeks (nicotine fading) for detoxification, others suggest abrupt discontinuation (cold turkey). Nicotine Replacement Pharmacologic therapy with nicotine replacement is increasingly popular in the treatment of nicotine dependence. The principle of nicotine replacement therapy is to provide the nicotine-dependent patient with nicotine in a form not associated with the carcinogenic and irritant elements in tobacco products. The substitution of tobacco with alternative nicotine delivery systems allows the patient to address behavioral aspects of the habit without having to experience nicotine withdrawal. At a later time, plasma nicotine levels can be reduced and eventually discontinued in a slow and controlled fashion. Several systems of controlled nicotine delivery have been developed and introduced into clinical practice. Transdermal Nicotine. Thin film impregnated with various doses of nicotine (7 mg, 14 mg, and 21 mg) are made into adhesive patches for transdermal administration. Nicotine patches deliver a predictable amount of nicotine and achieve steady-state plasma nicotine levels in the ranges achieved by smoking 10 to 30 cigarettes per day. The labeled dose refers to the amount of nicotine delivered rather than the amount of nicotine present in the patch. Transdermal nicotine is well absorbed, but the peak plasma concentrations are delayed by up to 10 hours after patch application. Placebo-controlled clinical trials with transdermal nicotine show efficacy in smoking cessation treatment. Nicotine replacement therapy with transdermal nicotine significantly reduces nicotine withdrawal symptoms and increases the likelihood of successful smoking cessation (10,11). A recent meta-analysis of 17 studies involving over 5,000 patients indicated that transdermal nicotine patches produced quit rates of 27.1% at end of treatment and 21.8% at 6 month follow-up, compared to 13.1% and 8.4% for placebo groups, respectively.

Transdermal nicotine is used as follows. After stopping tobacco use, one patch is applied to uncovered skin each 24-hour period and the previous patch discarded. Some patches are labeled for use during the daytime only and are not worn while the patient is asleep. Typical transdermal nicotine treatment involves applying a high-dose patch to skin for 2 to 4 weeks, an intermediate dose patch for 2 to 4 weeks, and then the smallest dose patch for 2 to 4 weeks. Side effects include irritation from the patch and nicotine effects (nausea, cardiac effects, etc.). It is important that patients not use tobacco products or other nicotine replacement methods while using the patch, as toxic nicotine blood levels may occur. It is also important that patients receive behavior-oriented treatment while using the patch. Nicotine Gum. This gum is a sweet, flavored polacrilex resin containing 2 or 4 mg of nicotine that is released slowly when the resin is chewed. Up to 90% of the nicotine in the resin is released into the saliva, although the amount of release and the rate of release depends upon the rate and duration of chewing. Nicotine is absorbed across the buccal mucosa, with a time to peak concentration of 15 to 30 minutes after start of chewing. The gum is marketed as Nicorette and has recently been made available as an over-the-counter medication, as well as being available by prescription. Patients must be instructed in the proper use of the gum, which is chewed slowly and intermittently whenever the individual feels the need for tobacco. When tingling of the mouth or tongue is perceived, chewing should cease for a short time, while still holding the gum in the mouth. Rapid chewing releases excess nicotine and may cause nausea and other side effects of nicotine toxicity. The gum is chewed for 20 to 30 minutes and then discarded. This method reduces tobacco craving and withdrawal discomfort with nicotine blood levels that rise and fall, mimicking smoking (12). Nicotine gum has been shown to be more effective than placebo in most clinical trials of its use in smoking cessation (13). Recent studies suggest that the 4 mg nicotine gum is more effective than the 2-mg gum in high nicotine-dependent smokers (14). Side effects of gum use include symptoms of nicotine toxicity and occlusive injuries of the teeth and dental appliances. Most patients achieve stable gum use within a few days if they can stop smoking. A schedule for tapering gum use is planned after the daily maintenance dose is established. For example, a patient using 15 pieces of gum each day during the first week of treatment gradually reduces the number to 10 per day by the end of the first month and 5 per day by the end of the second month. Patients are typically able to discontinue nicotine gum after 3 to 6 months of treatment. Nicotine Nasal Spray. Nicotine has recently become available in a solution for intranasal administration, to be used as source of nicotine replacement during smoking cessation treatment. The medication is administered in a concentration of 0.5 mg nicotine per 50 juL of metered spray vehicle. The recommended nicotine nasal dose is 1-2 mg (2-4 sprays) per hour, with a maximum recommended

daily dose of 40 mg. When nicotine is administered intranasally, the time to peak plasma concentration is 4 to 15 minutes. The bioavailability of nicotine nasal spray solution is approximately 53%, although peak plasma concentrations achieved vary considerably due to individual differences in absorption and variations in usage. Rhinitis or other nasal abnormalities may reduce absorption, reduce peak plasma nicotine concentrations, and increase the time to peak plasma concentrations. Side effects of the spray include irritation of the nasal and pharyngeal cavities, in addition to the physiological side effects of nicotine. It is recommended that tapering of nasal nicotine doses begin after 2-4 weeks and that use not exceed 8 weeks to minimize the chances of developing dependence on the nicotine spray. Nicotine Inhaler. Nicotine replacement using a nicotine inhaler (sometimes called a smokeless cigarette) to deliver nicotine orally by inhalation through a plastic tube has recently become available and is marketed as the Nicotrol Inhaler. An active, disposable nicotine cartridge consisting of a porous plug impregnated with 10 mg of nicotine is placed in the plastic tube, and the patient inhales through a plastic mouthpiece as if smoking a cigarette. The device delivers a dose of 13 jug nicotine per puff, for up to 400 puffs. The delivered nicotine is primarily absorbed through the buccal mucosa. This method most mimics smoking, as it involves bringing the device to the mouth and inhaling to obtain nicotine dosing. In a study of 247 smokers who had previously failed other nicotine replacement therapy, continuous abstinence rates were 28% with the active drug, compared to 18% with the placebo inhaler (15). Common side effects include dyspepsia, transient coughing, and mouth irritation.
Other Medications for Smoking Cessation

Clonidine: Oral and Patch. Clonidine has been found to be effective in the treatment of smoking cessation and the amelioration of nicotine withdrawal symptoms, reducing cigarette craving and other symptoms of nicotine withdrawal in dependent cigarette smokers who stopped cold turkey (16). Several other investigators have confirmed the efficacy of clonidine in reducing nicotine withdrawal and improving quitting rates. However, in other studies on the treatment of nicotine withdrawal, the effects of clonidine have been more equivocal. A transdermal clonidine therapeutic system, marketed as Catapres-TTS, was developed for the treatment of hypertension and is approved by the U.S. FDA for that indication. The medication is incorporated into a transdermal delivery device designed to adhere to the skin (a patch) and to provide stable therapeutic levels of drug for period of one week. A microporous membrane controls the rate of clonidine delivery to the skin surface, whereupon the drug diffuses into the skin. The dose received is proportional to the patch surface area. Bioavailability and efficacy studies demonstrate comparability to oral clonidine preparations (17). However, due to cutaneous compartmental pharmacokinetics, there is a delay of 48 to 72 hours before the therapeutic blood levels are achieved and a similar persis-

tence in clonidine levels after the patch is removed. A large multicenter clinical trial used transdermal clonidine combined with behavioral treatment for smoking cessation (18). The clonidine doses used in this study were 0.1 to 0.2 mg per day. Although there was some decrease in nicotine withdrawal symptoms with clonidine, there was no significant increase in quit rates, compared with placebo. Nevertheless, the reduction in nicotine withdrawal symptoms with clonidine may have benefits in selected patients (19). Some investigators have found an improved response in female smokers. Side effects of clonidine include hypotension and sedation. Clonidine is usually prescribed for a period of 3 to 4 weeks, with the dose gradually reduced over the detoxification period. As with other forms of treatment for nicotine dependence, clonidine should be used in conjunction with a behavioral recovery program.
TREATMENTS FOR OPIOID DEPENDENCE

Opioid abuse and dependence are significant social and medical problems in the U.S., with an estimated opioid addict population of greater than 500,000. These patients are frequent users of medical and surgical services because of the multiple medical sequelae of intravenous drug use, including infections (especially human immunodifficiency virus) and overdose. The crime and violence associated with the addict lifestyle engenders serious injuries to the addicts and to others. Opiate drugs affect organ systems due to stimulation of receptors for endogenous hormones, enkephalins, endorphins, and dynorphins. There exist at least three distinct opioid receptors, which are designated by the Greek letters ju, /c, and 3 (20). Drugs that act primarily through jureceptor effects include heroin, morphine, and methadone; such drugs produce analgesia, euphoria, and respiratory depression. Drugs mediated through the /c-receptor include the so-called mixed agonist-antagonists, buprenorphine, butorphanol, and pentazocine, which produce analgesia, but less respiratory depression. The ^-receptor appears to bind endogenous opioid peptides. The treatment of opioid dependence includes detoxification, followed by long-term rehabilitation. Several medications that use the principles of controlled drug delivery systems are used clinically for detoxification and rehabilitation of the opioid-dependent patient.
Opioid Detoxification: Clonidine

Opiate withdrawal, although rarely life threatening, is subjectively distressing. It is marked by increased sympathetic activity, intestinal hyperactivity, hypersensitivity to pain, and an intense craving to use more opiates. The peak period of acute withdrawal depends on the opiate used: for short-acting opiates such as morphine, heroin, or meperidine, the peak withdrawal is 1-3 days and duration is 5-7 days. For longer-acting opiates, such as methadone, the peak is 3-5 days and the duration 10-14 days. Clonidine hydrochloride is an imidazoline derivative originally approved as an antihypertensive medication. Clonidine is an agonist at presynaptic a-2 adrenergic re-

ceptors and blocks the release of central and peripheral norepinephrine. Noradrenergic neurons in the locus ceruleus of the brain show increased neuronal activity during opiate withdrawal and this effect can be blocked by a-2 adrenergic agonists such as clonidine (21). On the basis of this observation, clonidine was tested clinically as a blocker of opioid withdrawal signs and symptoms (22,23). Subsequent double-blind clinical trials confirmed that clonidine was more effective than placebo and slightly less effective then a slow methadone taper in reducing signs and symptoms of opiate withdrawal in both inpatients and outpatients. Clonidine was found to be effective in patients withdrawing from either short-acting opioids, such as heroin, or long-acting opioids, such as methadone. However, clonidine was never formally approved by the FDA for the treatment of withdrawal in opioid-dependent patients. Although most studies have been performed using oral clonidine, clonidine is available as a transdermal delivery system (described earlier), and this modality has been used successfully to treat opioid withdrawal (24). Advantages of the clonidine transdermal system include attainment of more constant plasma levels of clonidine (i.e., the avoidance of peaks and troughs) and the psychological benefit of an addicted patient not taking pills to relieve discomfort. A disadvantage of transdermal clonidine is a lag time of up to 72 hours for medication effect after applying the patch to the skin. Because of the lag time application of the clonidine transdermal patch and the attainment of new steady-state blood levels, supplementation of the patch with the more rapidly absorbed oral clonidine may be required to treat emergent withdrawal symptoms. Likewise, hypotension from overmedication with transdermal clonidine will take several hours to resolve after dose reduction. When used clinically to treat opioid withdrawal, clonidine suppresses approximately 75% of opioid withdrawal signs and symptoms, especially autonomic hyperactivity (tremor, piloerection, tachycardia), anxiety, and gastrointestinal symptoms (cramps and diarrhea). Clonidine is administered in increasing doses such that opioid withdrawal signs and symptoms are decreased but blood pressure is maintained. A typical schedule for transdermal clonidine uses 0.1 mg on day 1 following discontinuation of opiates, 0.2 mg on day 2, 0.3 mg on day 3, and 0.4 mg on day 4. This maximal dose is continued for 5-7 additional days for short-acting opioids and 10-14 additional days for long-acting opioids. Opioid withdrawal symptoms not significantly ameliorated by clonidine include drug craving, insomnia, and arthralgias and myalgias. Insomnia is best treated with a short-acting hypnotic such as chloral hydrate, and pain may respond to nonnarcotic analgesics such as a nonsteroidal antiinflammatory medication or acetaminophen. Side effects of clonidine include dry mouth, sedation, and orthostatic hypotension. Clonidine should be used cautiously in hypotensive patients and in those receiving other antihypertensive, antidepressants, stimulants, or antipsychotics.
Opioid Maintenance

The most widely used pharmacological treatments for opioid-dependent individuals include pharmacological

maintenance treatments with the opiate agonists methadone and L-a-acetylmethodol (LAAM), maintenance with the partial opiate agonist buprenorphine, and opiate antagonist therapy with naltrexone. AU of these medications are best used in the setting of a structured, maintenance treatment program, which includes monitored medication administration; periodic, random urine toxicological screening to assess compliance; and intensive psychological, medical, and vocational services. Maintenance treatments reduce use of illicit opiates by increasing drug tolerance, thereby decreasing the subjective effects of illicitly administered opiates, and by stabilizing mood, thereby decreasing self-medication. Maintenance treatments also provide an incentive for treatment so that they may be exposed to other therapies. Methadone Maintenance. Methadone is a synthetic opiate, which is orally active, possesses a long duration of action, produces minimal sedation or high, and has few side effects at therapeutic doses. A single daily dose of methadone will prevent the onset of withdrawal for at least 24 hours. Since its introduction in 1965, methadone maintenance has become a major modality of long-term treatment of opioid abuse and dependence (25). Currently, over 100,000 individuals are maintained on methadone in the U.S. Although orally administered, an elaborate medication delivery system has evolved to ensure the controlled administration of this medication. Methadone is dissolved in small aliquots of a sweetened, flavored liquid vehicle and stored in single-dose plastic bottles. Each dose of methadone is dispensed daily and must be consumed under the direct observation of the dispensing nurse or pharmacist to ensure compliance. Frequent urine samples are obtained at randomly determined intervals for toxicological screening to confirm the presence of methadone and the lack of other illicit drugs. In addition, patients receive counseling, medical, and social services to assist them in achieving a drug-free lifestyle. Long-standing program participants are allowed contingency take-home doses of methadone, which patients may self-administer. However, these are withdrawn for missing appointments or for evidence of illicit drug use. Doses of methadone usually range from 20 mg per day to over 100 mg per day. Higher doses are shown to be generally associated with better retention in treatment. Many studies have shown the efficacy of methadone maintenance in the treatment of addicts who are dependent on heroin and other opiates. Methadone-treated patients show increased treatment retention, improved physical health, decreased criminal activity, increased employment, and decreased chance of becoming HIV positive (26). Methadone is most effective in the context of a program that provides intensive psychosocial and medical services, and adequate methadone dosing. The use of methadone for maintenance is highly regulated by government agencies. Senay (27) provides an excellent recent review of the theory and practice of methadone maintenance. L-a-Acetylmethodol Acetate (LAAM). A long-acting, orally active opiate, the pharmacological properties of

LAAM are similar to methadone. Studies on LAAM have shown it to be equal or superior to methadone maintenance in reducing IV drug use, when used in the context of a structured maintenance treatment program (28). The advantages of LAAM include a slower onset of effects and a longer duration of action than methadone. This allows LAAM to be administered only 3 times per week, reducing the cost of preparation and monitoring of medication and reducing the use of take-home medications that may be diverted to illicit use. Patients treated with LAAM should be started on 20 mg administered 3 times weekly, with the dose increased weekly in 10 mg increments as necessary. Doses up to 80 mg 3 times weekly are safe and effective. Sublingual Buprenorphine. Buprenorphine is a partial agonist opiate medication (mixed agonist-antagonist), originally used medically as an analgesic. It has high affinity for the fi opioid receptor and the K receptor. Buprenorphine possesses both agonist and antagonist propertiesagonist properties predominate at lower doses and antagonist properties predominate at higher doses. Cessation in buprenorphine in dependent individuals results in a withdrawal syndrome that is much milder than that observed with pure opioid agonists. These properties of the drug suggested its use as a maintenance medication in the treatment of chronic opioid dependence. However, oral buprenorphine has poor bioavailability and only parenteral preparations of the medication are used. Sublingual (SL) administration is an effective way of administering medication that may not be orally active. SL administration of buprenorphine results in effective medication plasma levels and was therefore tested in the treatment of opioid dependence. In the setting of a structured treatment program, daily dosing of SL buprenorphine was found to effective in the maintenance treatment of narcotics addicts, reducing illicit drug use (29-31). Buprenorphine may also reduce concomitant cocaine use in opiate addicts (32). Buprenorphine doses usually range from 4 mg per day to up to 16 mg per day, administered sublingually. Advantages of buprenorphine include a milder withdrawal syndrome upon discontinuation and less potential for abuse, as agonist effects diminish at higher doses. Opioiddependent patients may be started on 2 to 4 mg buprenorphine immediately after opiates are discontinued, and the dose of buprenorphine titrated to 8 to 16 mg over several days (33). Naltrexone. Opioid antagonist therapy reduces the use of illicit drugs by blocking the effect of the drugs at neurotransmitter receptors, leading to decreased use. There is some evidence that opiate antagonists may block craving for opiates as well. Naltrexone (Trexan) is a long-acting, orally active opioid antagonist, which when taken regularly, entirely blocks ju opioid receptors and thus blocks the euphoric, analgesic, and sedative properties of opioids (34). Oral naltrexone is administered either daily to detoxified opioid users at a dose of 50 mg, or 3 times weekly at doses of 100 mg, 100 mg, and 150 mg. Although naltrexone is quite effective when taken as prescribed, most studies have demonstrated poor medication compliance among

subjects. The drug appears to be most effective in motivated individuals with good social support and appears less helpful for heroin addicts or less motivated individuals. Because of the low compliance with oral naltrexone formulations, there has been interest in the development of alternative drug delivery systems to improve medication compliance. Two parenteral depot formulations of naltrexone have been developed; injectable naltrexone microspheres coated with poly(DL-lactic acid) (35) and an implantable biodegradable copolymer polylactic/glycolic matrix delivery system (36,37). The injectable microspheres have been tested on animals and humans and found to result in plasma naltrexone levels that would effectively block exogenous opioids and that are stable for at least 30 days. Problems with residual organic solvent used in the microsphere preparation have delayed FDA approval of this method; however, new preparation techniques avoid the problem with organic solvents, and the injectable microspheres are being tested again. Both of these methodologies remain experimental but are undergoing continued testing. TREATMENTS FOR ALCOHOL DEPENDENCE Disulfiram An irreversible inhibitor of the enzyme acetaldehyde dehydrogenase, disulfiram (Antabuse) is used as an adjunctive treatment in selected alcoholic patients (38,39). If alcohol is consumed in the presence of disulfiram, the toxic metabolite acetaldehyde accumulates in the body, producing tachycardia, skin flushing, diaphoresis, dyspnea, nausea, and vomiting. Hypotension and death may occur if large amounts of alcohol are consumed. This unpleasant and potentially dangerous reaction provides a strong deterrent to the consumption of alcohol. Patients using disulfiram must be able to understand its benefits and risks. Alcohol present in foods, shaving lotion, mouthwashes, or over-the-counter medications may also produce a disulfiram reaction and must be avoided. As increased disulfiram compliance improves treatment success, there has been interest in the development of longlasting depot formulations of disulfiram to improve medication compliance (40). Several methods for depot disulfiram administration have been developed, including the implantation of disulfiram surrounded by a semipermeable membrane to retard absorption, direct tablet implantation, and the subcutaneous injection of disulfiram in vehicles such as methylcellulose or polysorbate 80. Unfortunately, most clinical studies have shown an inability of implanted forms of disulfiram to induce a significant disulfiram-alcohol reaction when subjects are challenged with alcohol (41). Naltrexone In clinical trials with recently abstinent human alcoholics, subjects treated with the opioid antagonist naltrexone had lower rates of relapse to heavy drinking, and more total abstinence, than did a placebo group (42,43). Subjects re-

ceiving naltrexone also report decreased craving and decreased high from alcohol. Naltrexone is thought to act by blocking the alcohol-induced release of dopamine in the nucleus accumbens and other brain areas that control the reinforcing properties of drugs and alcohol. One factor that appears important for the efficacy of naltrexone is medication compliance. Two placebocontrolled clinical trials with oral naltrexone demonstrated significant efficacy in reducing drinking only in subjects that showed high compliance with medication ingestion (44,45). Thus, there is interest in the development of alternative drug delivery systems for naltrexone that will enhance compliance and optimize medication effects to improve treatment. A recent report comparing oral naltrexone with injectable sustained-release naltrexone microspheres (35) in 20 patients found comparable effects of the two different preparations in reducing alcohol consumption (46). Side effects of the oral and sustained-release preparations were also similar. More research needs to be conducted on the sustained-release forms of naltrexone; however, the initial results are encouraging. SUMMARY Controlled drug delivery systems have been applied to the treatment of several addictive disorders, including nicotine dependence, opioid dependence, and alcohol dependence. In the case of nicotine dependence, several commercial products are available, giving clinicians and patients considerable flexibility in drug dosing. Controlled drug delivery systems are currently being studied in the maintenance treatment of alcoholism and opioid dependence. BIBLIOGRAPHY
1. D.A. Regier, M.E. Farmer, and D.S. Rae, J. Am. Med. Assoc. 264, 2511-2518 (1990). 2. D.R Rice, Alcohol Health Res. World 17, 10-11 (1990). 3. JM. McGinnis and W.H. Foege, J. Am. Med. Assoc. 270, 22012212 (1993). 4. American Psychological Association, Diagnostic and Statistical Manual, 4th ed., APA Press, Washington, D.C., 1994. 5. Centers for Disease Control, Morbid. Mortal. WkIy. Rep. 43, 342-346 (1994). 6. J.R. Hughes and D.K. Hatsukami, Arch. Gen. Psychiatry 43, 289-294 (1986). 7. N. Breslau, M. Kilbey, and P. Andreski, Am. J. Psychiatry 149, 464-469 (1992). 8. H.L. Greene, R. Goldberg, and J.K. Ockene, J. Gen. Intern. Med. 3, 75-87 (1988). 9. Agency for Health Care Policy and Research, CUn. Pract. Guideline 18B, 1-10 (1996). 10. J.L. Tang, M. Law, and N. WaId, Br. Med. J. 308, 21-26 (1994). 11. Transdermal Nicotine Study Group, J. Am. Med. Assoc. 266, 3133-3138 (1991). 12. N.G. Schneider, Addict. Behav. 9, 149-156 (1984). 13. M.G. Goldstein and R.S. Niaura, in J.A. Cocores, ed., Clinical Management of Nicotine Dependence, Springer-Verlag, New York, 1991, pp. 181-195. 14. N. Herrera et al., Chest 108, 447-451 (1995).

15. A. Hjalmarson, F. Nilsson, L. Sjostrom, and O. Wiklund, Arch. Intern. Med. 157, 1721-1728 (1997). 16. A.H. Glassman, F. Stetner, B.T. Walsh, and RS. Raizman, J. Am. Med. Assoc. 259, 2863-2866 (1988). 17. D.T. Lowenthal et al., Am. Heart J. 112, 893-900 (1986). 18. A.V. Prochazka et al., Arch. Intern. Med. 152, 2065-2069 (1992). 19. J.J. Green and D.H. Cordes, West. J. Med. 151, 79-80 (1989). 20. T. Reisine and G. Pasternack, in J.G. Hardman and L.E. Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, New York, 1996, pp. 521-555. 21. G. Aghajanian,iVatare (London) 276, 186-187 (1978). 22. D.S. Charney et al., Arch. Gen. Psychiatry 38, 1273-1278 (1981). 23. M.S. Gold, A.C. Pottash, D.R. Sweeney, and H.D. Kleber, J. Am. Med. Assoc. 234, 343-344 (1979). 24. L. Spencer and M. Gregory, J. Substance Abuse Treat. 6,113117 (1989). 25. V.P. Dole and M. Nyswander, J. Am. Med. Assoc. 93, 646-650 (1965). 26. J.C. Ball, W.R. Lange, CP. Myers, and S.R. Friedman, J. Health Soc. Behav. 29, 214-226 (1988). 27. E. Senay, Int. J. Addict. 20, 803-821 (1985). 28. W. Ling, R.A. Rawson, and P.A. Compton, J. Psychoact. Drugs 26, 119-128 (1994). 29. RA. Compton, D.R. Wesson, V.C. Charuvastra, and W. Ling, Am. J. Addict. 5, 220-230 (1996). 30. R.E. Johnson, J.J. Jaffe, and RJ. Fudala, J. Am. Med. Assoc. 267,2750-2755(1992).

31. T.R. Kosten, C. Morgan, and H.D. Kleber, Am. J. Drug Alcohol Abuse 17, 119-128 (1991). 32. T.R. Kosten, H.D. Kleber, and C. Morgan, Biol Psychiatry 26, 637-639 (1989). 33. T.R. Kosten, C. Morgan, and H.D. Kleber, NIDA Res. Monogr. 121, 101-119(1992). 34. R.B. Resnick, E. Schuyten-Resnick, and A.M. Washton,A7iraz/. Rev. Pharmacol. Toxicol. 20, 463-470 (1980). 35. E.S. Nuwayser, D.J. DeRoo, RD. Balskovich, and A.G. Tsuk, NIDA Res. Monogr. 105, 532-533 (1991). 36. R.H. Reuning et al., J. Pharmacokinet. Biopharm. 11, 369387 (1983). 37. A.C. Sharon and D.L. Wise, NIDA Res. Monogr. 28, 194-213 (1981). 38. C. Brewer, Alcohol Alcohol. 28, 383-395 (1993). 39. J. Chick, K. Gough, and W. Falkowski, Br. J. Psychiatry 161, 84-89 (1992). 40. M.D. Faiman, KE. Thompson, and KL. Smith, in CA. Naranjo and E.M. Sellers, eds., Novel Pharmacological Interventions for Alcoholism, Springer-Verlag, New York, 1992, pp. 267-272. 41. J.C Hughes and C C Cook, Addiction 92, 381-395 (1997). 42. S.S. O'Malley et al., Arch. Gen. Psychiatry 49, 881-887 (1992). 43. J.R. Volpicelli, A.I. Alterman, M. Hayashida, and CR O'Brien, Arch. Gen. Psychiatry 49, 876-880 (1992). 44. J. Chick, 10th World Psychiatry Conf, Madrid, Spain, Aug. 24, 1996. 45. J.R. Volpicelli et al., Arch. Gen. Psychiatry, 54, 737-742 (1997). 46. H.R. Kranzler, V. Modesto-Lowe, and E.S. Nuwayser, Alcohol CHn. Exp. Res. 22, 1074-1079 (1998).