Quick viewing(Text Mode)

Treatment of Alcohol Dependence with Medications

Treatment of Alcohol Dependence with Medications

Treatment of Dependence With

Treatment of With Medications

In recent years, the development of new medica- on alcohol. One such , , tions to treat alcohol dependence, representing holds promise in reducing the return to - the combined efforts of neuroscientists and ing, following a brief period of , clinical researchers, has begun a new era in that typifies alcohol dependence. Moreover, treatment. Until 1995, the only investigators are examining the possibility that medical treatment approved for use in the United combining a medication that reduces the risk States () simply provoked intense of relapse (such as acamprosate) with one that physical symptoms such as upon the reduces the risk of heavy drinking should relapse ingestion of alcohol. In contrast, newer for occur (such as an antagonist) may increase alcoholism treatment operate at the molecular treatment effectiveness. level of the processes that promote and maintain . The targeted actions of these research has focused not only newer drugs offer the possibility of more effective on drugs to treat alcoholism itself, but also on treatment options for the millions of alcohol- medications for coexisting conditions that can dependent persons in our Nation. threaten recovery. Current research continues to show that , both old and new, are Over the past decade, advances in knowledge of powerful agents for helping persons with alcohol the biology underlying drinking behavior have dependence who also suffer from to laid the groundwork for new pharmacologic gain and maintain abstinence from alcohol. treatments for alcohol dependence. For example, Patients with untreated depression often relapse it is now known that multiple chemical messenger to drinking, whereas those who take antidepres- systems in the brain, called sants generally participate more in treatment systems, are involved in problem drinking. programs and respond better. Recent studies Several medications that affect different neuro- in this area have strengthened the findings of transmitter systems have been tested in . previous research by using larger, more diverse patient samples and new types of antidepressants. In particular, one area of research has focused on a class of medications called “opiate antagonists.” Medications hold great promise but at present These medications interfere with neurotransmitter cannot replace psychological treatments for systems that produce pleasurable effects, such as people with alcohol dependence. These two feelings of , upon the use of alcohol and classes of treatment strategies are complementary other drugs. If patients resume drinking while rather than competitive, in that studies suggest taking opiate antagonists, they are not rewarded that pharmacologic agents may be combined with the expected “high” from the alcohol. Two effectively with skilled counseling to improve of these drugs, and , have treatment outcomes (O’Malley et al. 1992, 1996). shown promising results for treating alcohol This section focuses on recent advances in dependence. In 1995 naltrexone (ReVia) was pharmacotherapy research in two main areas: approved by the U.S. Food and Admin- (1) medications specifically used to treat alcohol istration (FDA) for treating alcohol dependence, dependence, and (2) medications to treat some while nalmefene is in the testing phase of patients who suffer not only from alcohol development. dependence but also from psychiatric disorders, primarily depression. (For an update on research In addition, researchers are evaluating medica- on psychological treatments, see the previous tions that target different neurotransmitter section “Treatment of Alcohol Dependence systems involved in maintaining dependence With Psychological Approaches” in this chapter.)

451 Chapter 8: Treatment Research

Medications for Alcohol Dependence Naltrexone. Studies in humans also support the hypothesis that opiate antagonists reduce the In 1992, alcohol researchers proposed the pleasurable effects associated with alcohol’s attributes of a “perfect medication” for treating stimulation of the endogenous system and alcohol dependence (Volpicelli et al. 1992). The related reward systems. Patients given naltrexone drug they were seeking would reduce the craving described less euphoria, or “high,” from drinking for alcohol so that an individual would be less than did patients taking a (Volpicelli et motivated to drink. The ideal drug also would al. 1995b). Similarly, social drinkers given block the reinforcing effects of alcohol so that if naltrexone in a laboratory told researchers they the individual resumed drinking, pleasant effects felt fewer effects of alcohol and more would not be felt. In addition, the medication of its sluggish, effects (Swift 1995; Swift would have few, if any, . With these et al. 1994). Thus, by reducing the positive goals in mind, researchers have made significant of drinking and increasing un- progress in recent years. pleasant effects, naltrexone may help abstinent individuals who relapse to refrain from heavy Blocking the Reward: Opiate Antagonists drinking. The treatment of alcohol dependence has In another study, social drinkers who were benefited from decades of research that have pretreated with naltrexone waited longer to have led to an understanding of the mechanics of both their first and their second (Davidson addiction and of the way in which certain et al. 1996b). This finding suggests that opiate medications can counter the effects of addictive antagonists block both the chemical changes in drugs. Substances like and , the brain elicited by environmental cues before called , act like chemicals the brain drinking and the “priming” effects of alcohol produces naturally, called endogenous , during drinking—phenomena associated with the which stimulate pleasurable feelings and suppress urge to drink and loss of control over drinking. pain. Medications known as opiate antagonists Researchers who reexamined data (O’Malley et bind with the brain’s receptors for endogenous al. 1995) from two previous clinical trials of opioids, thus blocking the desired effects of naltrexone (O’Malley et al. 1992; Volpicelli et al. heroin and similar drugs while having no effect 1992) found that patients with alcoholism who themselves. took naltrexone and who ultimately returned to drinking refrained a longer time until their first Alcohol is not an opiate-like substance, and drink and their first episode of heavy drinking researchers do not know the exact mechanism by than did patients who took a placebo. Among which opiate antagonists affect drinking. Animal the patients in the study who drank, those studies suggest, however, that these medications using naltrexone drank less frequently and on block some of alcohol’s rewarding effects. When a significantly smaller percentage of days than researchers administered an opiate antagonist did placebo-treated patients, and they were less (naltrexone) to rats that were later given alcohol, likely to relapse to heavy drinking. the medication decreased the amount of alcohol- induced , a neurotransmitter involved Persons with alcoholism share two core symptoms: in motivation and reinforcement that is available the tendency to drink more than they intend in a reward center in the brain (Benjamin et al. to and drinking at levels that lead to medical, 1993). Moreover, rats given larger doses of psychological, or social problems, such as missing naltrexone showed even greater decreases in dopa- work and failing to fulfill family responsibilities. mine. This “dose-dependent” effect demonstrated Naltrexone appears to have a significant effect that the opioid system is an important target for on both of these symptoms of alcohol depen- medications to control alcohol consumption and dence. In two early studies, the researchers reward. Recent studies on two opiate antagonists, gave naltrexone to recently detoxified outpatient naltrexone and nalmefene, are summarized below.

452 Treatment of Alcohol Dependence With Medications volunteers who came from diverse racial/ethnic with alcoholism found no serious adverse events and economic backgrounds and who had received associated with naltrexone treatment (Croop et different types and intensities of behavioral al. 1995). Although no systematic studies have treatments for alcoholism (O’Malley et al. 1992; ascertained the range of doses that might be Volpicelli et al. 1992). Regardless of differences used to treat alcoholism, the typical dose is in demographic traits and behavioral treatments, 50 milligrams per day (mg/day). At a much patients given naltrexone had similar outcomes higher dose—300 mg/day—naltrexone is across all groups: they drank less frequently, and associated with adverse effects (hepato- when they drank, they consumed less alcohol. ). The drug label notes that this medica- tion is not appropriate for patients with acute No medication can be fully effective unless it hepatitis or liver failure. is used as directed, that is, taken as scheduled and for the full course of treatment. The degree Follow-up studies of patients who have used to which patients are compliant in taking a medication can yield important information medication as directed is a key measure of about its long-term effects as well as the potential in all drug studies. Reasons for noncompliance for drug “rebound,” which could lead to include unpleasant side effects, expense, and relapse, when the medication is discontinued. complicated dosing schedules. Recent research Six months after treating patients for 12 weeks suggests that patients’ compliance with naltrexone with naltrexone, researchers (O’Malley et al. is excellent in a treatment research setting. When 1996) interviewed a subset of participants from naltrexone use was verified by testing, it their earlier study (O’Malley et al. 1992). They was found that 92 percent of naltrexone-treated found that two-thirds of the patients originally patients were compliant, compared with treated with a placebo, but only one-third of 78 percent of placebo-treated patients (O’Malley naltrexone-treated patients, had resumed drinking et al. 1992). Other investigators noted that to the point that they again met criteria for alco- naltrexone was especially effective in preventing hol abuse or dependence. Naltrexone-treated relapse to heavy drinking among patients who patients also were less likely to relapse during the took the medication regularly and who completed first month after they stopped using the medica- the 12-week treatment course (Volpicelli et al. tion and less likely to drink heavily during the 1997). Patients who took more of their naltrex- first 4 months after treatment. one pills correctly had lower percentages of drinking days then did patients who did not As mentioned, however, the study did find take all of them correctly. that one-third of the patients relapsed after the 12-week treatment period, suggesting that nal- Investigators have developed an effective new trexone should be continued beyond 12 weeks method for monitoring naltrexone and its for some people. At the 6-month follow-up major , 6-beta-naltrexol, in interview, patients were more likely to be plasma (Davidson et al. 1996a; Huang et al. abstinent from alcohol if they had been able to 1997). The new blood test, analyzed by high- sustain abstinence during the initial 12 weeks of performance chromatography with electro- treatment with naltrexone (O’Malley et al. 1996). chemical detection, may help researchers to refine Because establishing abstinence is linked with naltrexone dosing to improve its efficacy. Some better treatment outcomes, use of naltrexone patient groups, such as women and the elderly, beyond the 12-week period may be particularly often respond much better to medications at helpful to patients who have difficulty with lower dosages, whereas other groups require abstinence during initial treatment. relatively high levels. In addition, some patients may have no trouble Several investigators have examined the side achieving abstinence during initial naltrexone effects of naltrexone. A study of 570 patients treatment, but they may anticipate periods of

453 Chapter 8: Treatment Research

relapse risk, such as an upcoming vacation, or the three subtypes of opioid receptors that are experience sudden stressful events, such as the thought to reinforce alcohol consumption of a friend. These patients may benefit (Charness et al. 1983; Culpepper-Morgan et al. by using naltrexone again for short periods until 1995; Emmerson et al. 1994; Michel et al. 1985; they feel more secure about their coping skills Tabakoff and Hoffman 1983), whereas naltrexone in avoiding relapse. Longer term studies of specifically binds to just one subtype and maintenance treatment with naltrexone are under may affect the other two only at high doses way to determine the appropriate duration of (Sawynok et al. 1975). treatment for different groups of patients. This new study reinforced findings from a Determining which patients are likely to benefit small pilot study on nalmefene that showed that from this treatment is prudent because naltrexone alcohol-dependent patients taking 40 mg/day had is moderately expensive: the standard daily significantly lower rates of relapse in preliminary 50-mg tablet for an alcohol-dependent person studies than did either patients on the placebo or retails at almost $5. Additionally, as with any those on 10 mg/day of nalmefene (Mason et al. new medication, naltrexone must be used more 1994). widely before firm conclusions are drawn about risks and benefits. Early trials suggest that the In a recent study of 105 patients, those who patients who may derive the greatest benefit from were randomly assigned to nalmefene (20 or naltrexone are those who experience an intense 80 mg/day) were 2.4 times less likely to relapse urge to drink and who have physical symptoms, to heavy drinking during the 12 weeks of such as chronic pain or discomfort, coupled with treatment than those who received a placebo. poor cognitive functioning, such as impaired Although one-third of the patients treated with learning skills and (Jaffe et al. 1996; nalmefene did relapse to heavy drinking at least Volpicelli et al. 1995a). once during the trial, they had fewer subsequent heavy-drinking episodes than did those taking A large cooperative study is now under way at the placebo. The researchers found no significant 15 U.S. Department of Veterans Affairs medical differences between 20-mg and 80-mg doses of centers to examine alcoholism treatment with nalmefene, and the patients taking either dose naltrexone for up to 1 year. The 600 veterans of nalmefene had high rates of compliance and assigned to naltrexone or a placebo also will showed no evidence of medically serious side receive a standardized behavioral intervention, effects (Mason et al. 1999). the -based 12-step facilitation treatment designed for the project Replicating the results of naltrexone studies Matching Alcohol Treatments To Client with this structurally similar compound supports Heterogeneity (Project MATCH) (see also the the importance of further research on opiate previous section in this chapter, “Treatment of antagonists to treat alcohol dependence. Alcohol Dependence With Psychological Nalmefene may be an option for patients who Approaches”). The study will also evaluate the experience adverse side effects from naltrexone cost-effectiveness of naltrexone. or who do not respond to that drug.

Nalmefene. Nalmefene, a newer opiate antagonist Reducing Rates of Relapse: Acamprosate that is not yet approved by the FDA for treatment of alcoholism, is structurally similar to naltrexone The medication acamprosate interacts with but has potential advantages for treating alcohol different biochemical pathways in the brain than dependence. Unlike naltrexone, for example, those affected by opioid antagonists. Although nalmefene has shown no dose-dependent liver the precise is still under toxicity (Mason et al. 1999). In addition, investigation, acamprosate is known to affect two nalmefene is considered a “universal” opiate neurotransmitter systems involved in maintaining antagonist, in that it binds more readily with alcohol dependence: the glutamate system and

454 Treatment of Alcohol Dependence With Medications the gamma-aminobutyric acid system. While on the placebo (Geerlings et al. 1997; Lhuintre et chronic alcohol exposure disrupts both systems, al. 1990; Paille et al. 1995; Pelc et al. 1997; Sass causing changes that may persist for many et al. 1996; Soyka 1996; Whitworth et al. 1996). months following withdrawal, acamprosate Acamprosate produced better outcomes than the may act by restoring normal activity in these placebo in studies in which the drug was adminis- systems (al Qatari and Littleton 1995). tered for as long as 1 year, as well as in follow-up studies in which subjects were reinterviewed Having been available by prescription in France 6 to 12 months after stopping the acamprosate since 1989, and more recently in more than treatment (Geerlings et al. 1997; Sass et al. 1996). 30 countries around the world, acamprosate has The single European trial with negative results been used to treat more than 1 million alcohol- differed from the other 10 trials in that treat- dependent people. In the , the ment that is normally initiated immediately FDA has granted acamprosate the status of an after detoxification was delayed up to 2 months. investigational new drug. A 6-month By the time that study began, one-third of the was designed to evaluate the safety and efficacy subjects had relapsed (Soyka 1996). of acamprosate in the United States across 21 different treatment settings, including psychiatry, Although some of the 10 positive European trials internal medicine, and alcoholism treatment had stronger results than others, the outcomes programs (Mason and Goodman 1997). This consistently favored acamprosate over the placebo study has recently been completed, and the data in rate and duration of abstinence and other are now being analyzed. measures. When researchers analyzed pooled data from all 11 trials, the patients on acampro- Studies of acamprosate in animals and humans sate were found to have significantly higher rates have demonstrated many potential benefits. For of abstinence and treatment attendance than example, it decreases voluntary alcohol intake those on the placebo, as well as longer alcohol- with no effects on food and consumption, free periods (Mann et al. 1995). The effects of no potential for abuse, and no pharmacologic acamprosate were evident during the first 30 to effects other than those involved in reducing 90 days of treatment (Ladewig et al. 1993; Sass alcohol dependence (Soyka 1996). In addition, et al. 1996), the interval in which the risk of there is no evidence that acamprosate interacts drinking is the highest and pharmacologic pharmacologically with alcohol or with other support may be most effectively implemented medications prescribed for alcoholism, such as (Meyer 1989). In these trials, any additional disulfiram, or for depression, , psychoses, effect of behavioral therapy could not be or (Durbin et al. 1996). Moreover, evaluated because none of the trials included unlike naltrexone, acamprosate is not metabolized standardized behavioral therapy; instead, each to a meaningful extent in the liver; therefore, treatment center provided whatever behavioral patients with liver dysfunction can gain the therapy it routinely offered (Mann et al. 1995). same therapeutic effects as other patients (Wilde and Wagstaff 1997). Comparing and Combining Acamprosate With Naltrexone In 11 clinical trials in Europe, which included No single study has directly compared acampro- a total of 3,338 patients from many treatment sate with naltrexone. However, researchers have centers, researchers compared the effectiveness compared each medication with a placebo in of acamprosate with that of a placebo. In 10 of separate studies that yielded quite similar results. the studies, patients on acamprosate experienced At the end of the 12-week course of medication, higher abstinence rates and, for those who did 51 percent of the acamprosate-treated patients resume drinking, a significantly longer period of (Pelc et al. 1997) and 54 percent of the abstinence until their first drink than did patients naltrexone-treated patients (O’Malley et al. 1995)

455 Chapter 8: Treatment Research

had stopped drinking. The rates for placebo Researchers have examined whether alcohol intake were 26 percent and 31 percent, respectively. could be reduced by medications that increase the Although the abstinence rates achieved by both amount of available for binding with acamprosate and naltrexone were notably better receptors on nerve cells in the brain. Among the than the rates with placebo, nearly one-half of the “” agents that have been evaluated subjects remained at risk for drinking during the for alcoholism treatment are (Zoloft), treatment study. (Prozac), and several other “selective serotonin inhibitors” (SSRI’s), a class of Because several neurotransmitter systems are drugs developed in the 1980’s to treat depressive involved in maintaining alcohol dependence, disorders. These drugs act at the molecular level the effect of any single medication on alcohol where nerve cell endings release serotonin, which intake may be modest. Both acamprosate and then binds to specialized receptors—of which at naltrexone are well tolerated by patients, and least 14 different subtypes have been identified— the medications’ affinities for different neuro- on adjacent nerve cells (Fuller 1996). Normally, transmitter receptors may lead to different effects the nerve cells that release serotonin also reabsorb on drinking outcomes (such as preventing relapse some of it, but SSRI’s inhibit that reuptake so to heavy drinking or prolonging abstinence). that more serotonin is available to bind with Thus, the National Institute on receptors on other nerve cells. and Alcoholism is currently funding a coopera- tive, multicenter study that will test acamprosate In addition to medications that inhibit reuptake and naltrexone, both alone and in combination, of serotonin, other agents take advantage of and evaluate their use (vs. a placebo) in con- different mechanisms in the serotonin system. junction with behavioral interventions of either For example, a “serotonin ” moderate or minimum intensity. that blocks a specific receptor subtype (called 5-HT3) has been shown to reduce one of the Evaluating Serotonergic Agents for reinforcing effects of alcohol, the release of Treatment of Alcohol Dependence the neurotransmitter dopamine in the brain (Campbell and McBride 1995; Yoshimoto The neurotransmitter serotonin affects multiple et al. 1991). actions in the brain, including the regulation of mood states, appetite, and sleep. The exact Thus far, studies on the effectiveness of seroto- nature of the relationship between serotonin and nergic agents in reducing alcohol intake have alcoholism is unknown. One theory suggests that shown only a mild and transient effect in - individuals with alcohol dependence are naturally erate drinkers and no effect in alcohol-dependent deficient in brain serotonin. According to this patients (for a review of these studies, see Litten view, alcoholism may represent an attempt to et al. 1996). In one multicenter study involving increase brain serotonin levels. Another theory 423 alcohol-dependent patients, researchers suggests that serotonin either directly influences examined , a drug that blocks a the reinforcing effects of alcohol and other drugs serotonin receptor called 5-HT2, and found it or exerts an indirect influence through an effect no more effective than a placebo in controlling on the neurotransmitter dopamine. A third alcohol craving and consumption (Johnson et suggestion is that low levels of serotonin lead al. 1996). Because patients on higher doses of to impulsive behavior, including an inability to ritanserin had abnormalities in their electro- modulate alcohol intake. Abnormalities in the cardiograms, no further study of this drug was brain’s serotonin system may contribute to undertaken. anxiety, potentially leading to “self-medication” of anxiety symptoms with alcohol. Finally, Similarly, when researchers gave fluoxetine, a serotonin may affect general appetite behaviors. widely used SSRI, to 28 male inpatients with

456 Treatment of Alcohol Dependence With Medications severe alcohol dependence, they found it to be patients, including the older antidepres- no better than a placebo in reducing relapse rates sants such as and , which (Kabel and Petty 1996). These findings con- have been available since the 1960’s, and the firmed those of an earlier study of 101 patients newer SSRI’s such as sertraline and fluoxetine. in which fluoxetine was not any more effective The availability of SSRI’s has allowed more than a placebo in reducing alcohol consumption aggressive treatment of depression in alcohol- (Kranzler et al. 1995). dependent patients because these medications have few side effects and can be taken safely Although serotonergic agents have not fulfilled by individuals who continue to drink, unlike the promise they once seemed to offer in treating tricyclic and other antidepressants that interact alcoholism, a recent study in animals suggests this significantly with alcohol (Schottenfeld et al. as an area for further research. The researchers 1989). gave rats a combination of fluoxetine and a serotonin receptor antagonist called WAY As described below, studies show that regardless 100635, which is still in development (Zhou of the type of used, depressed et al. 1998). This combination of medications alcohol-dependent patients who take antidepres- reduced the rats’ alcohol consumption more than sants have better outcomes in terms of their either compound alone. The authors speculated drinking than do those who take a placebo. that combining these drugs increased the available Clinical trials of antidepressants for dually serotonin to a level not achievable by fluoxetine diagnosed patients tend to have small sample alone. sizes, which limits the extent to which the findings can be generalized to larger and more Overall, however, clinical findings to date suggest diverse patient groups. However, the scientific that the serotonergic agents studied thus far are methods used in these small studies are generally not effective for treating alcohol dependence rigorous, and, taken as a whole, the findings itself, but rather, as described next, for the suggest significant progress in refining treatment treatment of cooccurring psychiatric conditions for this subgroup of persons with alcohol such as depression. dependence who are at increased risk for illness and death because of their dual disorders. Medications for Patients With Both Alcoholism and Depression Recent studies of imipramine (McGrath et al. 1996) and fluoxetine (Cornelius et al. 1997) People with alcohol dependence often experience confirm previous work showing that depressed symptoms of depression when they stop drinking. people with alcoholism who are given anti- For most individuals, these symptoms disappear experience greater decreases in or wane during the first 1 or 2 weeks of absti- depression and alcohol consumption than do nence. However, studies have shown that patients those given a placebo (Kranzler et al. 1995; who continue to report serious depressed feelings Mason and Kocsis 1991; Mason et al. 1996; after the 1st week of abstinence are likely to have Nunes et al. 1993). Some participants in these a depressive disorder that coexists with their antidepressant trials continued to drink even alcohol dependence. These patients are often though their depression lifted, which demon- referred to as having “comorbid depression” strates the need for additional interventions or a “dual diagnosis.” If the depression is left specific to drinking. untreated, many will relapse to drinking. Thus, accurate diagnosis of depression and its swift In making decisions about diagnosis and treatment are critical in the care of alcohol- treatment of alcohol-dependent patients, some dependent patients. clinicians distinguish between primary depression, which occurs before the onset of alcoholism, and Investigators have examined different types of secondary depression, which occurs afterwards. antidepressant agents for dually diagnosed

457 Chapter 8: Treatment Research

Studies of both types of depressed patients with these are trials designed to explore whether alcoholism have shown essentially the same combining acamprosate and naltrexone, two findings: antidepressant medications improve highly tolerable and effective drugs, can enhance mood and reduce drinking whether the patients’ treatment outcomes when they are provided along depression is primary (McGrath et al. 1996; with behavioral therapies; to test the safety and Nunes et al. 1993) or secondary (Mason et al. efficacy of different dosages of acamprosate; and 1996). to study sertraline as a representative of the safe and tolerable SSRI’s for treating depression that Finding the optimal dosage of antidepressants for coexists with alcoholism. dually diagnosed patients has also been an area of investigation, because ineffective treatment of Studies will also be needed to identify the most depression may lead to relapse during the early appropriate medications for different subgroups. stages of abstinence. Many patients with a long- Current research has confirmed that alcohol is term history of alcoholism have liver dysfunction, metabolized differently by women (see review by which may alter their of certain Romach and Sellers 1998) and by older adults medications so that they require higher or (see review by Ownby et al. 1996) than it is by lower dosages. A 6-month study examining the younger men, who have constituted the majority metabolism of antidepressants by patients with of subjects in studies of the pharmacotherapy of and without current alcoholism found that alcoholism. Future research will need to examine alcoholic patients without may benefit data from women, older adults, and other sub- from higher dosages of antidepressants, because groups to determine the medications that are changes in their liver functioning during early most effective and acceptable, with the fewest abstinence speed up their metabolism of these adverse side effects, for different groups of drugs (Mason 1996). patients.

In Closing References

Alcohol’s precise effects on the reward centers al Qatari, M., and Littleton, J. The anticraving of the brain are still not fully understood, but drug acamprosate inhibits channel laboratory studies and clinical trials continue antagonist binding to membranes from the to increase our knowledge of new medications rat cerebral cortex [Abstract]. Alcohol Alcohol to augment behavioral therapies for alcohol 30(4):S12, 1995. dependence. In recent years, these studies have shown that: (1) naltrexone and a similar Benjamin, D.; Grant, E.R.; and Pohorecky, L.A. compound, nalmefene, help reduce the chance Naltrexone reverses -induced dopamine of heavy drinking when abstinent individuals release in the in awake, freely relapse; (2) acamprosate can prevent relapse moving rats. Brain Res 621(1):137–140, 1993. by making it easier to maintain abstinence; (3) SSRI’s are not useful in treating alcohol Campbell, A.D., and McBride, W.J. Serotonin-3 dependence itself; and (4) not only SSRI’s, receptor and ethanol-stimulated dopamine release but also other antidepressants, are successful in the nucleus accumbens. Pharmacol Biochem in treating coexisting depression that may lead Behav 51(4):835–842, 1995. patients with alcohol dependence to relapse if the depression is left untreated. Charness, M.E.; Gordon, A.S.; and Diamond, I. Ethanol modulation of opiate receptors in Currently, clinical trials are under way to search cultured neural cells. Science 222(4629): for new and more effective pharmaceutical agents 1246–1248, 1983. to treat alcohol-dependent individuals. Among

458 Treatment of Alcohol Dependence With Medications

Cornelius, J.R.; Salloum, I.M.; Ehler, J.G.; alcoholics: Results of a randomized, placebo- Jarrett, P.J.; Cornelius, M.D.; Perel, J.M.; Thase, controlled, double-blind study in out-patient M.E.; and Black, A. Fluoxetine in depressed alcoholics in the Netherlands, Belgium and alcoholics: A double-blind, placebo-controlled Luxembourg. Eur Addict Res 3(3):129–137, 1997. trial. Arch Gen Psychiatry 54(8):700–705, 1997. Huang, W.; Moody, D.E.; Foltz, R.L.; and Walsh, Croop, R.S.; Labriola, D.F.; Wroblewski, J.M.; S.L. Determination of naltrexone and 6-beta- and Nibbelink, D.W. An open label usage study naltrexol in plasma by solid-phase extraction and of naltrexone as adjunctive pharmacotherapy for chromatography–negative ion chemical individuals with alcoholism [Abstract]. Alcohol ionization–mass spectrometry. J Anal Toxicol Clin Exp Res Suppl 19(2):16A, 1995. 21(4):252–257, 1997.

Culpepper-Morgan, J.A.; Holt, P.R.; LaRoche, Jaffe, A.J.; Rounsaville, B.; Chang, G.; D.; and Kreek, M.J. Orally administered opioid Schottenfeld, R.S.; Meyer, R.E.; and O’Malley, antagonists reverse both mu and kappa opioid S.S. Naltrexone, relapse prevention, and delay of gastrointestinal transit in supportive therapy with alcoholics: An analysis the guinea pig. Life Sci 56(14):1187–1992, of patient treatment matching. J Consult Clin 1995. Psychol 64(5):1044–1053, 1996.

Davidson, A.F.; Emm, T.A.; and Pieniaszek, H.J., Johnson, B.A.; Jasinski, D.R.; Galloway, G.P.; Jr. Determination of naltrexone and its major Kranzler, H.; Weinreib, R.; Anton, R.F.; Mason, metabolite, 6-beta-naltrexol, in human plasma B.J.; Bohn, M.J.; Pettinati, H.M.; Rawson, R.; using liquid chromatography with electrochemical and Clyde, C. Ritanserin in the treatment of detection. J Pharm Biomed Anal 14(12): alcohol dependence—A multi-center clinical trial. 1717–1725, 1996a. Ritanserin Study Group. 128(2):206–215, 1996. Davidson, D.; Swift, R.; and Fritz, E. Naltrexone increases the latency to drink alcohol in social Kabel, D.I., and Petty, F. A placebo-controlled, drinkers. Alcohol Clin Exp Res 20(4):732–739, double-blind study of fluoxetine in severe alcohol 1996b. dependence: Adjunctive pharmacotherapy during and after inpatient treatment. Alcohol Clin Exp Durbin, P.; Hulot, T.; and Chabac, S. Pharma- Res 20(4):780–784, 1996. codynamics and of acampro- sate: An overview. In: Soyka, M., ed. Acamprosate Kranzler, H.R.; Burleson, J.A.; Korner, P.; Del in Relapse Prevention of Alcoholism. Berlin, Boca, F.K.; Bohn, M.J.; Brown, J.; and Liebowitz, Germany: Springer-Verlag, 1996. pp. 47– 64. N. Placebo controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Emmerson, P.J.; Liu, M.; Woods, J.H.; and Psychiatry 152(3):391–397, 1995. Medzihradsky, F. Binding affinity and selectivity of opioids at mu, delta, and kappa receptors in Ladewig, D.; Knecht, T.; Lehert, P.; and Fendl, A. monkey brain membranes. J Pharmacol Exp Ther Acamprosate—A stabilizing factor in the long- 271(3):1630–1637, 1994. term treatment of alcoholics. Ther Umsch 50(3):182–188, 1993. Fuller, R.W. Mechanisms and functions of serotonin neuronal systems: Opportunities for Lhuintre, J.P.; Moore, N.D.; Tran, G.; Steru, L.; neuropeptide . Ann NY Acad Sci Lancrenon, S.; Daoust, M.; Parot, P.; Ladure, P.; 780:176–184, 1996. Libert, C.; Boismare, F.; and Hillemand, B. Acamprosate appears to decrease alcohol intake in Geerlings, P.J.; Ansoms, C.; and van den Brink, weaned alcoholics. Alcohol Alcohol 25(6):613–622, W. Acamprosate and prevention of relapse in 1990.

459 Chapter 8: Treatment Research

Litten, R.Z.; Allen, J.; and Fertig, J. Pharma- controlled clinical trial. Arch Gen Psychiatry cotherapies for alcohol problems: A review of 53(3):232–240, 1996. research with focus on developments since 1991. Alcohol Clin Exp Res 20(5):859–876, 1996. Meyer, R.E. Prospects for a rational pharmaco- therapy of alcoholism. J Clin Psychiatry 50(11): Mann, K.; Chabac, S.; Lehert, P.; Potgieter, A.; 403–412, 1989. and Sass, H. “Acamprosate improves treatment outcome in alcoholics: A pooled analysis of 11 Michel, M.E.; Bolger, G.; and Weissman, B.A. randomized placebo controlled trials in 3,338 Binding of a new opiate antagonist, nalmefene, to patients.” Paper presented at the 34th Annual rat brain membranes. Methods Find Exp Clin Meeting of the American College of Neuropsycho- Pharmacol 7(4):175–177, 1985. pharmacology, San Juan, PR, 1995. Nunes, E.V.; McGrath, P.J.; Quitkin, F.M.; Mason, B.J. Dosing issues in the pharmaco- Stewart, J.P.; Harrison, W.; Tricamo, E.; and therapy of alcoholism. Alcohol Clin Exp Res Suppl Ocepek-Welikson, K. Imipramine treatment of 20(7):10A–16A, 1996. alcoholism with comorbid depression. Am J Psychiatry 150(6):963–965, 1993. Mason, B.J., and Goodman, A.M. and Medication Compliance O’Malley, S.S.; Croop, R.S.; Wroblewski, J.M.; Procedures: Therapist’s Manual. New York, NY: Labriola, D.F.; and Volpicelli, J.R. Naltrexone in Lipha Pharmaceuticals, Inc., 1997. the treatment of alcohol dependence: A combined analysis of two trials. Psychiatr Ann Mason, B.J., and Kocsis, J.H. Desipramine 25(11):681–688, 1995. treatment of alcoholism. Psychopharmacol Bull 27(2):155–161, 1991. O’Malley, S.S.; Jaffe, A.J.; Chang, G.; Rose, S.; Schottenfeld, R.; Meyer, R.E.; and Rounsaville, B. Mason, B.J.; Kocsis, J.H.; Ritvo, E.C.; and Six-month follow-up of naltrexone and Cutler, R.B. A double-blind, placebo-controlled for alcohol dependence. Arch Gen trial of desipramine for Psychiatry 53(3):217–224, 1996. dependence stratified on the presence or absence of major depression. JAMA 275(10):761–767, O’Malley, S.S.; Jaffe, A.J.; Chang, G.; 1996. Schottenfeld, R.S.; Meyer, R.E.; and Rounsaville, B. Naltrexone and coping skills therapy for Mason, B.J.; Ritvo, E.C.; Morgan, R.O.; Salvato, alcohol dependence: A controlled study. Arch Gen F.R.; Goldberg, G.; Welch, B.; and Mantero- Psychiatry 49(11):881–887, 1992. Atienza, E. A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of Ownby, R.L.; Mason, B.J.; and Eisdorfer, C. oral nalmefene HCl for alcohol dependence. Alcohol abuse among older adults and the elderly. Alcohol Clin Exp Res 18(5):1162–1167, 1994. J Pract Psychiatry Behav 2(4):216–222, 1996. Mason, B.J.; Salvato, F.R.; Williams, L.D.; Ritvo, E.C.; and Cutler, R.B. A double-blind, placebo- Paille, F.M.; Guelfi, J.D.; Perkins, A.C.; Royer, controlled study of oral nalmefene for alcohol R.J.; Steru, L.; and Parot, P. Double-blind dependence. Arch Gen Psychiatry 56(8):719–724, randomized multicentre trial of acamprosate in 1999. maintaining abstinence from alcohol. Alcohol Alcohol 30(2):239–247, 1995. McGrath, P.J.; Nunes, E.V.; Stewart, J.W.; Goldman, D.; Agosti, V.; Ocepek-Welikson, K.; Pelc, I.; Verbanck, P.; LeBon, O.; Gavrilovic, M.; and Quitkin, F.M. Imipramine treatment of Lion, K.; and Lehert P. Efficacy and safety of alcoholics with primary depression: A placebo- acamprosate in the treatment of detoxified

460 Treatment of Alcohol Dependence With Medications alcohol-dependent patients. A 90-day placebo- Volpicelli, J.R.; Alterman, A.I.; Hayashida, M.; controlled dose-finding study. Br J Psychiatry and O’Brien, C.P. Naltrexone in the treatment of 171:73–77, 1997. alcohol dependence. Arch Gen Psychiatry 49(11): 876–880, 1992. Romach, M.K., and Sellers, E.M. Alcohol dependence: Women, biology and pharmaco- Volpicelli, J.R.; Clay, K.L.; Watson, N.T.; and therapy. In: McCance-Katz, E.F., and Kosten, O’Brien, C.P. Naltrexone in the treatment of T.R., eds. New Treatments for Chemical . alcoholism: Predicting response to naltrexone. Washington, DC: American Psychiatric Press, J Clin Psychiatry 56(supp. 7):39–44, 1995a. 1998. pp. 35–73. Volpicelli, J.R.; Rhines, K.C.; Rhines, J.S.; Sass, H.; Soyka, M.; Mann, K.; and Zieglgäns- Volpicelli, L.A.; Alterman, A.I.; and O’Brien, P.O. berger, W. Relapse prevention by acamprosate: Naltrexone and alcohol dependence. Role of Results from a placebo-controlled study on subject compliance. Arch Gen Psychiatry alcohol dependence. Arch Gen Psychiatry 54(8):737–742, 1997. 53(8):673–680, 1996. Volpicelli, J.R.; Watson, N.T.; King, A.C.; Sawynok, J.; Pinsky, C.; and LaBella, F.S. On the Sherman, C.E.; and O’Brien, C.P. Effect of specificity of as an opiate antagonist. naltrexone on alcohol “high” in alcoholics. Life Sci 25:1621–1632, 1975. Am J Psychiatry 152(4):613–615, 1995b.

Schottenfeld, R.S.; O’Malley, S.S.; Smith, L.; Whitworth, A.B.; Fischer, F.; Lesch, O.M.; Rounsaville, B.J.; and Jaffe, J.H. Limitation and Nimmerrichter, A.; Oberbauer, H.; Platz, T.; potential of MAOI’s for the treatment of Potgieter, A.; Walter, H.; and Fleischhacker, W.W. depressive symptoms in abstinent alcoholics. Am Comparison of acamprosate and placebo in long- J Drug Alcohol Abuse 15(3):339–344, 1989. term treatment of alcohol dependence. Lancet 347(9013):1438–1442, 1996. Soyka, M. Clinical efficacy of acamprosate in the treatment of alcoholism. In: Soyka, M., ed. Wilde, M.I., and Wagstaff, A.J. Acamprosate: A Acamprosate in Relapse Prevention of Alcoholism. review of its pharmacology and clinical potential Berlin, Germany: Springer-Verlag, 1996. pp. 155– in the management of alcohol dependence after 171. detoxification. Drugs 53(6):1038–1053, 1997.

Swift, R.M. Effect of naltrexone on human Yoshimoto, K.; McBride, W.J.; Lumeng, L.; alcohol consumption. J Clin Psychiatry 56 and Li, T.K. Alcohol stimulates the release of (supp. 7):24–29, 1995. dopamine and serotonin in the nucleus accumbens. Alcohol 9(1):17–22, 1991. Swift, R.M.; Whelihan, W.; Kuznetsov, O.; Buongiorno, G.; and Hsuing, H. Naltrexone- Zhou, F.C.; McKinzie, D.L.; Patel, T.D.; induced alterations in human ethanol intoxi- Lumeng, L.; and Li, T.K. Additive reduction of cation. Am J Psychiatry 151(10):1463–1467, alcohol drinking by 5-HT1A antagonist WAY 1994. 100635 and serotonin uptake blocker fluoxetine in alcohol-preferring P rats. Alcohol Clin Exp Res Tabakoff, B., and Hoffman, P.L. Alcohol 22(1):266–269, 1998. interactions with brain opiate receptors. Life Sci 32(3):197–204, 1983.

461