This chapter describes the two clinical trials that initially established the use of naltrexone as an effective adjunct to psychosocial therapy in the treatment of alcohol dependence. In addition, the chapter summarizes several newer trials of naltrexone in different clinical populations, briefly reviews other recent advances in pharmacotherapies for alcohol dependence, highlights some of the clinical variables associated with successful demonstrations of naltrexone's efficacy, and suggests directions for future research. A summary of the most relevant clinical findings with respect to naltrexone treatment concludes the chapter.
The efficacy of naltrexone treatment for alcohol dependence was initially demonstrated by two back-to-back studies conducted first at the Philadelphia Veterans Affairs (VA) Medical Center (Volpicelli et al., 1992) and subsequently at Yale University School of Medicine (O'Malley et al., 1992). Both research projects were 12-week, double-blind, placebo-controlled clinical trials that administered either 50 mg/day of naltrexone hydrochloride or identical-appearing placebo tablets with standardized psychosocial therapy or rehabilitation counseling in small outpatient samples. In the VA study, patients also participated in day hospital treatment for 1 month followed by twice weekly group therapy. The subjects in the Yale study received either supportive therapy or cognitive behavioral coping skills treatment once a week. The subjects were recently detoxified or abstinent for 1 week and met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders (3rd edition, revised [DSM-III-R]; American Psychiatric Association, 1987). The study populations in both trials had no significant psychiatric illness or drug abuse problem other than alcohol.
The separate findings from both of these initial clinical trials were encouraging because they demonstrated the benefits of naltrexone as an adjunct to psychosocial therapy for the treatment of alcohol dependence (O'Malley et al., 1995). In fact, the findings were instrumental in the approval given by the Food and Drug Administration (FDA) in December 1994 to use naltrexone for this purpose--the first new medication approved by the FDA for treatment of alcohol dependence in nearly 50 years.
The subjects who took naltrexone in the VA Medical Center study (Volpicelli et al., 1992) had significantly more favorable outcomes than those randomized to placebo in terms of decreasing the mean number of drinking days, relapsing to clinically significant drinking, and experiencing less craving for alcohol (see Figure 4-1). Many of the subjects in both groups were nonabstinent during the study (57 percent of the placebo cohort and 46 percent of the naltrexone group). However, naltrexone-treated subjects drank on an average of 1.6 percent of study days compared with 8.3 percent of study days for the placebo group. Only 23 percent of the naltrexone-treated subjects met criteria for relapse to heavy drinking (five or more drinks on an occasion, drinking on 5 or more days in a week, or coming to a study appointment with a blood alcohol concentration level above 100 mg/dl), whereas 54 percent of the placebo-treated subjects relapsed.
The most impressive effect of naltrexone, however, was seen in patients who did imbibe: Only 8 of 16 naltrexone-treated subjects (50 percent) went on to a full-scale relapse after sampling alcohol compared with 19 of 20 placebo-treated subjects (95 percent). Mean alcohol craving scores, which declined gradually over the course of the study in both groups, were significantly lower at termination for the naltrexone group compared with the placebo group in a covariate analysis taking baseline craving into account. Craving in this study was assessed by simply asking the subjects to rate their craving from 0 to 9, where 0 was equivalent to no craving and 9 was craving so severe that the subject was unable to resist a drink.
The results of the Yale study confirmed and extended those from the first trial by Volpicelli and colleagues in finding naltrexone superior to placebo on measures of abstention, relapse, numbers of drinking days, amounts of alcohol consumed, and severity of alcohol-related and employment problems (O'Malley et al., 1992). Subjects who took naltrexone reported drinking on half as many study days (4.3 percent) as placebo-treated subjects (9.9 percent). Moreover, the naltrexone-treated subjects, who averaged 13.7 drinks during the trial, consumed only one-third as many standard drinks as the placebo-treated controls, who averaged 38 drinks. This difference was even greater between the naltrexone-treated subjects who completed the study--who averaged 12 drinks during the 12-week study--and those placebo-using subjects who remained in the study but averaged 44 drinks over the 3-month period.
To further explore the links between the two independent clinical trials that had slightly different subject populations and rehabilitation approaches, a combined analysis of the data from both studies was performed (O'Malley et al., 1995). The results for a total of 186 subjects in the combined samples (93 naltrexone- and 93 placebo-treated) validated the original findings. The naltrexone-treated group had higher rates of abstinence and significantly fewer relapses to heavy drinking than did the placebo cohort, particularly among the subset of subjects who did resort to alcohol consumption during the 3-month trials. Placebo-treated subjects were nearly twice as likely (1.87 times) as those receiving naltrexone to "slip" and, if they began to drink, they were also twice as likely (1.92 times) as those not on active medication to have an episode of heavy drinking. The naltrexone-treated group also drank on fewer days throughout the studies than did subjects who received placebo.
O'Malley and colleagues followed up 80 of the original 97 patients from the Yale trial 6 months after discontinuation of treatment to determine whether naltrexone in combination with either supportive or coping skills therapy improved long-term outcomes (O'Malley et al., 1996a). At followup, subjects in the naltrexone-treated group had lower overall relapse rates and were less likely to meet diagnostic criteria for alcohol abuse or dependence, as measured by the alcohol section of the Structured Clinical Interview for DSM-III-R (SCID), than were the subjects who had received placebo. However, the positive effect of naltrexone on abstinence rates only persisted for the first month following termination of medication, and its impact on relapse prevention declined over time. Moreover, by the end of the sixth month, the subjects who had received placebo/coping skills therapy had improved rates of drinking and relapse that were similar to those of both naltrexone-treated groups. The investigators speculated that the effects of coping skills/relapse prevention training, even without medication, take time to emerge but contribute to positive long-term outcomes by providing specific tools and reinforcing a reliance on personal resources after treatment cessation. They also noted that abstinence during treatment was a strong predictor of sustained improvement.
Further explorations of the data from the two original clinical trials (O'Malley et al., 1992; Volpicelli et al., 1992) have attempted to specify the characteristics of subjects most responsive to naltrexone and the baseline variables that predict continued alcohol consumption despite psychosocial treatments. One purpose of such analyses has been to assist in the matching of patients to the most appropriate treatments. These studies (Volpicelli et al., 1995a; Jaffe et al., 1996) suggest that patients with high levels of alcohol craving or poor cognitive abilities tend to benefit greatly from naltrexone therapy.
Since the results of the original trials of naltrexone were published in 1992, several new studies have been completed and preliminary results published or presented. Two of these investigations highlight the importance of medication compliance to the efficacy of naltrexone (Volpicelli et al., 1997; Croop and Chick, 1996). Volpicelli and colleagues conducted a 12-week study of 97 alcohol-dependent and recently detoxified patients at the University of Pennsylvania/VA Treatment Research Center who were randomized to placebo or naltrexone along with individual therapy. Therapy focused on relapse prevention and occurred twice a week for the first month, tapering to weekly sessions in the second and third months (Volpicelli et al., 1997). Although most of the procedures were the same as those in the original VA Medical Center study of male veterans (Volpicelli et al., 1992), the patient population in this study was more heterogeneous, with a broader mix of ethnicities, more women (approximately 25 percent), and more married participants. The psychosocial treatment also was less intensive. Unlike the findings from the original clinical trials, however, naltrexone was not impressively superior to placebo in preventing relapse to heavy drinking. Although only one-third of the total naltrexone-treated group (35.4 percent) relapsed during the study compared with more than half of the total placebo sample (53 percent), these differences were not statistically different.
The results of the 1997 study did more clearly favor naltrexone over placebo among subjects who cooperated fully with the study protocol, missing no more than two research sessions (Volpicelli et al., 1997). Only one-fourth (25.7 percent) of the 35 naltrexone-treated subjects who completed the study experienced a relapse compared with more than half (52.8 percent) of their counterpart treatment completers in the placebo group. Naltrexone-treated patients who completed treatment also reported less than half the number of drinking days (5.4 percent) than did those who received placebo (12.7 percent) and were more likely to remain continuously abstinent (64 percent vs. 35 percent). The investigators concluded that the benefits of naltrexone in reducing relapse to heavy drinking rely heavily on subjects' attendance and medication compliance. Consistent with this conclusion, the preliminary results of a double-blind placebo-controlled study of naltrexone conducted in the United Kingdom also found that naltrexone was superior to placebo only in the subset of patients who completed the 12-week trial and took 80 percent of their study medication (Croop and Chick, 1996). Thus, if the beneficial effects of this medication are to be fully realized, outpatient programs will need to incorporate naltrexone into a structured psychosocial treatment approach that facilitates both types of compliance.
Anton (1997) recently reported findings that more consistently favored naltrexone over placebo. The preliminary results of this study of 131 mild-to-moderately severe outpatient alcoholics who were relatively treatment-naïve indicated that naltrexone when combined with cognitive behavioral therapy (CBT) increased the nonrelapse rate from 40 percent in the placebo-treated group to 62 percent. In addition the percentage of days drinking and drinks per drinking day were also significantly decreased by naltrexone. Interestingly, the time between the first relapse drinking day (defined as five or more drinks per day for men and four or more drinks per day for women) and the second relapse drinking day was almost double for those treated with naltrexone and CBT compared with those receiving CBT alone. Naltrexone also allowed subjects to experience greater control and resistance over their thoughts about drinking and their urge to drink. Side effects of nausea, abdominal discomfort, daytime sedation, and nasal congestion were all experienced more frequently by the naltrexone-treated patients compared with placebo-treated patients.
Naltrexone was well tolerated by most patients: No one terminated due to adverse effects, and liver function normalized in a similar fashion in both the naltrexone- and placebo-treated groups. The results of this study, in which the patients had high treatment completion (83 percent) and medication compliance (70 percent), support the initial findings of the two 1992 studies (O'Malley et al., 1992; Volpicelli et al., 1992). It indicates that naltrexone can augment a highly useful psychosocial intervention in the outpatient treatment of alcoholism.
The average age of subjects participating in most studies of naltrexone is in the early forties. However, the population of older adults in the United States is increasing rapidly, and although little is known about the use of naltrexone with this population, many older alcohol-dependent individuals may be potential candidates for this medication. To address the efficacy of naltrexone in older alcoholics, Oslin and colleagues (Oslin et al., 1997) conducted a 12-week double-blind placebo-controlled study of male veterans, 50 to 70 years of age. Nursing staff administered the naltrexone to ensure compliance, giving subjects 100 mg each on Monday and Wednesday and 150 mg on Friday, using procedures similar to those used for opiate addicts taking naltrexone. Naltrexone was well tolerated by subjects, and they completed nearly 10 of the 12 weeks on average. Because of the small sample size, the differences between the groups could not be considered statistically significant, though there were observable trends. Specifically, 14.3 percent of those in the naltrexone-treated group relapsed, compared with 34.8 percent of those in the placebo-treated group (p = .117). However, among those who sampled alcohol, only three of the six subjects in the naltrexone-treated group subsequently relapsed, compared with all eight subjects who drank in the placebo group. Although the sample does not represent the oldest of the old, the study suggests that naltrexone is a viable treatment option for older adults.
Several studies have recently been completed, and more have been funded to investigate the efficacy of this approach with a variety of other patient populations, using different dosing levels and schedules, therapy combinations, treatment intensities, and time in care.
Concurrent cocaine abuse by alcohol-dependent persons is a more common problem than any other drug-alcohol combination, according to recent Epidemiologic Catchment Area (ECA) data (Regier et al., 1990). Drug-abusing alcoholic patients also have poorer treatment prognoses than individuals who only drink to excess. In an attempt to ascertain effective treatments for this comorbidity, Carroll and colleagues randomly assigned 18 outpatients meeting DSM-III-R criteria for cocaine and alcohol dependence but no other psychological disorder to either disulfiram (250 mg/day) or naltrexone (50 mg/day) together with weekly psychotherapy sessions over 12 weeks (Carroll et al., 1993). Although the investigators hypothesized that naltrexone would be associated with reductions in alcohol use comparable to those of disulfiram and also have a positive impact on cocaine use, disulfiram was found to be significantly more effective than naltrexone in reducing the frequency and quantity of alcohol use during treatment. Parallel but lesser reductions in cocaine use were also found among the subjects receiving disulfiram compared with those treated with naltrexone. Although the sample size was small and attrition was high in both groups (only four of nine subjects in the disulfiram group and two of nine in the naltrexone group completed all 12 weeks of treatment), the findings from this pilot study are disappointing with respect to naltrexone's lack of apparent efficacy as an adjunctive pharmacotherapy for patients with comorbid alcohol and cocaine problems.
A larger study of 109 alcoholics of whom approximately two-thirds had concomitant cocaine or opioid dependence found that over the course of a 6-month medication period, naltrexone was not significantly better than placebo in reducing alcohol consumption and relapse drinking (McCaul, 1996). However, early in the medication period (first and second months), individuals treated with naltrexone 100 mg did significantly better than the individuals treated with either naltrexone 50 mg or placebo. Furthermore, there was evidence that patients who had high blood levels of naltrexone's active major metabolite did significantly better than patients with low blood levels. A recent open-label study of naltrexone (150 mg/day) in alcohol- and cocaine-dependent adults did show dramatic reductions in both alcohol and cocaine use (Oslin et al., 1997). Thus, higher doses of naltrexone may be beneficial in this select population. Additional trials at this higher dose are currently being conducted.
A 1994 study randomized 14 heavy drinkers who met DSM-III-R criteria for alcohol abuse or mild dependence (having no more than three of the nine dependence criteria) to 6 weeks of brief counseling (a 30-minute session in week 1, followed by 10-minute "booster" sessions in weeks 2, 3, 4, and 6) and either 25 mg/day or 50 mg/day of naltrexone (Bohn et al., 1994). Assessments were conducted during treatment, at termination, and after a 1-month followup period. Total alcohol consumption decreased in both dosage groups during the treatment period (63 percent from baseline) and over the entire course of monitoring (48 percent). The intensity of drinking, frequency of heavy drinking (a minimum of six drinks a day), craving for alcohol, and indicator values of liver function tests also declined for both groups during treatment; and subjects maintained these improvements for the 1-month posttreatment period.
Researchers also have investigated the potential utility of naltrexone on a targeted or "as needed" basis in an open-label study of 21 individuals who had a diagnosis of alcohol abuse or mild alcohol dependence and who drank more than 14 drinks per week for women and more than 20 drinks per week for men (Kranzler et al., 1997). Subjects were provided with four sessions of skills training and five naltrexone tablets each week. They were instructed to take at least two per week and to use the others as needed. During the treatment period, significant improvements were observed on a range of drinking-related outcomes. These measures included frequency of drinking, amount consumed per drinking day, number of drinking days, gamma-glutamyl transpeptidase (GGTP) levels, alcohol problem severity, and craving. Over the course of the 3-month posttreatment followup, significant improvements were still apparent for several measures, including frequency of drinking, GGTP levels, drinks per drinking day, and the number of heavy drinking days.
Although the sample size in these two studies was small and there was no placebo control group, the results suggest that it is feasible to use naltrexone in heavy drinkers and those with milder alcohol-related problems who may present in primary care settings. Placebo-controlled double-blind studies are currently under way to follow up on these promising findings. Preliminary analyses of a study in which open-label naltrexone was provided in conjunction with a primary care model of counseling to alcohol-dependent subjects also indicated that patients were generally satisfied with this model of care and improved significantly on a range of clinical outcomes (O'Connor et al., 1997).
Given that alcoholism is often associated with other psychiatric disorders, investigators are beginning to describe the use of naltrexone to augment the treatment response of the subset of alcohol-dependent patients with comorbid psychiatric diagnoses. Researchers reported that 82 percent of a sample of 72 dually diagnosed patients had at least a 75 percent reduction in drinking when treated clinically with 50 mg of naltrexone (Maxwell and Shinderman, 1997 [see Case Study 1 in Appendix C]). A recent small open-label study examined the effect of naltrexone on alcohol use and depressive symptoms among 14 depressed alcoholics who were continuing to drink despite selective serotonin reuptake inhibitor (SSRI) therapy for depression (Salloum et al., 1998). Encouragingly, the introduction of naltrexone to their therapeutic regime was associated with significant reductions in craving and drinking and mild improvement in depressive symptoms. The combination of naltrexone and antidepressant therapy also appears to be safe based on the results of the large-scale multisite trial in which nearly one-third of the patients were receiving concurrent antidepressant therapy (almost all were taking SSRIs) (Croop et al., 1995, 1997). Larger controlled studies are needed to conclusively evaluate the potential effectiveness of naltrexone in dually diagnosed patients.
Additional analyses of data obtained from the initial clinical trials of naltrexone examined the subjective effects experienced while drinking alcohol among subjects who did not remain abstinent throughout the studies (Volpicelli et al., 1995b). Of the 70 subjects in the original VA study, 36 met this criterion (Volpicelli et al., 1992). A larger proportion of these naltrexone-treated subjects (7 of 12) than placebo-treated subjects (2 of 17) reported that the "high" produced by drinking alcohol was significantly less than usual. The naltrexone-treated patients also drank less alcohol than the placebo-treated subjects during the first drinking episode--with only 17 percent of the naltrexone group meeting relapse criteria during the initial slip compared with 65 percent of the placebo group. There was no difference between groups in reported intoxication, loss of physical coordination, levels of alcohol craving, memory disturbance, or loss of temper.
Volpicelli and colleagues speculated that these results reflect the blockade effects of naltrexone on opioid receptor activity with consequent loss of reinforcing pleasurable stimulation, although an alternative explanation might be the lower levels of alcohol consumed by the naltrexone-treated subjects during their slips (Volpicelli et al., 1995b).
A similar reexamination of data from the original Yale study (O'Malley et al., 1992) revealed differences between subjects in the naltrexone- and placebo-treated groups with respect to their retrospective recollections of subjective reactions to alcohol effects and reasons for terminating an initial drinking episode (O'Malley et al., 1996b). Although the mean number of drinks consumed during the initial drinking episode did not differ greatly, the proportion of subjects who met relapse criteria was significantly lower for naltrexone-treated subjects (50 percent) than for placebo-treated subjects (81 percent). The 16 patients on naltrexone who did sample alcohol reported lower levels of intoxication and lower levels of craving before, during, and after their drinking episode than did their placebo-treated counterparts. Furthermore, the two groups offered different reasons for stopping drinking: The naltrexone-treated subjects were more likely to report reduced incentives for drinking (e.g., lower craving), whereas the placebo-treated subjects emphasized various adverse consequences of drinking as reasons for their stopping. The groups did not differ significantly in their ratings of the pleasure associated with the experience. The investigators concluded that the findings are consistent with naltrexone's hypothesized effects on modifying alcohol craving and the urge to drink among alcohol-dependent persons.
Several other laboratory studies have investigated naltrexone's effects on subjective responses to drinking. Swift and colleagues used a double-blind, cross-over design to determine whether pretreatment with 50 mg of naltrexone affected a subsequent intoxicating dose of alcohol given to 19 nonalcoholic subjects (Swift et al., 1994). The results indicate that subjects reported feeling more sedated and less stimulated during the experiment on the day that they received naltrexone compared with the day that they received placebo naltrexone. Naltrexone pretreatment did not alter psychomotor performance or ethanol pharmacokinetics. Subjects pretreated with naltrexone also had more episodes of nausea and vomiting after the intoxicating dose of alcohol was administered, suggesting that these aversive effects may also decrease the desire to drink again. Given that nausea was not assessed prior to alcohol ingestion, however, the results do not clearly demonstrate whether the nausea was an adverse effect of naltrexone alone or the result of an interaction between naltrexone and alcohol. In fact, some dysphoria has been reported by detoxified opiate addicts treated with naltrexone (Gonzalez and Brogden, 1988). In direct contrast to the findings by Swift and colleagues, a subsequent study found that pretreatment with naltrexone did not significantly alter subjective responses to alcohol among light social drinkers (Doty and deWit, 1995).
A more recent study of the effects of naltrexone on drinking behavior found that naltrexone increased the time to the first sip for the first and the second drink in social drinkers who were observed in a bar setting over the course of 3 hours (Davidson et al., 1996). In addition, blood alcohol levels were lower on the day that subjects received naltrexone compared with the day that they received placebo naltrexone, confirming observed differences in drinking behavior.
King and colleagues noted that the euphoric effects reported by clinical samples of alcoholics after drinking may not be the same as those experienced by ordinary social drinkers (King et al., 1997). Pursuing previously observed differences in physiological responses to alcohol between subjects who are genetically at high or low risk for the development of alcoholism (Gianoulakis et al., 1990), these researchers examined the effect of naltrexone in these two groups on self-reported stimulation and sedation from alcohol as well as general mood states during rising and falling phases of intoxication as measured by breath alcohol levels (BALs). This comparison of 15 high-risk males with alcoholic fathers and 14 low-risk subjects--with no alcoholic relatives in two generations--confirmed the hypothesis that pretreatment with naltrexone would decrease the subjective stimulation (euphoria) experienced during the rising BAL phase immediately after alcohol consumption in the high-risk social drinkers compared with low-risk counterparts. The finding supports other research reports in humans and animals that opioid receptor antagonists decrease the reinforcing effect of drinking, especially among those who are at genetic risk for developing alcohol dependence. High-risk subjects in this study were also more likely than low-risk participants to correctly distinguish the naltrexone- from the placebo-influenced drinking sessions, reporting that alcohol effects achieved after receiving the placebo were more like everyday drinking. No significant naltrexone-related sedation effects during falling BALs were noted in either high- or low-risk groups, but more high-risk (four) than low-risk (one) subjects vomited during or shortly after the naltrexone session. The results of the King study suggest that such aversive effects of drinking after naltrexone pretreatment should not be overlooked, even though they were not statistically significant.
Extensive recent research has focused on identifying and testing a variety of drugs to alleviate acute withdrawal symptoms among alcohol-dependent patients, rapidly induce sobriety or prevent intoxication, reduce alcohol craving and consumption, and ameliorate concurrent psychopathology or simultaneous dependence on illicit drugs. These advances in medications development over the past 5 years, which reflect neurobiological findings underlying drinking behavior, are cogently presented in a recent review (Litten et al., 1996); some of the most relevant findings are briefly summarized here regarding medications that are currently available or likely to be available in the near future. Essentially, researchers now concur that alcohol consumption is influenced by interactions among several neurotransmitter systems (e.g., opioid, gamma-aminobutyric acid [GABA], serotonin, dopamine, glutamate) as well as hormonal systems.
In addition to studies of naltrexone, investigators are examining the efficacy--in reducing the frequency and amount of alcohol consumption as well as relapse rates--of other opioid antagonists that have a strong affinity for particular opioid receptor subtypes. Human studies with nalmefene, an antagonist with particular affinity for [delta] and [kappa] opioid receptors and less potential liver toxicity than naltrexone, have been particularly promising (Litten et al., 1996; Mason, 1996; Mason et al., 1994). Animal studies using naltrindole (a [delta] opioid receptor antagonist) and naltriben (a [delta]2 opioid receptor antagonist) are also encouraging.
Acamprosate (calcium acetylhomotaurinate) is a synthetic derivative of homotaurine, a structural analogue of GABA, which has yielded promising results in several European clinical trials with respect to decreases in drinking and increases in continuous abstinence or abstemious periods compared with placebo (for a review, see Wilde and Wagstaff, 1997). Acamprosate appears to be generally safe and has been shown to have a dose-response effect on drinking behavior. Treatment duration has varied between 3 and 12 months. A multisite clinical trial to test the efficacy and safety of acamprosate is currently being conducted in the United States.
Although the results of animal studies of SSRIs (e.g., fluoxetine [Prozac]) indicate that this type of medication reduces drinking, the effects among problem-drinking and alcohol-dependent humans have been far less impressive than those with naltrexone. The demonstrated antidepressant effects of SSRIs do, however, help in treating comorbid depression among alcoholics (Kranzler et al., 1995; Cornelius et al., 1997). In view of the sharply increasing use of SSRIs to treat a multitude of disorders, additional research is needed on the interaction between naltrexone and SSRIs in substance abuse treatment. The results of two preclinical studies suggest that agents that alter serotonin function may have some benefit in combination with naltrexone (Le and Sellers, 1994; Zink et al., 1997). Recent preliminary small-sample open-label studies tentatively suggest that the combination of antidepressant medications and naltrexone may be useful in reducing drinking in depressed (Salloum et al., 1998) and nondepressed alcohol-dependent patients (Farren and O'Malley, 1997). A larger placebo-controlled trial of the use of the SSRI sertraline to augment the efficacy of naltrexone in nondepressed alcohol-dependent patients is currently underway.
Serotonin Antagonists/Agonists
Laboratory studies and brief clinical trials of serotonin (5-HT3 and 5-HT2) antagonists have proved mostly disappointing, although animal models suggest that these antagonists suppress dopamine release in the mesocorticolimbic system and, by blocking reward systems, might decrease the desire to drink alcohol (LeMarquand et al., 1994; Pettinati, 1996). Some success has been achieved, however, by using the partial 5-HT1A agonist, buspirone, with patients diagnosed with alcohol abuse/dependence and collateral anxiety disorders (for a review, see Malec et al., 1996). When combined with cognitive behavioral therapy, this medication reduces anxiety symptoms and increases treatment retention. In addition, it appears to exert very modest effects on reducing the frequency of alcohol consumption and the risk of a return to heavy drinking in these patients (Kranzler and Meyer, 1989).
Patients with coexisting alcohol dependence and depression have been treated with the tricyclic antidepressants desipramine and imipramine with modest-to-good results in terms of improved mood and reduced risk of relapse (McGrath et al., 1996; Mason et al., 1996). Both antidepressants significantly improved depression and to a certain extent also reduced drinking behavior.
Both the literature and experience from clinical trials suggest that key areas for additional research on naltrexone treatment are
Determining optimal dosing regimens with consideration for patient acceptance, common adverse effects, efficacy, and costs
Determining the most effective initial duration of adjunctive naltrexone treatment and the conditions for extending or resuming use
Evaluating the cost-effectiveness of naltrexone treatment
Exploring the feasibility and acceptability of inpatient naltrexone induction to prevent relapse immediately after detoxification and to determine the potential for increased efficacy
Identifying "responder" subpopulations whose characteristics (e.g., severity of alcohol-related problems, comorbid psychopathology or drug dependence, cognitive impairment, familial history of alcoholism, reported craving, demographics, general health) predispose them to successful, adjunctive use of naltrexone either alone or in combination with other pharmacotherapies
Determining necessity for abstinence prior to initiating naltrexone or the feasibility of using this drug to help patients gradually reduce their drinking with the goal of abstinence
Determining the effect of naltrexone in alcohol withdrawal
Ascertaining the optimal psychosocial therapies (e.g., coping skills training, supportive therapy, cue extinction) and the intensity and duration with which they need to be applied for different patient subpopulations receiving adjunctive naltrexone
Ascertaining the drug's effects on both the mother and fetus during pregnancy, on lactation in the new mother, and on the breast-feeding infant
Researching the use of naltrexone with adolescent and elderly populations
Ascertaining the efficacy of naltrexone in other clinical populations, including alcoholics in the criminal justice system, social drinkers with health problems, and heavy drinkers
Determining the effectiveness of naltrexone in general populations of individuals with alcohol dependence
Conducting followup studies of treated populations to determine drinking-related outcomes at different intervals following termination of medication
Identifying effective strategies for enhancing compliance with medication administration, including the reduction of adverse effects, involving collaterals and other monitoring systems in assuring that medicine is taken as prescribed, and changing dosing regimens or developing depot formulations
Exploring the efficacy of other opioid receptor-specific antagonists (e.g., nalmefene)
Determining the biological mechanisms of alcohol's effects on endogenous opioids, the role of the opioidergic/dopaminergic reward system in alcoholism, and the relationships among several neurotransmitter systems that apparently influence drinking behavior
Determining the mechanisms responsible for reductions in drinking behavior over time (e.g., craving, protracted withdrawal symptoms)
Exploring combining naltrexone with other medications, such as selective serotonin reuptake inhibitors, disulfiram, and acamprosate
To date, most of the clinical studies of naltrexone as an adjunct to a broad spectrum of psychosocial therapies for alcohol-dependent or alcohol-abusing patient populations in brief-to-intensive structured treatment programs have demonstrated the superiority of this medication over placebo for reducing
The percentage of days spent drinking
The amount of alcohol consumed on a drinking occasion
Relapse to excessive and destructive drinking
Naltrexone also appears to significantly reduce the euphoric high experienced by alcohol-dependent drinkers and social drinkers who are at risk for becoming dependent because of their familial history of alcoholism. The effect of naltrexone on reducing the reinforcing properties of alcohol may help break the addictive drinking cycle in which one drink leads to another. Over the 6 months after treatment, patients who received naltrexone still have somewhat better outcomes than those given placebo with respect to overall relapse rates and drinking-related problems, although the positive effects of the medication seem to diminish after termination. However, many clients who continue to use the information and skills that they obtained and/or developed during treatment can and do stay sober. Compliance with the medication regimen and attendance at treatment sessions are both strong predictors of improved outcomes for populations treated with naltrexone.
Naltrexone's effect on decreasing alcohol craving is not as clear: The results of some studies indicate a significant reduction in this measure from baseline to termination compared with placebo, whereas others show few or inconsistent medication effects on the urge to drink, which is notoriously subjective and difficult to validate. Naltrexone, at a daily dose of 50 mg, does not appear to be efficacious in reducing alcohol and cocaine use among the sizable number of alcohol-dependent patients who simultaneously abuse cocaine. It may have, however, some efficacy among patients with other comorbid psychopathologies or at different dosage levels. A number of treatment-related issues need further exploration and resolution through additional research.
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