OUTLINE

Is there a role for medications in the treatment of Alcohol Dependence?

Vania Modesto, M.D., M.P.H.

8/23/2000

S1

I. Introduction

A. The major goal of this lecture is to review the literature on the development of medications as adjunctive agents for the treatment of alcohol dependence.

B. An optional exercise is to ask:

1. How many of you have treated detoxifying alcoholics?

    1. How many of you have prescribed a pharmacological agent to help the patient stay sober (after detoxification)?

Point out that question number one is well established, at least for cases of moderate to severe withdrawal.

For the second question, however, pharmacologic Calvinism appears to prevail—that is, the notion that the only good drug is a dead drug.

 

S2

C. There are at least three situations in which medications can be used in the treatment of alcohol dependence.1

    1. The most widely accepted circumstance is in the treatment of alcohol withdrawal.
    2. The treatment of independent psychiatric conditions that may co-occur with alcohol dependence (major depression, anxiety disorders, schizophrenia).
    3. The last and perhaps most controversial clinical situation is for the continued rehabilitation of alcohol dependence. This will be the topic of this lecture.

 

S3

II. Medications in Alcohol Dependence Rehabilitation: An Introduction

A. While detoxification is seen as a legitimate period of treatment in which medication (benzodiazepines) has an established role, there are few studies relevant to the rehabilitation phase of treatment. In fact, traditional treatment approaches have been primarily psychosocial and consist of group counseling and 12-step programs.

    1. Alcohol is a chronic disorder with high relapse rates.2
    2. Prevention of relapse to heavy drinking is a major challenge to treatment.
    3. As a result, there has been increasing interest in the use of pharmacological agents to improve the efficacy of existing treatments.

 

S4

B. Several medications are currently being used in alcohol rehabilitation.3

    1. Renewed interest led to the FDA approval of naltrexone (Trexan or Revia) in 1994 for the treatment of alcohol dependence.
    2. Disulfiram (Antabuse) sensitizing or deterrent agent, was approved for the treatment of alcoholism nearly 50 years earlier.
    3. Acamprosate (Campral) has been available by prescription since 1985 in France and more recently in European as well as Latin American Countries. A multi-center trial evaluating the safety and efficiency of acamprosate in alcohol dependent outpatients was recently completed in the United States.
    4. Nalmefene (Revex), like naltrexone, is an opiate antagonist currently approved for acute opioid intoxication. It has greater affinity for kappa and delta receptors than naltrexone, and appears to be less hepatotoxic than naltrexone.

S5

C. Neurobiology and the development of medications

    1. serotonin.4
    2. In order to understand the mechanism of actions that reduce alcohol consumption, it is important to understand the actions of alcohol on specific neurotransmitters and the neurotransmitter changes that mediate continued alcohol use and the development of dependence.5 This is explained in more detail in the lecture by Dr. Ramchandani.
    3. An example occurs with dopamine.6
      1. At low alcohol doses intoxication is characterized by pleasurable, stimulating effects. Most individuals also report reductions in anxiety and tension and a sense of well-being. These behavioral effects promote drinking and are believed to be mediated in part through brain dopaminergic systems. (Ventral tegmentun area ® nucleus accumbens)
      2. With repeated alcohol use, this system may become increasingly sensitized so that behavioral stimuli associated with alcohol use may also release dopamine and act as a primer for alcohol consumption.
      3. The dopamine system is tied to the opioid system.7
      4. Given the importance of the reinforcing effects of alcohol to initiate and maintain drinking, a medication that reduces these effects may decrease alcohol consumption.
      5. These same systems might be affected by medications that change other neurochemical systems such as serotonin and GABA.
    1. An alternative approach involves using medications that increase the aversive effects of alcohol (sedation, nausea, vomiting). This should also decrease consumption by discouraging alcohol-drinking behavior.

 

S6

III. The Possible Use of Disulfiram

A. Disulfiram is an alcohol-sensitizing agent approved in 1950. Using alcohol after taking this drug causes unpleasant effects such as nausea, diarrhea, and changes in blood pressure.

B. How does it work?2

    1. Disulfiram inhibits aldehyde dehydrogenase (ALDH), the enzyme that catalyzes the oxidation of acetaldehyde to acetic acid. If alcohol is ingested after ALDH is inhibited, blood acetaldehyde levels rise, which produce the DER (Disulfiram-ethanol-reaction).
    2. The DER is an aversive reaction that varies in intensity both with the dose of disulfiram and the volume of alcohol consumed – it is the prospect of such a reaction that is thought to deter drinking.

C. What is Disulfiram’s efficacy?

Although some small-scale studies have shown it to be superior to placebo, in the largest controlled trial, a multi-center VA study8, more than 600 alcoholics were randomly assigned to disulfiram (either 1 mg or 25 mg) or a control group. In this study, disulfiram failed to demonstrate efficacy.

 

S7

  1. The Possible Use of Opioid Antagonists

A. Opioid neurotransmission has been implicated in alcohol consumption. Three lines of evidence support this association.9

    1. The administration of a mu-opioid agonist increases alcohol consumption in animals. Also, humans on methadone maintenance may increase their alcohol consumption.
    2. While opioid agonists appear to increase ethanol consumption in animals, opioid antagonists have the opposite effect in several animal species including alcohol- preferring and non-alcohol-preferring rodents. So, opiate receptor antagonists generally decrease alcohol consumption.
    3. A third line of evidence is that alcohol dependent people may have low baseline serum b-endorphin levels.

B. The observation that naltrexone decreases drinking in animals led to studies assessing the effects of naltrexone on human alcohol consumption.10,11

S8

1. Naltrexone was approved in the U.S. for the treatment of alcohol dependence based on the results of 2 controlled trials showing the medication to be superior to placebo in the prevention of alcoholic relapse.

2. A study of 70 alcohol dependent subjects10 in a veteran population determined that 50 mg per day of naltrexone was an effective augmentation to an intensive day treatment program in preventing relapse to heavy drinking. This study revealed that naltrexone-treated patients had a significant delay in the time interval between detoxification and first drink consumption when compared with placebo-treated patients. Naltrexone also slowed the progression from the first drink to heavy drinking when compared with placebo.

3. Although the study by O’Malley et al.11 showed similar results, they also evaluated the combined effects of naltrexone with either relapse prevention training or supportive therapy. Thus, this study was clearly unique in examining not only the pharmacologic, but also the psychotherapeutic aspects of treatment as well. This study showed that naltrexone was more efficacious in preventing the initiation of drinking when paired with supportive therapy. However, once the subject sampled alcohol, naltrexone plus cognitive behavioral therapy was better at preventing full-blown relapse.

S9

C. Naltrexone’s most commonly reported side effects are nausea, headache, anxiety, and sedation.10,11

    1. Individuals taking naltrexone can also be insensitive to opioid analgesia for up to 72 hours of administration. This effect can be countered with higher doses of opioids.12
    2. High doses of naltrexone (300 mg/day) have been associated with hepatotoxicity, but this is rarely observed with doses of 50 mg per day.13 Nevertheless, naltrexone should be used with extreme caution in persons with hepatitis or severe liver dysfunction.
      1. Liver function should be monitored prior to naltrexone treatment and periodically during treatment in these patients.

b. This agent should not be administered to patients currently using opioids or to those who have received opioids within 2 weeks prior, as it may precipitate opioid withdrawal.

S10

D. How might naltrexone work in alcoholics?

    1. We have discussed that the stimulant, pleasurable reinforcing effects of alcohol are mediated through the dopaminergic systems of the brain. Opiate antagonists appear to block alcohol-induced dopamine release in the nucleus accumbens, presumably resulting in decreased pleasure and a decrease in alcohol intake. Indeed, a reduction in the pleasurable effects of alcohol by opiate antagonists has been observed in several studies14 including some studies of social drinkers in naturalistic bar settings.15
    2. Naltrexone may decrease drinking by alleviating cravings, as has been reported by subjects receiving naltrexone during placebo-controlled trials.10,11 In fact, in one of those trials, naltrexone reduced drinking more effectively in patients reporting the highest levels of craving at study entry.11
    3. Naltrexone might work by increasing some of the aversive effects of alcohol, such as nausea and vomiting.
    4. Finally, naltrexone may decrease alcohol consumption by altering neuroendocrine responses to alcohol.6 Ethanol consumption is associated with activation of hypothalamic-pituitary-adrenal axis and release of ACTH, beta-endorphins and glucocorticoids. Some of the positive effects of alcohol are hypothesized to be mediated by this neuroendocrine mechanism.

S11

E. Some additional issues regarding naltrexone

    1. Subsequent clinical studies with naltrexone have been mixed, sometimes supporting its effectiveness,16 sometimes not.17
    2. In another study,18 Volpicelli found that compliance with naltrexone is variable. Only among highly-compliant patients was naltrexone significantly better than placebo on a variety of drinking measures. In the United States, naltrexone has not been studied in patients who did not receive psychotherapy. So, as of now, there is no evidence that it is effective as a sole treatment.
    3. Hence, naltrexone is to be used in the context of a comprehensive psychosocial program. It is recommended for use in the first 50 days of alcohol abstinence.
    4. The usual dose is 50mg/day although doses of 25 mg/day to 100 mg/day have been reported to be useful.6

In sum, while some studies of naltrexone are encouraging, a number of questions remain regarding optimal dosing, treatment duration, psychosocial therapy interactions and types of patients more likely to benefit.

  1. A few studies have examined another opioid antagonist, nalmefene.19,20
    1. The largest was a 12-week double-blind placebo-controlled trial20 comparing 20 mg and 80 mg/day of nalmefene in 105 alcohol dependent patients. All groups received CBT. There were no significant differences on drinking outcomes among the subjects on 20 mg and 80 mg of nalmefene. There was, however, a significant advantage of nalmefene over placebo. Significantly fewer patients treated with nalmefene relapsed to heavy drinking compared to those treated with placebo.
    2. Nalmefene was relatively well tolerated. Headaches, insomnia and nausea were the most common side effects.
    3. Perhaps the main advantage of nalmefene over naltrexone is that unlike naltrexone, nalmefene is not hepatotoxic at higher doses.

S12

  1. The Possible Importance of Serotonin Boosting Drugs

A. The serotonin (5-HT) system also appears to be involved in the consumption of alcohol. Preclinical studies have considered the association between drinking behaviors and 5-HT systems in several different ways.21

    1. Acute administration of alcohol has been shown to cause the release of 5-HT in the nucleus accumbens of rodents. Conversely, chronic administration of alcohol results in decrease release of 5-HT in the nucleus accubens in rodents.
    2. Various neuropathologic studies examined the density of 5-HT receptors and the concentration of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in various brain regions of rodents. 5HT and 5HIAA were found to be less concentrated in the nucleus accumbens in "high level" alcohol-drinking rats compared with "low-level" alcohol-drinking rats.
    3. In sum, the majority of basic science research demonstrates an apparent relationship between abnormal 5-HT neurotransmission and excessive alcohol consumption.

S13

B. Some human studies also support a relationship between alcohol consumption and a reduction in 5-HT transmission.21

    1. Reduced levels of 5-HIAA were found in the cerebral spinal fluid of heavy drinkers.
    2. Reduced levels of 5-HIAA were found in individuals with lack of impulse control, aggressiveness, and with vulnerability to mood and anxiety disorders. Perhaps the overlap between these behaviors and alcohol dependence is mediated by 5-HT dysfunction.

3. The effects of 5-HT pharmacotherapy were assessed in a variety of drinkers (heavy, alcohol dependent, and comorbidly depressed) in clinical trials. The Selective Serotonin Reuptake Inhibitors (SSRIs) [e.g., citalopram (Celexa), fluoxetine (Prozac) and others] were shown to produce modest reductions in alcohol consumption among heavy social drinkers. These reductions were observed at higher daily dosages than antidepressant dosages.22 These promising findings led to the study of SSRIs in alcoholics.

S14

C. There were some positive studies:

    1. The results of a study23 involving pretreatment of alcoholics on an inpatient unit who then consumed alcohol showed a reduction in alcohol consumption. However, the effect was observed for only a one-week period.
    2. Another study24 compared the effects of fluoxetine, acamprosate and placebo in alcoholics with "positive" and "negative" family histories. Both treatment groups were more effective than placebo in reducing the number of drinks consumed. The effect of fluoxetine, however, was significant only in "positive" family history patients. In contrast, the effect of acamprosate was significant only in "negative" family history patients.

S15

D. Other studies showed negative results:

    1. The results of a study by Kranzler et al.25 showed 75% reductions in drinking in both fluoxetine and control groups receiving cognitive behavioral therapy (CBT). In this study of 101 alcohol dependent patients randomized to either 60 mg/day of fluoxetine or placebo, no advantage of fluoxetine over placebo was observed.
    2. The study by Kabel and Petty26 also showed no effect of fluoxetine compared with placebo among severe alcoholics recruited from an alcohol treatment program at a VA. These negative results have cast a dimmer light on the idea of treating alcohol dependence with SSRIs.

S16

E. In addition to the SSRIs, other medications affecting the serotonergic system were also studied. Results were either negative or mixed.

F. Thus, the effects of serotonergic medications on human drinking behavior are more limited and the results less consistent than in animal studies.

    1. There is no clear answer to the question of whether there is a role for a serotonergic medication in the treatment of alcohol dependence.

S17

2. Some investigators21 have argued that results of 5-HT pharmacotherapy have been inconsistent because trials were conducted in heterogeneous alcoholic populations. Perhaps not all alcohol dependent individuals have 5-HT abnormalities. Male antisocial alcoholics (e.g., type 2 or type B) may represent a useful subtype.

S18

    1. Medications that target the 5-HT system may have the greatest impact in alcohol-dependent individuals With impairment in mood and anxiety disorders.

 

S19

  1. The Possible Importance of Acamprosate

A. Acamprosate (calcium acetylhomotaurinate) is a synthetic compound that has a chemical structure similar to that of naturally occurring amino acid mediators, homotaurine and GABA.27

B. It has been available in France since 1989 and most recently in most European and Latin American Countries. More than 1.4 million patients have been treated with acamprosate since it became commercially available.

C. Fourteen out of 16 controlled clinical trials (4,500 subjects) conducted across 11 European countries have demonstrated evidence for acamprosate’s efficacy. These studies have shown that acamprosate-treated patients had a significantly greater rate of treatment completion, time to first drink, and abstinence rates than patients treated with placebo.27

D. Although the precise mechanism of action or cellular target of acamprosate is unknown, it appears to act primarily by restoring NMDA receptor tone in the glutamate system, which is deranged during chronic alcohol consumption. Acamprosate also affects GABA neurotransmission. It may work by decreasing cravings. 28

S20

  1. Unlike other medications used in the prevention of relapse to heavy drinking, acamprosate is primarily excreted by the kidneys and is not metabolized in the liver to any meaningful extent.28 Since many alcohol-dependent patients have liver dysfunction, this medication can be an important addition to the treatment of alcohol dependence.
  2. No serious adverse effects were reported in double-blind trials. Main adverse effects were diarrhea (10%), rash, and fluctuations in libido. These side effects were mild and transient and the percentage of patients withdrawing from European trials did not differ between placebo and acamprosate.28
  3. Unlike naltrexone, acamprosate will not precipitate an acute opioid withdrawal syndrome in patients on opioid agonists.

S21

H. Further studies are needed to identify subgroups of alcoholics who may be most responsive to acamprosate. This is underscored by the findings of Gerra et al.24 who found that acamprosate significantly reduced the number of drinks consumed only in patients without a family history of alcoholism. Although there is consistent evidence that acamprosate is efficacious in decreasing the number of days drinking, its effects are modest.

S22

VII. Some Conclusions

A. Is there a role for the use of medications in the rehabilitation of alcohol dependence?

    1. Overall, medications have not shown large effects in the prevention of heavy drinking:
      1. Disulfiram, an alcohol-sensitizing agent, has shown limited efficacy. It may be of value for more motivated patients.
      2. Naltrexone, an opioid antagonist, has shown mixed results; three well-conducted trials have supported its efficacy. In contrast, two others have shown either lack of efficacy or efficacy limited to highly compliant patients. Initial studies on nalmefene, another opiate antagonist, appear promising. There is a current US multicenter trial evaluating nalmefene.
      3. There is no clear answer to the question of whether there is a role for serotonergic medications in the treatment of alcohol dependence.
      4. Although the results of a US acamprosate multicenter trial are pending, this medication has the best documented efficacy in the European literature. Its effects, although consistent, are modest.
    1. Other unresolved issues:
      1. There is a need to determine what medications are most effective in various types of alcohol-dependent individuals.
      2. The optimal dosing, treatment duration, and interactions with existing psychosocial treatments need to be defined for each medication.
      3. Pharmacological (e.g., depot formulations) and psychosocial (e.g., motivation enhancement) strategies to promote compliance need to be further investigated.
      4. As data become available, it is important to educate physicians, the community, and AA groups to improve the acceptability of medications to treat alcohol dependence and counteract the historical sense of pharmacologic Calvinism in this field.
  1. In sum, although medications to reduce alcohol consumption have not shown large effects, the FDA approval of naltrexone, along with studies on acamprosate and nalmefene, suggest growing interest in this field. This interest is fueled by increasing understanding of neurobiological mechanisms that maintain alcohol dependence and awareness that medications can be combined with psychosocial treatments to improve the treatment outcomes of patients with alcohol dependence.

References

  1. Schaffer A, Naranjo CA: Recommended drug treatment strategies for the alcoholic patient. Drugs 56:571-585, 1998
  2. Kranzler HR, Amin H, Modesto-Lowe V, Oncken C: Pharmacologic treatments for drug and alcohol dependence. The Psychiatric Clinics of North America 22:401-423, 1999
  3. Garbutt JC, West SL, Carey TS, Lohr KN, Crews FT: Pharmacological treatment of alcohol dependence: A review of the evidence. JAMA 281:1318-1325, 1999
  4. Le AD, Tomkins DM, Sellers EM: Use of serotonin (5-HT) and opiate-based drugs in the pharmacotherapy of alcohol dependence: An overview of the preclinical data. Alcohol Alcohol (Suppl) 1:27-32, 1996
  5. Lewis MJ: Alcohol reinforcement and neuropharmacological therapeutics. Alcohol Alcohol (Suppl) 1:17-25, 1996
  6. Swift RM: Opioid antagonists and alcoholism treatment. CNS Spectrums 5:49-57, 2000

7. Gianoulakis C: Implications of endogenous opioids and dopamine in alcoholism: Human and basic science studies. Alcohol Alcohol (Suppl) 1:33-42, 1996

  1. Fuller RK, Branchey L, Brightwell DR, et al: Disulfiram treatment of alcoholism: A veterans administration cooperative study. JAMA 256:1449-1455, 1986
  2. Ulm RR, Volpicelli JR, Volpicelli LA: Opiates and alcohol self-administration in animals. J Clin Psychiatry 56 (Suppl) 7:5-14, 1995
  3. Volpicelli JR, Alterman AI, Hayashida M, et al: Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49:876-880, 1992
  4. O’Malley SS, Jaffe AJ, Chang G, et al: Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry 49:881-887, 1992
  5. Crabtree BL: Review of naltrexone, a long-acting opiate antagonist. Clinical Pharmacy 3:273-280, 1984
  6. Brahen LS, Capone TJ, Capone DM: Naltrexone: Lack of effect on hepatic enzymes. J Clin Pharmacol 28:64-70, 1988
  7. Swift RM: Effect of naltrexone on human alcohol consumption. J Clin Psychiatry 56 (Suppl) 7:24-29, 1995
  8. Davidson D, Palfai T, Bird C, Swift R. Effects of naltrexone on alcohol self-administration in heavy drinkers. Alcohol Clin Exp Res 23:195-203, 1999
  9. Anton RF, Moak DH, Waid LR, Latham PK, et al: Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry 156:1758-1764, 1999
  10. Kranzler HR, Modesto-Lowe V, Van Kirk J: Naltrexone vs nefazodone for treatment of alcohol dependence. Neuropsychopharmacology 22:493-503, 2000
  11. Volpicelli JR, Rhines KC, Rhines JS, Volpicelli LA, et al: Naltrexone and alcohol dependence. Role of subject compliance. Arch Gen Psychiatry 54:737-742, 1997
  12. Mason BJ, Ritvo EC, Morgan RO, Salvato FR, et al: A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HC1 for alcohol dependence. Alcohol Clin Exp Res 18:1162-1167, 1994
  13. Mason BJ, Salvato FR, Williams LD, Ritvo EC, et al: A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 56:719-724, 1999
  14. Pettinati HM, Oslin D, Decker K: Role of serotonin and serotonin-selective pharmacotherapy in alcohol dependence. CNS Spectrums 5:33-46, 2000
  15. Naranjo CA, Sellers EM: Serononin uptake inhibitors attenuate ethanol intake in problem drinkers. Recent Dev Alcohol 7:255-266, 1989.
  16. Gorelick DA, Paredes A: Effect of fluoxetine on alcohol consumption in male alcoholics. Alcohol Clin Exp Res 16:261-265, 1992
  17. Gerra G, Caccavari R, Delsignore R, Bocchi R, et al: Effects of fluoxetine and Ca-acetyl-homotaurinate on alcohol intake in familial and nonfamilial alcohol patients. Current Therapeutic Res 52:291-295, 1992
  18. Kranzler HR, Burleson JA, Korner P, DelBoca FK, et al: Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Psychiatry 152:391-397, 1995
  19. Kabel DI, Petty F: A placebo-controlled, double-blind study of fluoxetine in severe alcohol dependence: Adjunctive pharmacotherapy during and after inpatient treatment. Alcohol Clin Exp Res 20:780-784, 1996

27. Mason BJ, Ownby RL: Acamprosate for the treatment of alcohol dependence: A review of Double-blind, placebo-controlled trials. CNS Spectrums 5:58-69, 2000

28. Wilde MI, Wagstaff AJ: Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification. Drugs 53:1038-1053, 1997