The past 15 years have brought remarkable progress in our understanding both of the reasons people become dependent on alcohol and of how to approach treatment. Accurate instruments exist to help assess patients with an alcohol use disorder, and effective techniques are available to help people initially stop excessive drinking. More recently, new medications have been shown to facilitate recovery both from alcohol addiction and other comorbid psychiatric disorders. The current challenge is to transfer the knowledge we have learned about alcohol addiction into standard clinical practice.
This article reviews the essential components of alcohol addiction, discusses how understanding the neurobiology of alcohol can lead to a better understanding of why some people become addicted, and explains how we can apply this knowledge to develop medications to help treat patients. Medications such as naltrexone and acamprosate are shown to be effective components to alcohol addiction treatment and can work together with other medications and therapies for patients with comorbid psychiatric disorders. These new therapeutic approaches offer clinicians new options for treating patients with alcohol addiction.
Criteria from the Diagnostic and Statistical Manual of Manual Disorders, fourth edition, text revision (DSM IVTR),1 for the definition of dependence are presented in the Sidebar. Distilled down to its essential elements, dependence (addiction) refers to compulsive use of a drug, such as alcohol, because of which the person has impaired control over use once an episode of drug use begins. This impaired control leads to excessive use, and the excessive use leads to a variety of medical and psychosocial problems. DSM IV-TR recognizes that physiological adaptation to the drug (drug tolerance and withdrawal) is not necessary or sufficient criteria to diagnose someone with an dependence but that physiological adaptation often occurs with addiction and is important to assess because of its implications for treatment.
DSM-IV Criteria For Alcohol Dependence
A maladaptive pattern of alcohol use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period:
Tolerance, as defined by either of the following:
A need for markedly increased amounts of alcohol to achieve intoxication or the desired effect.
Markedly diminished effect with continued use of the same amount of alcohol.
Withdrawal, as manifested by either of the following:
The characteristic withdrawal syndrome several hours to a few days following cessation (two or more of the following): autonomic hyperactivity (eg, sweating or pulse rate greater than 100), increased hand tremor, insomnia, nausea or vomiting, transient visual, tactile or auditory hallucinations or illusions, psycho-motor agitation, anxiety, or grand mal seizures.
Alcohol or other substances are taken to relieve or avoid withdrawal symptoms.
Alcohol is taken in larger amounts or over a longer period than was intended.
There is a persistent desire or unsuccessful efforts to cut down or control drinking.
A great deal of time is spent to obtain alcohol, drink alcohol, or recover from its effects.
Important social, occupational or recreational activities are given up or reduced because of drinking alcohol.
Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychologic problem that is likely to have been caused or exacerbated by alcohol.
With physiological dependence: evidence of tolerance or withdrawal (ie, either item 1 or item 2 is present).
Without physiological dependence: no evidence of tolerance or withdrawal (ie, neither item 1 nor item 2 is present).
It is not clear why certain people have impaired control over alcohol use. Concepts such as addictive personality offer little insight and simply describe the behavioral pattern of addicted individuals. The scientific developments of the past 15 years do present some important insights into understanding why some people become addicted. Historically, alcohol was viewed as a “dirty drug,” having nonspecific effects on nerve membranes leading to central nervous system depression. In more recent years, we have come to a radical new understanding of the pharmacology of alcohol. It is alcohol's effects on specific neurotransmitter systems that lead to the pleasurable or sedative sensation one feels while drinking.
The experience of being activated or energized is related to alcohol's ability to enhance dopamine activity. Euphoria is related to both increased dopamine activity and increased opioid activity in the brain. The ability of alcohol to reduce anxiety may be related to alcohol's ability to enhance GABA activity. Much of the sedative effects from alcohol use relates to alcohol's ability to enhance GABA and decrease NMDA receptor activity. Alcohol withdrawal is related to compensatory increase in NMDA receptor activity and decrease in the inhibition of the sympathetic nervous system.
Activation of NMDA receptors excites the neuronal activity. The NMDA receptor, when it is stimulated by its agonist, acts as a excitatory neurotransmitter. The amino acids glutamate and glycine are responsible for stimulating this receptor and when people drink alcohol, the NMDA system is inhibited.2 By reducing excitatory neurotransmitter activity, the net affect of alcohol is to cause sedation. Over time, the ability of alcohol to inhibit the NMDA system becomes less as the NMDA compensates for the effects of alcohol. This leads to tolerance to the sedative effects of alcohol. When a person stops drinking, the NMDA system becomes hyperactive; this is responsible for many of the withdrawal symptoms.2
Alcohol also has important effects on the dopamine system. Alcohol, like other drugs of abuse, stimulates dopamine activity at the nucleus accumbens. This effect is a likely reason for alcohol causing feelings of euphoria in some people. Chronic stimulation of dopamine at the nucleus accumbens leads to tolerance to the alcohol high. When a person stops chronic alcohol use, there may be a rebound craving for alcohol due to relatively low levels of dopamine activity.3
In addition, alcohol affects the opioid system. For people who have a strong family history of alcoholism, alcohol has a stronger effect in stimulating a release of endorphins.4 The endorphin system not only has direct effects in reducing the feeling of physical and emotional pain but also enhances dopamine activity and contributes to feelings of pleasure.
Important individual differences in alcohol's specific pharmacologic effects explain why some people are at risk for addiction. The source of individual differences is likely due to genetic factors. Family studies consistently show that alcoholism runs in families, and twin studies show that the more genes people share, the higher the association for risk of alcoholism. If one of your biological parents is an alcoholic, the risk of you becoming alcohol dependent is increased by two times.5 This increased risk is present even if you are adopted at birth and raised by nonalcoholic parents.
What is inherited that increases the risk for alcoholism? One suggestion is that natural tolerance to the sedative effects of alcohol puts one at risk.6,7 Without alcohol sedation, there are no natural breaks during alcohol drinking, and a drinking episode can easily escalate into an alcohol binge.
A second theory is that some people inherit an increased sensitivity to the euphoric effects of alcohol.8 People with increased euphoria will experience a greater high when they drink. A third set of factors is that certain personality variables predispose one to abusing alcohol. Impulsive people may be at an increased risk because they tend to not focus on the long-term consequences of their drinking but on the immediate pleasurable effects.9 Similarly, some people may disregard social conventions and start drinking at an early age, when the adolescent brain is more at risk from excessive drinking. Finally, some people may be particularly sensitive to unpleasant feelings, including facial flushing, when they drink. By lacking an alcohol metabolizing enzyme, these people often feel sick after just one or two drinks.6
Patients with a mental health disorder have an increased risk of a coexisting substance abuse disorder. For example, for patients who have any mental health disorder, the risk of having a substance use disorder increases 270%.10 Some disorders confer a particularly high risk. For example, patients with schizophrenia have a 5-times increased risk for a substance use disorder. Panic disorder is another condition that has a high rate of alcoholism.11
Given the high rate of comorbidity, it is especially important for mental health professionals to screen for alcohol use disorders. Several useful screening tools can be used to assess for an alcohol use disorder, including the CAGE and Alcohol Use Disorders Identification Test (AUDIT)12 questionnaires. If screening tests suggest the presence of an alcohol use disorder, a thorough biopsychosocial assessment for alcoholism should be conducted. This evaluation should assess for medical, psychiatric, and social consequences of alcohol use. It is not enough to screen and assess for an alcohol use disorder; clinicians have a responsibility to initiate treatment. The techniques for treating alcohol abuse and dependence have improved dramatically and can be used safely and effectively by general psychiatrists and other mental healthcare professionals.
Biochemical Basis of Alcohol Withdrawal
The primary goal of detoxification is to achieve a drug-free state to help manage acute withdrawal symptoms and to help to prepare the patient for further treatment. It is important to treat alcohol withdrawal symptoms aggressively; repeated withdrawal from alcohol causes sensitization and increase the risk for severe withdrawal symptoms such as seizures.13
In general, the neurobiology of alcohol withdrawal is opposite from the neurobiology of alcohol intoxication. This occurs because the body compensates for the chronic effects of alcohol, and when alcohol is withdrawn, the effects of these compensatory neurobiological effects are felt. For example, alcohol suppresses noradrengeric activity, and alcohol withdrawal is associated with increased noradrenergic activity. Similarly, the NMDA system is inhibited by alcohol, and alcohol withdrawal is associated with increased NMDA activity. The net effect of these changes is that alcohol withdrawal is associated with increased neuronal activity and an overexcited brain and peripheral sympathetic nervous system.1
It is important to remember that alcohol withdrawal symptoms mimic comorbid psychiatric symptoms. Sweating, rapid heart rate, and anxious feelings could be confused with anxiety and panic, while sleep disturbances, poor appetite, and lethargy could be confused with depression. Alcohol hallucinations can be confused with psychotic disorders. Also, while most alcohol withdrawal symptoms are gone after a week, some symptoms may persist for longer periods after drinking stops. This makes it particularly difficult to disentangle withdrawal symptoms from a primary psychiatric disorder.
Treatment of Alcohol Withdrawal
It is important to treat symptoms of alcohol withdrawal aggressively. Treatment relieves patient discomfort, improves treatment retention, and prevents serious medical complications from alcohol withdrawal, such as delirium tremens (DTs) and alcohol withdrawal seizures. While inpatient referrals may be needed for particularly severe patients, the large majority of alcohol-dependent patients can be treated safely and effectively in an ambulatory setting.14,15
Traditional alcohol treatment programs use only 12-step approaches or psychotherapy to treat patients. The psychotherapies researched in alcohol addiction include brief interventions and motivational therapy designed to help patients start treatment, stay in treatment, and stay motivated to do something about their problems. Cognitive-behavioral psychotherapy is another popular therapy used in research studies and is designed to help patients cope with craving and how to deal with stress without using alcohol.
The 12-step programs are based on the Alcoholics Anonymous (AA) approach and involve encouraging patients to work the 12 steps and attend AA meetings. Other therapies that focus on social approaches to treatment, such as therapeutic communities, community reinforcement programs, and marital or family therapy, are used to treat alcohol dependent patients.
What research has shown that, in general, there is not much difference in the outcome of these types of psychosocial therapies? Generally, about half of all patients relapse in the first 3 months of treatment; in the course the course of 1 year, more than 75% of people relapse.
Benzodiazepines typically are used to treat alcohol withdrawal symptoms effectively. Some physicians recommend using long-acting benzodiazepines such as chlordiazepoxide, which have the advantage of gradual self-tapering. Other strategies include using short-acting benzodiazepines such as oxazepam, which has an advantage because it is not metabolized by the liver, making it easier to target the dose for specific withdrawal symptoms.
Other medications that help in detoxification include beta blockers such as propranolol and alpha- and two-adrenergic agonists such as clonidine. This includes medicines that reduce sympathetic hyperactivity. More recently, the use of anticonvulsants such as carbamazepine has been studied, and these compounds appear to be as safe and perhaps more effective than benzodiazepines.16 The anticonvulsants may be particularly helpful in patients with a history of alcohol withdrawal seizures.
Recent advances in the neurobiology of alcohol addiction have helped in the development of medications to improve treatment outcomes. The use of medication has been successful for the treatment of other drug addictions, such as opiate and nicotine addiction. Medications have had a dramatic effect in reducing the stigma of mental disorders and bringing treatment within mainstream medicine. Just as medications ushered in a new age for the treatment and understanding of psychiatric disorders, the hope is that the development of medications for addiction treatment will dramatically affect how we approach and understand addictive disorders.
Certain classes of medications can reduce the signs and symptoms of alcohol withdrawal, including acute and protracted alcohol withdrawal symptoms. Medications may be used to reduce the pleasure associated with drinking or the urge to drink. Other medications may cause an unpleasant reaction when mixed with alcohol. Medications also may be used to treat co-existing psychiatric disorders, reducing the risk of alcohol relapse.
Some of the specific medications that have been tested for efficacy in alcoholism treatment include disulfiram, acamprosate, naltrexone, serotonin reuptake blockers such fluoxetine and sertraline, and sertonergic agents such as ondansetron.
Disulfiram has been available for more than 50 years as an approved medication for alcoholism treatment. This medication is an alcohol-sensitizing agent. By inhibiting the metabolism of the acetaldehyde, it produces an unpleasant reaction when alcohol is consumed.
Figure 1 gives data from a classic disulfiram study conducted by Fuller and colleagues.17 In this study, disulfiram was tested for its effectiveness against not only placebo but also against a dose of disulfiram too low to have any pharmacologic effect, with the patients receiving the low-dose pill told they were receiving the regular medication. The results of the study show that compliance turned out to be the most important predictor of remaining abstinent. Patients who were compliant in taking the pill had a much higher abstinence rate than people who were noncompliant, but there was no improvement in abstinence rates for subjects taking disulfiram in either dose when compared with placebo. More recent studies suggest disulfiram can be effective when combined with family or couples therapy and when a concerned party observes the patient taking disulfiram.18
Alcohol abstinence rates for two doses of disulfiram compared with placebo in 406 men. Medication compliance was shown to be the primary factor in maintaining abstinence.17
The second FDA-approved medication for the treatment of alcohol dependence is naltrexone. Both animal and human studies have shown that drinking alcohol actually increases the release of the body's naturally occurring opiates — endorphins — and that these opiates bind to the receptor sites in the brain and result in the pleasurable effects of alcohol.19 This led to the development of the clinical use of naltrexone for the treatment of alcohol dependence.
The typical naltrexone study includes a baseline period in which people undergo detoxification and are free of alcohol for a short time, followed by random assignment to receive naltrexone or placebo for the following 12 weeks. Typically, patients receive 50 mg of naltrexone per day, as well as standard psychosocial support. Outcome measures are assessed during the 12 weeks of the study and often at follow-up periods for up to 1 year after the initial study is completed.
Two reviews of more than 2 dozen randomized clinical trials concluded that naltrexone significantly reduces the percentage of subjects who relapse to excessive alcohol use, the percentage of days in which alcohol drinking occurs, and craving for alcohol.18,20 In several studies that assessed alcohol craving, those receiving naltrexone reported lower levels of craving than subjects taking placebo.21–23 Often, participants report that even in high-risk situations, their desire to drink is much more under volitional control.
Naltrexone reduces alcohol drinking and particularly a relapse to excessive alcohol drinking. While naltrexone does not typically prevent subjects from having a slip, naltrexone helped subjects keep one drink from turning into a relapse.24,25 For example, in Figure 2, we can see the relapse rates for a typical naltrexone trial.25 Relapse is defined as a man having five or more drinks in 1 day or a woman having four or more drinks in 1 day. In this study, naltrexone was associated with a reduction of approximately 50% in relapse rates during the 12-week trial.25 While the effectiveness of naltrexone is not always statistically significant in randomized clinical trials,26,27 studies generally show similar results. In a resent meta-analysis, naltrexone was associated with a 38% reduction in alcohol relapse.20
Relapse rates using naltrexone for the treatment of alcohol dependence. The cumulative relapse rate is defined as the time to the first episode of heavy drinking (P < .01).25
Naltrexone effectively blocks the high associated with drinking. Patients in one study were asked to rate if they got as “high” as they expected from their first drinking episode. While those taking placebo reported they got as high as they expected, those who were taking naltrexone reported they got less high then they expected.24
The major side effect of naltrexone is nausea that usually subsides after a couple of days. Naltrexone has few drug interactions, the primary one with opioids. Because naltrexone blocks opioid receptors, a current user of an opioid such as methadone would experience opiate withdrawal symptoms if given naltrexone. The absolute contraindication for using naltrexone is current use of opioids, particularly if the patient is taking long-acting opioids such as methadone.
In addition to actual use of opioids, it is important to consider that medical disorders requiring occasional use of opioid analgesics also are a contraindication for use of naltrexone. For example, a patient with severe pain that requires occasional opioid narcotics to reduce the pain should not take naltrexone. This includes patients with sickle cell anemia.
Naltrexone also is contraindicated in females who are pregnant or breastfeeding. Data showing that it safe to administer naltrexone to patients who are pregnant or breastfeeding are insufficient.
Acamprosate recently was approved by the FDA for the treatment of alcohol dependence in the US, but it has a long history of use in Europe. Much of the acamprosate research was conducted in Europe and Asia. The results in more than a dozen clinical trials involving more than 3,000 subjects consistently show that acamprosate increases abstinence rates.28–30
Acamprosate works in the treatment of alcohol dependence because of its interaction with the GABA neurotransmitter system. Specifically, acamprosate inhibits the excitatory NMDA receptor. Animal studies demonstrate that acamprosate reduces alcohol drinking in an alcohol deprivation model. That is, normally, for rats that have been drinking for some time, if alcohol is taken away for a couple of days and then given back, alcohol drinking will increase dramatically. Acamprosate blocks this alcohol-deprivation effect. We can look at this as a model of relapse. After detoxification when someone stops using alcohol, there is a period in which alcohol craving increases. Acamprosate in humans similarly reduces the tendency to go back to drinking after alcohol detoxification.
Acamprosate does not cause physical dependence and is not associated with any withdrawal symptoms. It apparently works by reducing the hyperactivity seen in the NMDA system during alcohol withdrawal, especially for patients who have active protracted withdrawal symptoms. Acamprosate has a different mechanism of action from naltrexone and different effects on alcohol drinking. Naltrexone generally improves relapse rates and alcohol craving but has little effect on total abstinence rates. Acamprosate, in contrast, typically produces significant improvements in abstinence rates and increases the time before any drinking occurs.28–30
The results of a typical acamprosate trial are presented in Figure 3.31 This German study involved 272 patients treated for 48 weeks with about 2 mg of acamprosate daily or placebo. They also received routine counseling. Patients in the placebo group quickly reduced their abstinence rate and began to sample alcohol; by the end of 48 weeks, only 21% had remained abstinent throughout the trial. In contrast, patients taking acamprosate had twice the abstinence rate, with 43% remaining completely abstinent throughout the trial. Interestingly, these differences continue at 1 year follow-up. Only 17% of the placebo group had remained abstinent after 1 year, while in the acamprosate group, the abstinence rate was 37%. Again, acamprosate seems to double the abstinence rate compared with placebo.
Results of a study of acamprosate for the treatment of alcohol dependence.31 A total of 272 patients were entered into the study during a 2-year period and evaluated using the Kaplan-Meier survival analysis survival function estimate. Continuous abstinence rates were assessed for the treatment and follow-up periods.
The main safety concern with acamprosate is that it is excreted by the kidney, so patients with renal insufficiency need to avoid it. On the other hand, acamprosate is not metabolized by the liver, so it can be used in patients with liver disease. No abuse potential is associated with acamprosate, and it does not cause any withdrawal symptoms.
The side effect profile of acamprosate is very good. The main side effect is diarrhea; about 12% of patients experience diarrhea while taking the medication (1998 mg/day), compared with 3.4% of those taking placebo.32
Acamprosate does not produce any significant drug reactions. For example, a person can take acamprosate and drink alcohol without any synergistic effect in terms of sedation. Acamprosate may be given with drugs such as disulfiram, antidepressants, anxiolytics, and opioids. One area of particular interest is the combination of the acamprosate with naltrexone. Studies are being conducted done to compare the safety and efficacy of this combination and suggest that this combination may have synergistic effects in terms of treatment efficacy.33 Patients who take acamprosate and naltrexone in combination have a better outcome than those who take either drug alone.
Other Pharmacologic Options
For patients with co-existing depression and alcohol addiction, tricyclic antidepressants may be useful for improving treatment outcomes for both disorders. Mason and colleagues34 conducted a double-blind placebo-controlled trial using disipramine. The medication not only improved depression symptoms but also reduced the number of drinking days. In similar study conducted by McGrath,35 disipramine improved depression scores, and there was a trend for a reduction in drinking (Pagano, see page 473).
One question regards the addition of neuroleptics in patients who are alcohol dependent and schizophrenic? In a study conducted by Drake,36 151 alcohol-dependent patients with schizophrenia were followed for 3 years; 36 received clonazapine, and the others received typical neuroleptics. Approximately 80% of the patients who received clonazapine were in sustained remission from their schizophrenia after 3 years, compared with 33% of those who received the other neuroleptics.
There are very important new advances in the treatment of alcohol dependence. As we understand the pharmacologic effects of alcohol, we can treat alcohol abuse and dependence safely and effectively. Alcoholism is associated with a high rate of comorbidity with other psychiatric disorders, so it is critical for clinicians who treat patients with mental health disorders to be aggressive in screening for alcohol addiction and initiating treatment. Treatment includes not only good psychosocial support and referral to self-help groups but also the use of medications when needed.
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