An Introduction to Pharmacotherapy of alcohol misuse, dependence and withdrawal

By: George A. Kenna, Kostas Agath and Robert Swift

While there is a large volume of research on alcohol misuse, dependence and withdrawal, the pharmacologic solutions are not as directly evident as this amount may suggest. There are widespread cultural determinants as to what constitutes alcohol misuse though the definitions for dependence are much clearer. Yet we do not have good solid pharmacologic treatments to prevent or decrease alcohol usage in the alcohol-dependent individual, though results from the recent COMBINE study suggest a more prominent and effective role for naltrexone in conjunction with medical management. Acamprosate did not fare as well in this trial even though it has been approved for alcohol dependence, and questions of heterogeneity among patient populations might explain conflicting findings. The effectiveness of disulfiram appears to rely heavily upon the patient’s determination to remain abstinent. Anticonvulsants may have a role here, but more data is needed. Benzodiazepines remain the gold standard for treatment of symptoms of alcohol withdrawal, while a number of studies also support the use of some anticonvulsant drugs in assisting with withdrawal, especially in cases of mild-to-moderate severity.

There is a large volume of research on the pharmacological treatments for alcohol misuse, dependence and withdrawal. Part of that research is marred by methodological difficulties (Moncrieff & Drummond 1997), necessitating increasingly sophisticated means of grading the available evidence to allow generalizability of findings (Mayo-Smith, 1997, Garbutt et al., 1999, Scottish Intercollegiate Guidelines Network –SIGN, 2003, Lingford-Hughes et al., 2004).

Harmful use of alcohol

Harmful use refers to physical and/or mental damage due to a pattern of alcohol use in the absence of a diagnosis of another specific form of alcohol disorder (such as dependence). It is an ICD-10 diagnosis without a direct equivalent in DSM-IV, and its diagnosis depends upon the accurate reporting of alcohol-related physical or mental health problems (Babor, 1992). Harmful alcohol use (problem drinking) is believed to play a role in behavior associated with a pattern and amount of alcohol use considered hazardous such as decreased worker productivity, increased unintentional injuries, aggression and violence against others, and child and spouse abuse (Gmel & Rehm, 2003). Additionally, many individuals may periodically abuse alcohol at harmful levels, yet not be alcohol dependent.

While the frequency and intensity of these markers increases with increased amounts and frequency of alcohol use, there is no firm quantitative definition for harmful alcohol use in the United States. For example, data from the National Health Interview Survey (Dawson, 1994), suggests that the risk of occupational injuries increases with the frequency of five or more drinks per occasion. Older workers who normally drink one or two drinks (equivalent to 1.5 ounces of 80 proof liquor) a day report the lowest risk of injuries contrasted with people who drink five or more drinks a day, who report more than a fivefold increase in risk (Zwerling et al., 1996). Heavy drinking is alcohol consumption exceeding 14 drinks per week for men (or more than four drinks per drinking occasion), more than seven drinks per week for women (or more than three drinks per occasion), and greater than seven drinks per week for all adults 65 years and older (National Institute on Alcohol Abuse and Alcoholism (NIAAA), 2000). Heavy alcohol use has also been defined (Office of Applied Studies, National Survey on Drug Use and Health (NSDUH), 2004) as drinking five or more drinks at the same time on at least five separate occasions during the previous month.

Appropriate pharmacological treatment is largely dependent on the health problem addressed (depression, anxiety, cardiovascular, endocrine, gastrointestinal abnormalities). Naltrexone has been tried but the research evidence has not supported its use in harmful use (Davidson et al., 2004, Kranzler et al., 2003, Davidson et al., 1999, Rubio et al., 2002). In the United Kingdom no official guidelines for the pharmacological treatment of harmful alcohol use exist. Research on the use of NTX for non-dependent problem drinkers is limited. Kranzler et al. (2003) compared the effects of 50 mg of NTX or matching placebo in a sample of early problem drinkers who received NTX either daily or in targeted high-risk situations for drinking, in addition to brief coping skills therapy. Participants in the targeted group received a diminishing number of tablets (started at 1 tablet daily for week one, then 1 less tablet per week) over an 8-week treatment period. While NTX was better than placebo in reducing heavy drinking frequency, NTX did not significantly reduce the number of drinking days. Regardless of whether participants received NTX or placebo, there was a reduction in the likelihood for any drinking by participants in the targeted condition. However, as the number of tablets declined to fewer than three per week in the targeted NTX group, this group no longer exhibited a decreased risk for heavy drinking.

Davidson et al. (1999) found no differences in heavy drinkers between NTX and placebo in either drinking days or drinks per drinking day over a 7-day period in the home environment, but did find advantages of NTX for reducing craving and decreasing the reinforcing effects of alcohol. Moreover, Davidson et al. (2004) reported that placebo-treated hazardous drinkers fared better than those treated with NTX in terms of abstinence, drinks per drinking day and craving, although the results may have been confounded by gender and family history of alcoholism. Rubio et al. (2002) in an open randomized trial with mildly dependent drinkers found delayed effects at 12 months after 12 weeks of a controlled drinking program either alone or in combination with NTX. The NTX group had fewer drinking days, heavy drinking days and less craving.

The dosing strategy for the use of naltrexone for harmful drinking in non-dependent alcoholics is unclear at present. But presently, there is insufficient evidence at this time to support daily or targeted use of NTX for harmful alcohol use, and its use is best reserved for moderate-to-severe alcohol dependence.

Alcohol dependence

The pharmacological treatments of alcohol dependence focus on relapse prevention once detoxification is complete. They are intended as an adjunct to psychosocial treatments (Slattery et al., 2003; Lingford-Hughes et al., 2004) and not as a monotherapy.

Alcohol withdrawal

For many alcohol-dependent individuals with significant physical dependence, a cluster of withdrawal symptoms known as ‘alcohol withdrawal syndrome’ (AWS) may occur upon cessation or reduction of alcohol consumption or reaching a level of such significant tolerance that individuals cannot consume enough alcohol to delay withdrawal. Estimates suggest that as many as 2 million Americans may experience symptoms associated with alcohol-related withdrawal annually (Abbott et al., 1995).

Depending directly on the degree of physical dependence, this syndrome can range from creating significant discomfort to mild tremor to alcohol withdrawal-related delirium, hallucinosis, seizures, and potentially death (Kozak et al., 2000; Bayard et al., 2004). Though most alcohol-dependent persons do not fit the stereotypical image of an alcoholic, individuals who are nutritionally compromised, dehydrated, or have other organ deficiencies are at more risk for withdrawal. Repeated withdrawal episodes may contribute to the development of alcohol dependence and to negative consequences associated with excessive alcohol consumption (Finn & Crabbe, 1997). Predictors for AWS complications include the duration of alcohol consumption, total number of prior detoxifications from alcohol, and previous withdrawal-related seizures and episodes of alcohol withdrawal delirium (AWD) (Asplund et al., 2004).

Withdrawal-related seizure is considered a more severe manifestation of AWS, as is AWD or ‘delirium tremens’ as traditionally called. The incidence of seizures in alcohol dependent individuals waiting for detoxification ranges from 1% to 15% (Chan, 1985). AWD is estimated to have a mortality rate of approximately 1 in 20 patients who go into alcohol withdrawal (Trevisan et al., 1998).

The pharmacological treatment of alcohol withdrawal aims at reducing the severity of non-specific features (such as elevated blood pressure, high pulse, tremor, agitation, anxiety, depression), and avoiding the occurrence of specific features (such as seizures, delirium tremens). The distinction between specific and non-specific symptoms is reflected in differential efficacy of the various pharmacological agents employed for the treatment of alcohol withdrawal.

Several reviews agree that benzodiazepines reduce both the specific and non-specific symptoms of alcohol withdrawal and are the treatment of choice for alcohol withdrawal syndrome (Mayo-Smith, 1997, Lingford Hughes et al., 2004), and the only recommended monotherapy for it (Franck, 2003). Amongst benzodiazepines there is no evidence to support one agent over another, although longer half-life seems to be better in preventing specific symptoms (Mayo-Smith, 1997) with chlordiazepoxide the most popular choice in the absence of liver failure (Lingford-Hughes et al., 2004), even in the elderly (Mayo-Smith, 2004) albeit with a reduced dosage (Franck, 2003).

Apart from benzodiazepines, a few other agents were found to be superior to placebo in treating non-specific symptoms of alcohol withdrawal syndrome, although there is no consensus about their place in treatment because of either non-proven efficacy in treating specific symptoms or because of dangerous side effects. For example, chlormethiazole, a popular alternative first-line treatment of alcohol withdrawal, although superior to placebo, has no proven efficacy in the prevention of seizures and its outpatient use is marred by potentially serious side effects such as respiratory depression and increased airway secretion (Williams & McBride, 1998).

Carbamazepine is also superior to placebo in treating nonspecific symptoms of alcohol withdrawal (Franck, 2003), and more recent evidence shows that it is as effective as benzodiazepines in seizure prevention during withdrawal (Hilbom et al., 2003), a finding that was disputed in previous reviews (Mayo-Smith, 1997, Franck, 2003).

Benzodiazepines are frequently administered in a fixed-schedule tapering regime, where clients are assigned to an initial dosage in a predetermined reduction program (Mayo-Smith, 1997). Fixed-schedule tapering regimes do not take into account the great variation of withdrawal severity apart from the onset of the regime, but their acceptability is based on the minimal need of specialist monitoring during detoxification (MayoSmith, 1997). Alternative benzodiazepine regimes consist of administration of a variable dose titrated against the Clinical Institute Withdrawal Assessment Alcohol revised (CIWA-Ar) scale (Sullivan et al., 1989) that is administered either at set intervals during the day (such as hourly), or at the request of a client when they experience withdrawal features. Although the use of the alternative regimes is preferable in reducing the total amount of benzodiazepine administered, they need availability of trained staff and they are not suited for clients with a seizure risk (Mayo-Smith, 1997; Lingford-Hughes et al., 2004).

References

Peter Tyrer and Kenneth R. Silk, Cambridge Textbook of Effective Treatments in Psychiatry, Cambridge University Press 2008.

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