Recommended Drug Treatment Strategies for the Alcoholic Patient

Ayal Schaffer and Claudjo A. Naranjo

Psychopharmacology Research Program, Sunnybrook Health Science Centre, Departments of

Pharmacology, Psychiatry and Medicine, University of Toronto, Toronto, Ontario, Canada

Contents
Abstract............................................................................................ 571
1. Diagnosis.............................................................................................. 572
2. Alcohol Intoxication............................................................................ 573
3. Alcohol Withdrawal Syndrome ................................................................. 573
4. Decreased Consumption and Relapse Prevention.......................... 574
4.1 Naltrexone.................................................................................................... 574
4.2 Nalmefene.................................................................................................... 576
4.3 Acorn prosate .................................................. .................................................... 577
4.4 Serotonergic Drugs...................................................................................... 577
4.5 Alcohol Sensitisers....................................................................................... 578
4.6 Other Agents................................................................................................ 578
5. Treatment of Alcohol Dependence with a Comorbid Psychiatric Ding nosa...... 579
5.1 Depression.................................................................................................... 579
5.2 Anxiety Disorders............................................................................................. 580
5.3 Bipolar Disorder........................................................................................... 580
6. Conclusions ............................................................................................ 581

Abstract

Significant progress has been made in the pharmacotherapy of alcoholism, specifically in the areas of
withdrawal reaction, decreasing consumption, relapse prevention, and comorbid psychiatric illnesses.
Psychosocial interventions are an important component of treatment strategies, and studies into the
efficacy of medications often include psychotherapy or other nonpharmacological modalities. Increasingly,
however, the evidence reveals the effectiveness of drug treatments for various components of the illness.
Many different pharrnacological agents and dosage regimens have been investigated for the treatment of
the alcohol withdrawal syndrome. The effectiveness and simplicity of giving long-acting benzodiazepines,
using a loading-dose technique, make this regimen first-line therapy.
Both naltrexone (an opioid antagonist) and acamprosate (calcium acetylhomotaurinate) increase rates of
abstinence and decrease relapse rates in alcohol-dependent individuals who are in abstinence-orientated
programmes. If patients enter a comprehensive treatment programme, either naltrexone or acamprosate
should be considered as an option in the treatment plan. The choice of medication is most likely to be
determined by the availability of each, which differs considerably throughout the world. Selective
serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) seem to have short term effects, and
are more effective in depressed alcoholics-dependent and in men. For all medications there is wide
variability in treatment response (i.e. effect size) and compliance seems to be essential for successful
treatment.
Preliminary evidence suggests the usefulness of pharmacotherapy in treating alcohol dependence in the
presence of other comorbid psychiatric illnesses. Antidepressants have shown efficacy in the treatment of
alcoholism with comorbid depression, as has buspirone for the treatment of comorbid chronic anxiety
symptoms. Further understanding of the neurobiological mechanisms of dependence in animals and
humans as well as improved knowledge of predictors of treatment response will lead to improvements in
the pharmacotherapy of alcohol dependence.
This article reviews the pharmacological strategies that have been directed towards the treatment of
alcohol dependence, focusing on the areas of intoxication, withdrawal syndrome, decreasing
consumption, relapse prevention and comorbid psychiatric illnesses. Progress in the pharmacotherapy of
alcohol dependence and related problems has been made through the integration of basic and clinical
pharmacological strategies. Studies in animals and humans indicate relationships between serotonin (5-
hydroxytryptamine; 5-FIT), dopamine, glutamate, y-aminobutync acid (GABA) and endogenous opioids
11~
with the start, continuance and stopping of alcohol consumption. Although most researchers have
focused on one neurotransmitter system, a behaviour as complex as alcohol dependence probably
involves several neurotransmitters.

1. Diagnosis
2
Alcoholic patients are more frequent users of medical services than the general population.[ ] This readily
available access to individuals with alcohol-related problems puts physicians in an excellent position to
131
diagnose the illness. Evaluation for alcoholism should be viewed as an integral part of a medical or
psychiatric assessment in all patients. The ideal strategy should include a clinical interview which involves
screening questions for alcohol problems, as well as inquiring into the quantity and frequency of alcohol
consumption. Standard screening tests for alcoholism include the
4 15
Michigan Alcoholism Screening Test (MAST)[ ] and the CAGE questionnaire. ] The CAGE is a brief, 4-
item test that consists of 4 yes/no questions:

• Have you ever felt you should cut down on your drinking?
• Have people annoyed you by criticising your drinking?
• Have you ever felt bad or ~uiIty about your drinking?
• Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover
(eye-opener)?

A score of 1 or more on the CAGE questionnaire, or a history of large quantity or high frequency of
alcohol consumption, should lead the clinician to a further, more detailed evaluation of alcoholism. This
includes additional history to fully characterise the extent of drinking, and identify the presence of alcohol
withdrawal symptoms, anxiety, depression or other comorbid psychiatric or medical illnesses.
In addition, a physical examination and laboratory tests are indicated to support the results of the
13~
assessment. Useful signs to identify on physical examination include: abnormal skin vascularisations,
6 7
hand tremor, rhinophyma, hepatomegaly and signs of past or present injury.[ . ] Serum y-
15 91 9~ 0
glutamyltransferase (GGT) ' and mean corpuscular volume (MCV)[ ' ] have been identified as
objective markers of alcoholism; however, they have low sensitivity for the identification of less severe
11-13
alcoholism.[ ] 2. Alcohol Intoxication
4
Alcohol intoxication is a major cause of traffic accidents, suicides and hospital admissions.[t ] The search
for an alcohol antagonist has been in progress since the time when the ancient Greeks believed that the
precious stone amethyst could block or reverse its behavioural effects; hence the term 'amethystic' agent.
However, today there are many ethical and legal problems with allowing intoxicated individuals to drive
cars, operate machinery or drink alcohol excessively without the perception of harm.
A single amethystic agent may never be found because alcohol affects various classes of synaptic
receptors, neurotransmitters and neurohormones. Specific agents that have been investigated as alcohol
antagonists in humans include: levodopa, aminophylline (theophylline ethylenediamine), ephedrine,
15 161 17
naloxone, lithium, calcium antagonists, fructose~ ' and more recently pyridoxine.[ ] Initial results could
not be replicated or confirmed for any of these agents.[l] Therefore, acute alcohol intoxication is usually
111
treated with supportive care.

3. Alcohol Withdrawal Syndrome

When alcohol intake is abruptly discontinued or reduced and blood alcohol concentrations decrease
rapidly, a characteristic withdrawal syndrome results. The severity of the reaction varies with the
intensity and duration of the preceding alcohol exposure. The symptoms of a mild reaction are tremor,
insomnia and irritability lasting 48 hours or less, which, in a severe reaction, are followed by
1 181
hallucinations, seizures and delirium tremens.t , While controlled studies have confirmed the p0tency of
nonpharmacological interventions such as monitoring of signs and symptoms and general nursing
1191 1201
care, patients with a history of withdrawal seizures or comorbid illness, or those in moderate to
8 21
severe withdrawal, should also receive pharmacotherapy,[t . ] as summarised in table1.[l,ts,20,22-37J
A nationwide survey in the US of 176 inpatient alcohol treatment programmes revealed a wide variety of
1351
treatment regimens being used. The most commonly used medications were the benzodiazepines,
including chlordiazepoxide (33%), diazepam (16%) and the shorter-acting oxazepam (7%) and lorazepam
(4%). Others included barbiturates (11%), phenytoin (10%), clonidine (7%), ~-adrenoceptor antagonists
(3%), carbamazepine (1%) and antipsychotics (1%). 52% of the programmes used a fixed dosage
regimen with additional doses as needed, and only 9% used a front-loading dose technique.
Earlier studies described the effectiveness of the diazepam loading dose technique in which patients with
moderate to severe withdrawal are administered 2Omg of oral diazepam hourly until they show clinical
11 22~
improvement or become mildly se dated. ' This approach was supported by a double-blind, controlled
trial of 101 inpatients who were randomised to either fixed-schedule therapy of chlordiazepoxide 4 times
daily or to symptom-triggered therapy in which medication was given hourly in the presence of continued
symptoms (which in essence resembles the loading dose technique, except that asymptomatic patients
received no further medication). The mean duration of treatment, as well as the total dose of
chlordiazepoxide, was significantly lower in the symptom-triggered group (9 vs 68 hours, and 100 vs
123
425mg, respectively). ]

Table I. Alcohol intoxication and withdrawal

Medication comments References
Intoxication None Supportive care only 1
Alcohol withdrawal Long.acting Loading dose technique 1,20,22,23
syndrome benzodiazepine (e.g. is effective, simple and
diazepam or tolerated, and lowers the
chlordiazepoxide) duration of treatment and
total dose, e.g. diazepam
2Omg P0 hourly until
improved or mildly
sedated. Drug of choice,
other than in the elderly
or in severe liver disease
Lorazepam Drugs of choice in the 24
elderly or in severe liver
disease
Clonidine Superior to placebo, but 25-29
inconsistent compared
with benzodiazepines
Atenolol Superior to placebo, but 30
additional evidence not
available
Carbamazepine Probably efficacious, but 18,31-34
adverse effects limit
routine use
Chiormethiazole Less effective and less 18,35
well tolerated than
benzodiazepinea
Barbiturates Good evidence of 36,37
efficacy; however,
narrow safety margin
limits use

PO = orally
In clinical situations where impaired hepatic metabolism is a concern (e.g. the elderly, liver disease), it
appears that lorazepam is the best tolerated benzodiazepine given that it does not undergo hepatic
oxidation, and thus has more predictable pharmacokinetics. t24] Recently released practice guidelines
recommend benzodiazepines for the treattnent of alcohol withdrawal syndrome, with ~-blockers,
clonidine, carbamazepine and antipsychotics used only as adjunctive therapy. Symptom-triggered
2
therapy was the preferred regimen, with structured assessment scales for monitoring.[ O]
Several medications have undergone randomised trials for evaluation in the treatment of alcohol with-
drawal syndrome. Clonidine (an or2-adrenoceptor agonist) has been reported to be superior to pla-
1251
cebo; however, when it was compared with benzodiazepines in double-blind studies, the results were
inconsistent with regard to efficacy and preventing complications. (26-29] Atenolol has also been found to
1301
be superior to placebo for the treatment of alcohol withdrawal, but no further investigations have been
done.
Double-blind studies comparing carbamazepine and oxazepam in the treatment of alcohol withdrawal
3 133~
syndrome found similar efflcacy;[ .32] however, concerns about the methodology in these studies, as
134~ 1
well as adverse effects, have limited the utility of carbamazepine as a routine treatment. t8] There is
1361
evidence that barbiturates are efficacious in this application, but a narrow margin of safety raises
concems about their routine
1371
use. Chlormethiazole is a sedative-hypnotic agent that has been used for the treatment of alcohol
1151
withdrawal syndrome in Europe. Studies have shown it to be superior to placebo, but these results are
1351
inconsistent, and concerns that it is less effective and less well tolerated than benzodiazepine5 have
limited its widespread use.
Research continues into other treatments for alcohol withdrawal syndrome, based on various theories
about the cause of the syndrome. Specific modalities that have been investigated include:
13941~ 42 43 134 44 145 46~
analgesic nitrous oxide, phenytoin,[ . ) valproic acid (sodium valproate), . ] flumazenil '
147~491 150
calcium antagonists, 5-HT3 antagonists, ] N-methyl-D-aspartate (NMDA) receptor antago-
8 5~~ 1521 53 1541
nists,~~ ' dexamethasone, tiapridet ] and testosterone. Data on the benefit of these pharma-
cotherapies are limited at this time and further studies are required. However, none appears to provide
significant benefit over benzodiazepines.

4. Decreased Consumption and Relapse Prevention

Numerous types of medications to decrease alcohol consumption and prevent clinical relapse have been
tested, many of which are summarised in table ~ The choice of which medication to use is not only based
on the evidence, but is also dependent on the availability of medications, which often differs markedly in
different regions of the world.

4.1 Naltrexone

A large body of research has described the role of the endogenous opioid system in alcohol consumption.
Some studies have shown that the reinforcing properties of drinking alcohol are related, in part, to
1961
increases in endogenous opioid activity following alcohol use, thus hypothesising a mechanism for
1971
opioid antagonist therapy. Genetically determined differences in endogenous opioid response to
1981
alcohol intake have also been related to risk of alcoholism.
In late 1994, naltrexone became the first drug in over 40 years to be approved in the US for treating
159 601
alcohol dependence. [55] A combined analysis of the original 2 trials ' that led to approval was re-
cently reported. In a total of 186 patients, naltrexone showed significant differences over placebo with
regard to abstinence at the end of the 12-week treatment period (54 vs 31%) and time to first episode of
1611 1621
heavy drinking. A 6-month post-treatment follow-up of 80 patients in the study by O'Malley et al.
showed the naltrexone group to have higher abstinence levels at 1 month (67 vs 40%), lower relapse
rates at 4 months (35 vs 57%) and fewer patients meeting criteria for alcohol abuse (10 vs 24%) or
1621
dependence (13 vs 39%) at 6 months. Reanalysis of the original trials showed that, while treatment
with naltrexone did not significantly reduce the likelihood of sampling alcohol, it did significantly reduce
164
the rates of clinical relapse 1631 and that this was probably due to lower levels of craving, ] as well as
1651
reports of feeling less 'high' after drinking.
Table II. Medications used to decrease alcohol consumption and prevent clinical relapse
Medication Comments References
Naltrexone Approved for treating alcohol 55
dependence
Reduces consumption in heavy 56-58
social drinkers
Increases abstinence, lowers 59-66
relapse rates and may have an
anticraving effect
Contraindicated in severe liver 67
disease, or in the presence of
acute infection or
immunodeficiency
Increase monitoring if used by 67
women of childbearing age, or in
patients with polysubstance
abuse
Start St 25 mg/day with increase 67
in 2 days to 50 mg/day
Acamprosate Approved in Europe 68
Increases abstinence, may have 69-73
anticraving effect
Contraindicated in pregnant or 74
lactating women, renal or severe
hepatic
impairment, children and the
elderly
Dosage of 1.3 g/day if <60kg 71,72,74
bodyweight and 2 g/day if >60kg,
with 1y duration
Fluoxetine No benefit, with possible worse 75-78
outcomes
Citalopram Transient effects with no 79-82
improvements in outcome. More
effective in men than in women
Fluvoxamine Poorly tolerated, thus limiting use 83
Ondansetron May reduce the desire to drink 84,85
At a dosage of 0.25mg bid, 86
reduces consumption in mildly to
moderately
alcohol-dependent individuals
Ritanserin In social drinkers, improves some 87
alcohol-related measures but
limited effect
on alcohol intake
Alcohol-aensitising agents Clinical use being challenged 88-91
[disulfiram, calcium carbimide given no apparent benefit over
(calcium cyanamide)] placebo, poor compliance
May be effective when 91-93
compliance is assured by regular
supervision in a
structured programme
Bromocriptine Long-acting injectable shows no 94
benefit in relapse prevention
Oral route appears to reduce
 craving in those with specific D2
receptor genotype
bid twice daily.

In a more recent double-blind trial, 97 alcohol-dependent individuals were given psychosocial treatment
and randomly assigned to naltrexone or placebo for 12 weeks in an outpatient setting. This more
naturalistic design, where compliance was not ensured, showed naltrexone overall to have nonsignificant
effects in reducing relapse rates (53 vs 35%) and number of drinking days (6 vs 11%), with significant
1661
improvement in drinking outcomes only in those who were highly compliant with the medication.
Interindividual variability in response to naltrexone has been observed; thus, another area of investigation
with naltrexone is patient/treatment matching. Studies have suggested that naltrexone showed more
163 99 163~
benefit in patients with high baseline craving, . ] somatic distress and poorer cognitive
99
f~~~tioning.l i An ongoing study is attempting to identify a relationship between a noninvasive
measurement of endogenous opioid activity and response to naltrexone. The effect of naloxone when
combined with alcohol expectancy on an individual's response to pain is being evaluated as a possible
biological predictor of response in a double-blind, placebo~controlled trial of naltrexone plus cognitive
11
behavioural therapy. 00]
1561
Population studies in the US found 15 to 21% of men and 5 to 6% of women to be frequent drinkers.
Some investigators have therefore focused on the effects of naltrexone on alcohol consumption,
hypothesising that it may be useful in the secondary prevention of alcohol dependence. Studies in social
or nondependent heavy drinkers have revealed a number of changes with patients taking naltrexone
156 571 157 551
while using alcohol, which include: reduced craving, ' an aversive effect ' and greater subjective
1551 156
intoxication, as well as lower total consumption and fewer heavy drinking days. ] These data,
however, are insufficient to make recommendations regarding the use of naltrexone in nondependent
heavy drinkers.
Issues relevant to the clinical use of naltrexone have been well summarised in a recent risk-benefit
1671
assessment. Naltrexone is a pure opioid antagonist with no agonist activity and therefore no abuse
potential. No evidence of tolerance or dependence has been found. There is little concern about drug-
drug interactions since the major metabolite (6-~-naltrexol) is not metabolised via the cytochrome P450
enzyme system. It has an excellent safety profile, with the most common adverse effects being nausea
and vomiting and less commonly headache, anxiety and fatigue. These often resolve within days and
may represent a mild opioid withdrawal reaction. Suggestions have therefore been made that the regimen
should start at a dosage of 25 mg/day, with an increase to the full 50 mg/day after 2 days.
Initial concerns regarding hepatotoxicity were based on reported increases in transaminases in stud-
ies of patients taking naltrexone 300 mg/day; however, the majority were asymptomatic, and all resolved
1101 1021 60
when the drug was stopped. ' There is no evidence of hepatotoxicity at recommended dosagesf ]
but, given the concerns, naltrexone is contraindicated in the presence of acute hepatitis, or during marked
liver damage or failure. Other concems include use by women of childbearing age who should have their
birth-control methods monitored, since naltrexone stimulates luteinising hormone (LH) which may lead to
unexpected ovulation. In addition, due to naltrexone increasing cortisol levels, patients with acute
infection or immunodeficiency must weigh the risks and benefits of the treatment in this situation, as these
arc not known. If there is concern about initiating an opioid withdrawal syndrome in the presence of
polysubstance use, a naloxone challenge test should be performed before stattting therapy. Patients
should be instructed to wear a notice identifying them as using naltrexone, explaining that it is an opioid
antagonist and that therefore much greater doses of opiates would be needed if these are required in an
emergency.
Drawing on the effectiveness of naltrexone that has already been described, there are several further
3
issues that require exploration. A study in animals has shown the usefulness of periodic naltrexonelto ]
and some have suggested resuming treatment in patients during high-risk periods after the recommended
initial 12-week treatment period ft 04] Another consideration is combination pharmacotherapy, with a
1t05
recent trial comparing naltrexone with sertraline versus naltrexone alone in 18 alcoholic patients. ]
However, the group receiving combination treatment showed no further improvement in several drinking
outcomes and relapse over those receiving naltrexone alone. Optimal length of therapy, effectiveness
with only minimal psychosocial intervention, initiation during inpatient programmes and higher doses all
1104
require further study. ]
4.2 Nalmefene

Studies using other opioid antagonists, specifically nalmefene (nalmetrene), have shown promismg
results. In a 12-week, double-blind, randomised, placebo-controlled trial of 21 alcohol-dependent patients,
those receiving nalmefene 40 mg/day had significantly lower rates of relapse, and a greater number of
11061
abstinent days. Nalmefene was well tolerated and has potential advantages over naltrexone, including
no dose-dependent hepatotoxicity and more effective binding to central opiate receptors.

4.3 Acamprosate

Acamprosate (calcium acetyl-homotaurinate) is another medication which has attracted much attention
over the past few years, especially in Europe where it has been approved for the treatment of
168~
alcoholism. Although not yet fully understood, it appears to act by several mechanisms, including
1691
inhibiting hyperexcitation of excitatory amino acids (e.g. glutamate), reducing calcium ion fluxes,
1741
increasing GABA uptake, increasing serotonin levels, and noradrenergic antagonism.
Four randomised, double-blind, placebo-controlled trials with a total of 1453 detoxified alcohol-dependent
169 721
patients, lasting 3 to 27 months, have recently been published. - The treatment groups consistently
showed significantly higher rates of continuous abstinence (33 vs 15%), mean duration of abstinence [the
percentage of days a patient is abstinent divided by the total number of days in the study (48 vs 34%)J
and retention in study [the number of patients who remain in the study for its duration (51 vs 38%)]
compared with the controls. Even though the results are significant, the size of the effect (acamprosate-
placebo) was relatively small (18, 14 and 13%, respectively). Several of these studies suggested an
anticraving effect, with one finding significantly lower psychological dependence in the treatment
1721
group. Similar results of significantly increased abstinence rates and retention in study were found
1731
from a pooled analysis of 11 trials involving 3338 patients.
Specific issues pertaining to the clinical use of acamprosate have been summarised in a recent re-
1741
view. Usually, the recommended dosage is 1.3 g/day for patients who are <60kg, and 2 g/day for
1741
those >60kg, to be taken in 3 divided doses with meals. However, in the absence of adequate dose-
response relationship studies, dosage recommendations are empirical. Two studies failed to show any
171 721
significant differences in results between dosages of 1.3 and 2 g/day, ' and although there were
1721
trends towards a better outcome at the higher dosage, compliance may be a problem since diarrhoea,
17~1
the most common adverse effect, is dose-dependent. Treatment should be started soon after
detoxification, with a recommended duration of 1 year. Acamprosate has an excellent safety profile, as
there is no evidence of addictive potential or overdose toxicity, and a low risk of drug-drug interactions
since it is not metabolised, but directly excreted in the urine. Acamprosate is contraindicated in pregnant
or lactating women, and in patients with renal impairment or severe hepatic failure. Due to limited
experience in the elderly, its use should be avoided.

4.4 SerofonergiC Drugs

Studies in animals and humans indicate the importance of serotonergic neurotransmission in the
11071
regulation of alcohol consumption. Several selective serotonin reuptake inhibitors (SSRIs), including
fluoxetine, fluvoxamine and citalopram, have been investigated in terms of decreasing alcohol
consumption and preventing relapse.
Fluoxetine 60 mg/day has been tested in 2 recent randomised, double-blind, placebo-controlled trials
175 761
involving a total of 129 alcohol-dependent patients. ' Both trials showed that treatment did not reduce
rates of relapse; in fact, one study revealed a trend towards lower abstinence rates in the fluoxetine
1751 1761
group, with the other showing greater compliance and retention in study for the placebo group. A
reanalysis of one study displayed poorer drinking-related outcomes in the treatment group among those
1771
characterised as being type B alcoholics (i.e. early onset and greater alcohol-related problems).
Another trial involving fluoxetine 60 mg/day for 2 weeks showed no effect on decreasing consumption in
nonmotivated, mildly to moderately dependent alcoholic individual 5~f75]
A double-blind study in mild to moderate alcohol-dependent patients given citalopram 40 mg/ day or
placebo for 12 weeks with a brief psychosocial intervention showed a significant reduction in alcohol
intake only during the first week of citalopram. Thereafter, both placebo and citalopram groups reduced
791
their drinking similarly, thus putting the clinical utility of citalopram into question.[ Further analysis of this
study revealed a significantly greater response to citalopram in men than in women after 12 weeks of
501
treatment.~ Two studies in severely alcohol-dependent patients revealed some improvement in drinking
behaviours in those receiving citalopram 40 mg/day, though these did not translate into significantly lower
81 521
abstinence rates.~ ' Other studies using citalopram without a brief psychosocial intervention have
shown that individual responses vary to a large degree, with no specific patient characteristics predicting
t08~
response.~ ' 09]
In 2 trials using fluvoxamine, 18 of the 26 patients receiving active drug dropped out, mostly due to
531
adverse effects.~ Thus, the effect of SSRIs is usually short term.
It has been hypothesised that serotonin antagonists reduce the reinforcing effects of alcohol and
11
decrease the desire to drink.~ Pretreatment with ondansetron (a 5-HT3 receptor antagonist) in healthy
volunteers and social drinkers was found to augment certain stimulant, sedative and pleasurable effects
184 851
following a standard dose of alcohol. ' Patients reported a decreased desire to drink, possibly
mediated by increased intoxication and/or aversive effects. In a 6-week, double-blind, placebo-controlled
trial in which all patients were taught coping skills, ondansetron 0.2Smg twice daily was found to
significantly reduce the number of drinks per drinking day in those with a baseline drinking level of <10
drinks per day. No effect was found in the group receiving ondansetron at a dosage of 4 mg/day. [86]
Pretreatment with ritanserin (a 5-HT2 receptor antagonist) in healthy volunteers, followed by a dose of
11
alcohol, showed no change in CNS-depressant effects. 10139 heavy social drinkers were randomised,
in a double-blind fashion, to either ritanserin S or 10 mg/day or placebo, with no other treatment. There
was slightly less desire for alcohol in the S mg/day group, and decreased liking of alcohol in the 10
1871
mg/day group. However, neither treatment showed significant effects on outpatient alcohol intake.
These results suggest that ritanserin has limited efficacy for reducing heavy drinking.

4.5 Alcohol Sensitisers

Currently, 2 pharmacotherapies widely used in clinical practice to maintain abstinence are the alcohol-
sensitising agents disulfiram and calcium carbimide (cyanamide). These drugs inhibit hepatic aldehyde
dehydrogenase (ALDH), causing increased blood acetaldehyde levels after alcohol ingestion. The result
111
is a highly unpleasant episode of flushing, weakness and nausea. At present their efficacy is being
questioned given that several large trials failed to show any benefit over placebo, and that
188 901
nonpharmacological factors appeared to explain the earlier findings. -
A review of 24 studies with oral disulfiram, and 14 with implanted disulfiram, concluded that the evidence
1911
for the use of this drug was equivocal, with most studies using poor methodology. In addition, poor
compliance with these medications has put in doubt their clinical effectiveness. If compliance is assured
by regular supervision, then disulfiram has shown a benefit in decreasing alcohol consumption and
1921
increasing total abstinent days. Some, therefore, suggest a role for the use of disulfiram in the context
91 931
of a structured programme with contracts and meaningful incentives for compliance.[ . Factors limiting
the use of disulfiram and calcium carbimide include several contraindications (e.g. severe liver disease,
111
pregnancy, heart disease, greater age), CNS and liver toxicity, and multiple drug-drug interactions 1-
113]

4.6 Other Agents

There is evidence of altered dopamine function in alcoholic patients both when drinking and when
detoxified.ft 14J Long-acting injectable bromocriptine (a dopamine D2 receptor antagonist) was recently
studied in a double-blind, placebo-controlled trial with 366 moderately and severely alcohol-dependent
patients being randomised to 6 monthly injections of bromocriptine 25 or SOrug, or placebo. No
94
significant differences in rates of relapse were found between the treatment groups.t ] In another trial,
oral bromocriptine was given to alcoholic individuals in a double-blind, placebo-controlled design.
Interestingly, a reduction in craving occurred in the actively treated patients who were found to have the
A1 allele of the D2 receptor. f95] This again raises the issue of potential patient treatment matching, in this
instance involving a specific genotype.
1151
Other medications recently investigated in relapse prevention include 4-hydroxybutyric acid (GHB),[
6 17~
interferon[tt l and nitrous oxide.~' Although preliminary results are encouraging, they all used open-
label designs or were plagued by poor methodology. Of additional concern is that both GHB and nitrous
oxide have an abuse potential, which is likely to limit their role in this patient population.
5. Treatment of Alcohol Dependence with a Comorbid Psychiatric Diagnosis

Alcohol dependence is often associated with a comorbid psychiatric diagnosis. In a survey of 928 alcohol-
dependent men seen at a Veterans Administration Centre, 62% met lifetime diagnostic criteria for at least
one other psychiatric illness.fttSJ Several of these illnesses and possible treatments are presented in
table 111,[1t9-t30]

5.1 Depression

A recent large survey of alcohol-dependent individuals found a history of primary depression in 15.2% of
the group and secondary depression in 26.4%.tt3t] Primary depression is defined by the first episode of
depression having occurred before the onset of alcohol abuse or occurring during periods of prolonged
abstinence.tt 20]
Imipramine was assessed in a 12-week open trial involving 60 alcoholic patients with primary depression,
9
and 45% showed improvement in both mood and drinking.[tt t The responders from this trial were then
eligible for a randomised, placebo-controlled, double-blind discontinuation study which revealed a trend
towards decreased relapse in the treatment group. In a second randomised, placebo-controlled trial
involving similar patients, no overall effect on drinking was found; however, reduced consumption was
20~
evident in those with improved mood.~~ Unfortunately, a 25% dropout rate in the treatment group due
to oversedation and anticholinergic adverse effects remains an obstacle for imipramine use.
Desipramine was studied in a 6-month, placebo-controlled, double-blind trial involving 71 detoxified
1211
patients with alcohol dependence, 28 of whom had secondary depression.~ Results showed a sig-
nificant improvement in mood symptoms among the depressed patients, as well as a trend towards a
decrease in relapse to alcohol drinking in both treatment groups.

Table Ill. Comorbid psychiatric diagnoses associated with alcohol dependence

Diagnosis Medication Comments References
Depression Imipramine May reduce alcohol use 119
in patients whose
primary depression
improves
Adverse effects result in 120
high dropout rate
Desipramine Good efficacy in treating 121
secondary depression,
with possible lower
relapse rates
Fluoxetine Reduces alcohol 122,123
consumption, with lower
relapse rates and
improvements in
depression
Anxiety disorder Buspirone Improvements in both 124,125
drinking outcomes and
anxiety symptoms
Post-traumatic stress Sertraline Preliminary results show 126
disorder reductions in psychiatric
symptoms and
improvements in drinking
outcomes
Antisocial personality Nortriptyline Limited evidence tinds 127,128
disorder higher abstinence rates
and lower consumption
only in those with a
 concurrent mood or
anxiety disorder
Bipolar affective disorder Vaiproic acid (sodium Small study suggests 129,130
valproate) improvement in mood
and reduced
consumption

An open trial involving 12 depressed alcohol-dependent individuals, treated with fluoxetine at 20 to 40

221
mg/day for 8 weeks, resulted in significant improvements in depression and alcohol consumption.~' A
12-week, double-blind study randomised 51 depressed alcoholics to fluoxetine 20 mg/day or placebo, and
found that treatment with fluoxetine had significant effects in lowering alcohol consumption, increasing
23
time to first episode of heavy drinking, and decreasing depressive symptoms.tt ]
These results, in combination with those from the tricyclic antidepressant trials, provide strong support for
the pharmacological treatment of depression occurring in the alcoholic patient. Some researchers have
suggested that, since a majority of depressions resolve once detoxification is complete, clinicians wait for
1132 133~
2 weeks of abstinence before starting any antidepressants. ' In contrast, others have shown the
34
stability of depression in alcoholic individuals over time,[t ] and that the presence of either primary or
secondary depression at entry into treatment for alcoholism increased the rate of relapse, and decreased
135~
time to first drink.~ Further trials are thus required to provide more clarity in this area.

5.2 Anxiety Disorders

36
In the Epidemiological Catchment Area surveyfl ] 19.4% of those with a history of alcohol abuse or
dependence also had a lifetime diagnosis of an anxiety disorder. Evidence suggests that anxiety is likely
to be both a cause and a consequence ofalcoholism.~ 137] Nonpharmacological treatments are indicated
for managing transient anxiety sympfoms, with medications recommended for the treatment of chronic
anxiety disorders.
Buspirone, a 5-HTIA partial agonist, has been used in the treatment of anxiety disorders coexisting with
alcoholism. A 12-week, double-blind trial involving 61 patients randomised to buspirone 2Omg three times
daily or placebo revealed significantly greater retention in the study, fewer drinking days at 6-month
124
follow-up, and a trend to slower relapse for the treatment group.[ ] Are-cent meta-analysis of buspirone
1251
in this population again showed increased treatment retention and improvements in anxiety.( A trial of
buspirone in alcoholic patients not selected for a comorbid anxiety disorder failed to show an
improvement in alcohol consumption, while still leading to significant improvements in several
psychopathological measures ff35]
In patients with alcohol dependence, the lifetime prevalence of post-traumatic stress disorder (PTSD) has
1139~
been shown to be 10% in men and 26% in women. Nine such patients were treated with sertraline
1126
200 mg/day for 12 weeks in an open-label fashion. ] The results showed significant decreases in all 3
symptom clusters of PTSD, increased days of abstinence and decreased consumption at 3-month follow
up. Limitations included the presence of other comorbid disorders such as depression in several patients,
as well as a high dropout rate, with 3 noncompleters, 2 of whom were lost to follow-up. A large, controlled
study is needed to confirm effectiveness.
Patients with antisocial personality disorder tend to be refractory to treatment, especially in the presence
of other psychiatric disorders. 29 patients with antisocial personality disorder, alcohol dependence and a
current affective or anxiety disorder had significantly fewer drinking days and increased abstinence rates
1281
following treatment with nortriptyline for 6 months.[ No improvement was found for those who did not
1251
have a current affective or anxiety disorder.~

5.3 Bipolar Disorder

36~
Of patients with bipolar affective disorder, 40% have an associated alcohol use disorder.~' An open trial
investigated valproic acid for 16 weeks in 9 patients with bipolar affective disorder and a concurrent
29
substance dependence, 8 of whom used alcohol alone or in combination with other drugs.[l )
The trial showed significant improvements in both mania and depression, as well as decreased alcohol
consumption at 6 months' follow-up. Finally, 2 case reports of patients with alcohol abuse, panic disorder
and either bipolar or organic affective disorder described large improvements in alcohol use, panic
130~
attacks and affective episodes or instability when they were treated with valproic acid.~ Controlled
studies are needed.

6. Conclusions

There has been significant progress in the drug treatment of alcoholic patients. Recommended
management of the alcoholic patient is summarised in figure 1. Given the many different medications that
are discussed here, it is clear that no single pharmacological agent will be useful in all cases of alcohol
dependence. Psychosocial modalities remain central to managing this illness, and in many of the trials
involving pharmacological agents patients also received psychotherapy or other non-pharmacological
interventions. Increasingly, however, adding medications to these other modalities is being shown to be
effective in treating various components of the illness.
During an alcohol withdrawal syndrome, treatment with long-acting benzodiazepines, using a loading
dose technique, has been shown to be a well tolerated and effective strategy. Once patients are
abstinent, there is evidence to suggest that both naltrexone and acamprosate decrease consumption and
help reduce relapse. If patients enter a comprehensive treatment programme, and do not have any
contraindications to the medications, either naltrexone or acamprosate should be considered an integral
component of their treatment plan. In patients with alcohol dependence and a comorbid psychiatric
disorder, there is increasing evidence that pharmacotherapy is an effective tool. Specifically,
antidepressants may be useful for a comorbid depression, and buspirone may be useful for chronic
anxiety symptoms.
Further basic science and clinical research developments should produce more detailed information
regarding the treatment of alcoholism, leading to improvements in the pharmacological strategies used in
alcoholic patients.

Acknowledgements
We gratefully acknowledge Ms Karen E. Bremner, Ms Linda Neuman and Ms Shauna 0. Brail fur their
assistance in the preparation of this manuscript.
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Correspondence and reprints: Professor Claudjo A. Naranjo, University of Toronto, Sunnybrook Health
Science Centre, Psychopharmacology Research Program, 2075 Bayview Avenue, Room F327, Toronto,
Ontario, Canada M4N 3M5. F-mail: [email protected]