The efficacy of disulfiram compared with acamprosate and naltrexone shows
definitive efficacy advantage for disulfiram when the patients are assigned to
supportive care that verifies adherence.
205,206 Although no advantage was seen for
combining disulfiram with naltrexone in dually diagnosed alcohol-dependent
In one study, disulfiram combined with acamprosate resulted in increased
days of cumulative abstinence.
The recommended starting dose of disulfiram is 250 mg once daily, with a range of
and does not experience a disulfiram–ethanol reaction, the dose can be increased to
500 mg, because a significant proportion of patients may not experience a
disulfiram–alcohol reaction at the usual 250-mg daily dose.
increased, however, at doses exceeding 250 mg. Dosing starts at least 12 to 24 hours
after abstinence initiation (when the blood or breath alcohol concentration is zero).
Treatment continues, depending on the particular needs of the individual, but is
generally at least 90 days, and maintenance therapy may be required for years.
Contraindications, Warnings, and Interactions
Because of the intense cardiovascular and physical changes that occur in the
disulfiram–ethanol interaction, disulfiram is contraindicated in patients with cardiac
disease, coronary occlusion, cerebrovascular disease, and renal or hepatic failure.
At somewhat higher doses, psychotic reactions have occurred. It is not definitive that
disulfiram causes fetal abnormalities when administered during pregnancy but some
disulfiram should only be used during pregnancy if the expected benefit to the mother
and fetus is greater than the possible risk to the fetus; however, it should be avoided
in the first trimester (category C). No information is available about the safety of this
medicine during breast-feeding.
Disulfiram can also be hepatotoxic and should be used cautiously in patients with
liver disease. Liver function should be established at baseline and after 14 days of
treatment, and a complete blood count (CBC) and liver function tests (LFTs) should
R.M. has normal hepatic function; however, LFTs should be monitored at baseline
and periodically during treatment. Although not all clinicians agree, most would
recommend—at minimum—baseline LFTs: ALT, AST, and GGT and withholding
disulfiram when LFTs are more than three times upper limits of normal.
elevated, repeat LFTs every 1 to 2 weeks until normal, and then every 3 to 6 months
if no elevations, with an awareness that increased LFT results may signal a return to
drinking rather than disulfiram toxicity.
214,215 Persistently elevated LFTs may also
indicate viral hepatitis (B or C), for which alcoholics have a higher risk, and thus the
need to order a hepatitis profile. Currently, guidelines point out that a reduction in
alcohol use will lead to more normalized LFTs. Psychiatric adverse effects include
disorientation, agitation, depression, and behavioral changes such as paranoia,
withdrawal and bizarre behaviors, and worsening of schizophrenia, especially at
doses greater than 250 mg daily.
216,217 Disulfiram should be avoided or used very
cautiously in persons with these conditions although it can be used safely at a dose of
250 mg daily in alcohol-dependent patients with concomitant psychiatric disorders,
207,218,219 Common side effects of disulfiram include
drowsiness, particularly in the first few weeks of treatment, a metallic or garlic taste,
and sexual dysfunction. The dose can be taken at bedtime if drowsiness or tiredness
Disulfiram is a potent inhibitor of the CYP2E1 oxidase and can interact with
anticoagulants (warfarin), antiepileptics (phenytoin, carbamazepine), some
benzodiazepines (e.g., diazepam), and tricyclic antidepressants (amitriptyline,
desipramine), potentially increasing the toxicity of these medications. Delirium can
result in combination with monoamine oxidase inhibitors. Adverse effects with
disulfiram that mimic the alcohol–disulfiram interaction can also occur with
To receive optimal results with disulfiram, patients must receive regular
counseling and be closely monitored for any changes in hepatic function. Having
someone participate in helping to validate the administration process is known to
lead to better outcomes. Discontinuation of disulfiram should occur only after
consultation with the prescriber and counselor involved. Patients must stop the
medication for at least 3 days (up to 14 days in some) before being exposed to
products containing alcohol. It is important to educate patients taking disulfiram
respiratory difficulty, nausea, vomiting, decreased appetite, dark colored urine, or a
change in pigmentation in the skin or eyes (primarily yellowing).
Generally, given the special circumstances needed for success, disulfiram is not the
drug of choice for treating alcoholism. The social, medical, and psychiatric status of
a candidate is an important consideration in the use of disulfiram. R.M. would appear
to be a reasonable candidate for disulfiram given he has agreed to have his
medication administration supervised (in this case by his wife), his steady
employment, and his motivation to sustain abstinence. R.M. should also receive
counseling and support services on a regular basis.
Acamprosate (Campral) has multiple actions, but is principally a glutamate and
GABA modulator. The key mechanism of action is considered to be as a weak
functional antagonist of the glutamate NMDA receptor, possibly mediated through
indirect modulation of the receptor site via antagonism at the mGluR5 receptor.
series of meta-analyses and systematic reviews demonstrated that when used as an
adjunct to psychosocial interventions, acamprosate improves drinking outcomes such
as the length and rate of abstinence.
180,222–224 This effect is less likely if acamprosate
is not initiated quickly after a detoxification.
225,226 Evidence indicates that the effect
of acamprosate on abstinence lasts after the treatment is stopped.
appears to be especially useful in a therapeutic regimen targeted at promoting
abstinence and can be used in primary care settings as well as specialized addiction
228 Few contraindications to treatment exist. Little consistent
information is found about patient characteristics that predict improvement while
taking acamprosate. In a meta-analysis of all US and European studies, predictors of
abstinence were motivation, readiness to change, baseline abstinence, initial first
week compliance, and living with a partner or child.
229 A pooled analysis of seven
European trials, however, found no significant predictors of the abstinence outcome
230 Candidates for acamprosate should be committed to abstinence and
begin the medication after being abstinent from alcohol.
In a systematic review of the efficacy data related to acamprosate, proof for
efficacy of acamprosate was strong.
231 Moreover, several acamprosate studies have
reported positive results. For example, in a study of 272 severely dependent
alcoholics, patients receiving acamprosate showed a significantly higher continuous
abstinence rate within the first 2 months of treatment compared with patients
184 Of acamprosate-treated patients, 40% were continuously
abstinent for a 48-week period compared with 17% of those who received placebo.
Acamprosate has also been studied for periods of up to a year. In a long-term
follow-up (12 months) after trial completion, acamprosate still maintained an effect
on abstinence rates, but not on nondrinking days. Some studies have found limited to
191,233–236 although two of the studies may have been
191,233–236 One of these studies also had a short treatment period, and
the other had a long delay in initiating treatment.
suggest that acamprosate is a safe and well-tolerated drug for the promotion of
Acamprosate is dispensed in 333-mg tablets and the usual dose is 666 mg/day 3
238 Patients can be started on the full dose without titration. Acamprosate
is not well absorbed from the GI tract and with a terminal half-life of around 30
hours it takes several days to achieve desired blood levels of the medication.
medication appears to be safe and effective in alcoholics, with minimal side effects.
It does not appear to produce sedation and does not cause drug dependence. Main
adverse effects of acamprosate appear to be GI, including nausea, diarrhea, and
bloating. Nausea or diarrhea can be easily managed, but if symptoms are severe or
persistent, the dose should be reduced by one-third to one-half. The duration of
therapy ultimately depends on treatment success and the willingness of the patient to
continue therapy indefinitely.
Contraindications, Warnings, and Interactions
Acamprosate is excreted unchanged in the urine and should not be used in patients
with impaired kidney function (creatinine clearance [CrCl] <30 mL/minute) or in
patients who previously exhibited hypersensitivity to acamprosate.
should be 333 mg 3 times daily in patients with moderate renal impairment (CrCl
30–50 mL/minute). Acamprosate should only be used during pregnancy when the
benefit clearly outweighs the risk as the drug has been shown to be teratogenic
238 Tetracyclines may be inactivated by the calcium component in
acamprosate during concurrent administration.
238 Naltrexone increases plasma levels
of acamprosate, although the clinical significance of this interaction is unknown and
the two can be safely used together.
238,239 Suicidal ideation and attempted and
completed suicides have occurred in patients taking acamprosate.
Acamprosate must be used in combination with a psychosocial program such as
cognitive-behavioral therapy (CBT) or regular Alcoholics Anonymous (AA)
meetings. Acamprosate may be taken without regard to meals. The tablets should not
be crushed and should be taken whole. Although no interaction with alcohol occurs,
abstinence in combination with counseling and social support is required to attain
optimal treatment. Patients should report persistent diarrhea, sudden or excessive
weight gain, swelling of the extremities, respiratory difficulties, fainting, or thoughts
A retrospective long-term study in 353 alcohol-dependent patients, supervised
disulfiram was found to be superior to acamprosate, particularly in patients with a
long history of alcohol dependence.
Naltrexone blocks the action of endorphins when alcohol is consumed, and this
results in an attenuation of the dopamine release at the nucleus accumbens thought to
be crucially important to positive reinforcement, reward, and craving.
naltrexone therapy has been recommended for all alcohol-dependent patients who do
not have a medical contraindication to its use, a survey of 1,388 US physicians
specializing in addiction reported that they prescribed naltrexone to an average of
240 The main self-reported reasons why physicians did not
prescribe naltrexone to more patients were that patients refused to take the
medication or comply with prescribing regimens (23%), and that patients could not
Evidence seems to support the use of naltrexone as an adjunct to psychosocial
interventions, with higher abstinence rates in short-term treatment, and as a deterrent
to progressing from a lapse to a full-blown relapse.
180,209,241,242 Naltrexone is as
efficacious as disulfiram and probably more efficacious than acamprosate.
Several studies indicate that naltrexone is most effective in patients with strong
182,245 poor cognitive status at study entry,
observation is consistent with the demonstrated effect of naltrexone in reducing
craving. Evidence also indicates that persons with a family history for alcoholism,
early age at onset of drinking, and comorbid use of other drugs are more likely to
Comprehensive reviews of pharmacotherapies for alcoholism concluded that oral
naltrexone produced a consistent decrease in the relapse rate to heavy drinking and in
drinking frequency, although it did not enhance absolute abstinence rates.
More specifically, several studies using naltrexone report the opioid antagonist to be
more effective than placebo in reducing relapse rates, in increasing the percent of
182,183,247 and in reducing craving in heavy drinkers.
studies fail to demonstrate a significant difference with placebo.
may explain the discrepancies in results of the different clinical trials with
naltrexone. Many of the studies included small sample sizes and may lack the
statistical power to demonstrate treatment effects.
235 Several large sufficiently
powered studies also reported negative results.
191 clearly supports the effectiveness of naltrexone in that each
of the groups of patients receiving naltrexone in conjunction with medical
management had a higher percentage of days abstinent than those receiving placebo
plus medical management without naltrexone or combined behavioral intervention
(CBI). Naltrexone also reduced the risk of heavy drinking. Extended-release
naltrexone injection 380 mg is safe and well tolerated in alcohol-dependent
In two double-blind, randomized, placebo-controlled trials, the
efficacy of once-monthly extended-release injectable or depot forms of naltrexone
198,257,258 which suggests the advantage of increased compliance.
reported that men receiving naltrexone injection had significantly
better treatment outcomes than women, and women who received naltrexone
demonstrated no difference from those who received placebo. Additionally, because
a robust effect was seen for naltrexone injection compared with placebo for people
coming into the study abstinent, the FDA required the manufacturer to place a
requirement for abstinence when starting the medication on its product information. In
the primary care setting, naltrexone injection given for 3 months and offered with
physician-delivered medical management was found to be effective in the treatment
Naltrexone has been approved for use in the first 90 days of abstinence when the risk
of relapse is highest. It has also been shown to be safe and well tolerated by patients
for periods of up to a year. Treatment with naltrexone should continue based on the
response to the medication. Discontinuation should only be considered in
consultation with the health care provider. The usual dose of naltrexone is 50 mg
daily, although doses of 25 mg to 100 mg daily have been reported to be effective,
particularly in those with lower blood concentrations of the drug.
such as nausea or headache, are more common in the initial few days of therapy.
Starting with a 25-mg dose (half a tablet)
for the first two to four daily doses may reduce the incidence of side effects. Because
of its long half-life (4 hours, or 13 hours for 6-β-naltrexol, naltrexone’s active
metabolite), naltrexone has been studied as three times weekly doses of 100 mg on
Mondays, 100 mg on Wednesdays, and 150 mg on Fridays (or the equivalent of 50
202 This method may facilitate supervised or observed administration of
naltrexone, because only three (versus seven) observations are required per week.
However, this schedule is not recommended for most cases.
The extended-release injection (380 mg) should be administered by deep IM
injection every 4 weeks deep into a gluteal muscle, alternating buttocks each
injection. No dose adjustment is required for mild or moderate renal or hepatic
impairment, but naltrexone has not been studied in severe renal or hepatic
Contraindications, Warnings, and Interactions
Naltrexone is contraindicated in patients with a history of sensitivity to naltrexone
with acute hepatitis or liver failure; in those who are physically dependent on
opioids, receiving opioid analgesics, or in acute opioid withdrawal. The benefit of
using naltrexone during pregnancy should clearly outweigh the risk. The concurrent
administration of naltrexone and opioid analgesics is contraindicated. To avoid
triggering an acute abstinence syndrome, patients must be opioid free for a minimum
of 7 to 14 days before initiating treatment with naltrexone, as substantiated with a
urine drug test. Although rarely performed, a naloxone challenge test can be used
before treatment with naltrexone to rule out concurrent use of opioids. Naltrexone is
in the FDA pregnancy category C, and it is unknown whether naltrexone passes into
A possible clinical concern with naltrexone tablets or long-acting injectable
naltrexone is pain management. Any attempt to overcome the opioid blockade
produced by naltrexone using exogenous opioids may result in fatal overdose. Should
a patient be in pain after receiving an injection, the first drug of choice should be a
nonopioid, such as a nonsteroidal anti-inflammatory drug (NSAID). If the patient is
still in pain, an opiate can be used, but it will most likely have to be administered in
a higher dose and more frequently. When reversal of naltrexone blockade is required
for pain management, patients should be monitored in a setting equipped and staffed
for cardiopulmonary resuscitation and monitored for signs of respiratory depression.
In a yearlong safety study, the most common side effects were nausea, dizziness,
sedation, headache, anxiety, and blurred vision.
260 Should such side effects occur,
reducing the dosage by one-half often reduces the side effects. Large doses (e.g., 200
mg) of naltrexone can cause liver failure. Patients should report excessive tiredness,
unusual bleeding or bruising, loss of appetite, pain in the upper right part of the
stomach, any discoloration of the skin or eyes, a change in stool color or urine,
thoughts of suicide, or signs of pneumonia. Patients receiving extended-release
naltrexone injection must also monitor the injection site for any type of reaction, e.g.,
swelling, tenderness, bruising, or redness-69% for naltrexone v 50% for placebo).
Reactions that do not resolve in 2 weeks may result in induration, cellulitis, abscess,
sterile abscess, or necrosis. Some patients may need to be evaluated for surgical
The rationale for combining medications is that acamprosate reduces negative
reinforcement and naltrexone attenuates positive reinforcement.
hypothesis, a randomized, controlled study of 160 patients performed in Europe
demonstrated that although combining naltrexone and acamprosate was more
effective than either placebo or acamprosate alone, adding acamprosate was not
significantly more effective than naltrexone alone.
COMBINE trial randomized more than 1,300 individuals in a double-blind fashion to
receive placebo, naltrexone, or acamprosate alone or in combination with medical
191 Results from this study suggest that acamprosate has no
significant effect on drinking versus placebo, either by itself or with any combination
of the other treatments in the study. Furthermore, patients receiving placebo and
medical management (MM) from a health care professional had better outcomes than
patients receiving CBI (a CBT-like therapy that includes 12-step facilitation) alone.
From the available evidence, it is acceptable to combine acamprosate with
naltrexone with the expectation that in some patients it may not be any more effective
Topiramate has multiple mechanisms of action, including enhanced GABAA
inhibition that results in decreased dopamine facilitation in the midbrain, thought to
be of potential benefit in the treatment of alcohol use disorder, maintenance
261 Additionally, it causes antagonism of kainate to activate the
kainate/AMPA glutamate receptor subtypes and inhibition of type II and IV carbonic
262 Topiramate is not FDA-approved for the treatment of
A randomized, double-blind, placebo-controlled trial used an escalating dose from
25 to 300 mg/day of topiramate or matching placebo in 150 alcohol-dependent men
and women during the first 8 weeks of a 12-week period.
same dose for the last 4 weeks of the study. All patients in the study received brief
behavioral compliance enhancement therapy (BBCET) that was a 10- to 15-minute
meeting with a health care professional that focused on resolving side effect issues
and facilitated adherence. Participants receiving topiramate reported significantly
fewer drinks per day and drinks per drinking day, significantly fewer drinking days,
significantly more days of abstinence, and significantly less craving than those on
placebo. The evidence suggests that although abstinence was not a goal at the start of
the topiramate study, the medication may be more beneficial during the abstinence
initiation phase of treatment.
In a phase II clinical trial, the use of topiramate for
alcohol dependence treatment was confirmed by outcomes demonstrating that
topiramate recipients showed a significantly greater lowering of percentage of heavy
drinking days and drinks per drinking day, and a higher percentage of days abstinent.
In the treatment of alcohol dependence, topiramate is titrated from 25 mg/day up to
300 mg/day over a 6-week period (100 mg in the morning; 200 mg in the afternoon)
or to the patient’s maximal tolerable dose. Abrupt discontinuation of topiramate has
been associated with seizures in patients without a history of seizures, and for this
reason, gradual withdrawal of the drug (e.g., a 25% decrease in the dosage every 4
days for 16 days) is recommended.
In addition to paresthesias (tingling in the extremities), other prominent side effects
include mental confusion, slowness in thinking, depression, and somnolence, which
may be attenuated by titration when initiating therapy, and the development of renal
calculi in about 1.5% of patients.
264 Adequate hydration is encouraged, particularly in
patients who may be at risk for developing calculi. Topiramate can cause
drowsiness, dizziness, changes in memory, a change in taste (particularly with
carbonated beverages), vision changes (particularly associated with increased
intraocular pressure), pressure to the touch, loss of appetite or weight loss, and
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