# Substance Abuse Treatment 

# 

# Advisory

# 

# *Breaking News for the Treatment Field*

# 

# Fall 2005, Volume 4, Issue 1

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Substance Abuse and Mental Health Services Administration

Center for Substance Abuse Treatment

www.samhsa.gov

# 

**Acamprosate: A NEW MEDICATION FOR ALCOHOL USE DISORDERS**

**What is acamprosate?**

Acamprosate (calcium acetyl homotaurinate) is a new prescription
medication to help people who are alcohol dependent. Acamprosate is the
third medication, after disulfiram (Antabuse^®^) and naltrexone
(ReVia^®^), to receive U.S. Food and Drug Administration (FDA) approval
for postwithdrawal maintenance of alcohol abstinence. It is the first
new medication approved for this purpose in a decade. FDA approved
acamprosate in July 2004. It became available in the United States in
January 2005, under the trade name Campral^®^ Delayed-Release Tablets.
Acamprosate has been used for nearly 20 years in Europe, where it has
been found to be safe and effective for treating alcohol dependence
(Mann et al. 2004; Tempesta et al. 2000).

**How does acamprosate work?**

Chronic, heavy use of alcohol affects several neurotransmitter systems
in the brain. These neurotransmitter systems adapt to the chronic
presence of alcohol. Once they have adapted, these systems are only in
equilibrium with alcohol. When alcohol use ceases, the systems become
disregulated and enter a pathologic hyperexcitatory state. It is thought
that acamprosate helps modulate and normalize brain activity,
particularly in the glutamate and gamma-aminobutyric acid (GABA)
neurotransmitter systems. Although acamprosate's mechanism of action has
not been clearly established, it may work by reducing symptoms of
postacute (protracted) withdrawal, such as insomnia, anxiety, and
restlessness.

**How does acamprosate's activity compare with that of other medications
used to treat alcohol dependence?**

Acamprosate differs in significant ways from disulfiram and naltrexone,
the other two agents approved by FDA for alcohol abstinence maintenance
(table 1).

+---------+---------------------+-----------------+--------------------+
| **Table |                     |                 |                    |
| 1:      |                     |                 |                    |
| Com     |                     |                 |                    |
| parison |                     |                 |                    |
| of      |                     |                 |                    |
| Drugs   |                     |                 |                    |
| A       |                     |                 |                    |
| pproved |                     |                 |                    |
| for     |                     |                 |                    |
| Main    |                     |                 |                    |
| tenance |                     |                 |                    |
| of      |                     |                 |                    |
| Abs     |                     |                 |                    |
| tinence |                     |                 |                    |
| From    |                     |                 |                    |
| Al      |                     |                 |                    |
| cohol** |                     |                 |                    |
+=========+=====================+=================+====================+
| **Medic | **Acamprosate       | **Disulfiram    | **Naltrexone       |
| ation** | (Campral)**         | (Antabuse)**    | (ReVia)**          |
+---------+---------------------+-----------------+--------------------+
| **Me    | Is not completely   | Inhibits        | Blocks brain       |
| chanism | understood; appears | aldehyde        | opioid receptors;  |
| of      | to                  | dehydrogenase   | eliminates         |
| A       | modulate/normalize  | causing         | euphoria           |
| ction** | alcohol-disrupted   | sickness (e.g., | associated with    |
|         | brain activity,     | flushing,       | alcohol use; makes |
|         | particularly in the | nausea,         | alcohol use less   |
|         | GABA and glutamate  | headache,       | rewarding; does    |
|         | neurotransmitter    | sweating,       | not cause sickness |
|         | systems; does not   | weakness,       | if alcohol is      |
|         | cause sickness if   | increased blood | ingested; reduces  |
|         | alcohol is          | pressure) when  | craving            |
|         | ingested; reduces   | alcohol is      |                    |
|         | craving for alcohol | ingested; does  |                    |
|         |                     | not reduce      |                    |
|         |                     | craving         |                    |
+---------+---------------------+-----------------+--------------------+
| **      | Abstinence at       | Abstinence at   | Abstinence at      |
| Optimal | treatment           | treatment       | treatment          |
| Patient | initiation,         | initiation and  | initiation         |
| S       | immediately         | during ongoing  |                    |
| tatus** | following acute     | administration; | Patients who       |
|         | withdrawal;         | commitment to   | relapse while      |
|         | commitment to       | recovery        | taking naltrexone  |
|         | recovery            |                 | may benefit from   |
|         |                     |                 | continuing the     |
|         | Patients who        |                 | medication         |
|         | relapse while       |                 |                    |
|         | taking acamprosate  |                 |                    |
|         | may benefit from    |                 |                    |
|         | continuing the      |                 |                    |
|         | medication          |                 |                    |
+---------+---------------------+-----------------+--------------------+
| **E     | None known          | Metronidazole   | Opioid-containing  |
| xamples |                     | (Flagyl^®^);    | medications,       |
| of      |                     | paraldehyde;    | thioridazine,      |
| Drugs   |                     | medications     | yohimbine, and     |
| Ca      |                     | containing      | oral hypoglycemics |
| using** |                     | alcohol; and    |                    |
|         |                     | phenytoin,      |                    |
| **      |                     | warfarin,       |                    |
| Interac |                     | isoniazid,      |                    |
| tions** |                     | rifampin,       |                    |
|         |                     | diazepam,       |                    |
|         |                     | ch              |                    |
|         |                     | lordiazepoxide, |                    |
|         |                     | imipramine,     |                    |
|         |                     | desipramine,    |                    |
|         |                     | and oral        |                    |
|         |                     | hypoglycemics   |                    |
+---------+---------------------+-----------------+--------------------+
| **Side  | Most common:        | Most common:    | Most common:       |
| Ef      | diarrhea and        | dis             | opioid withdrawal  |
| fects** | intestinal cramps,  | ulfiram-alcohol | symptoms           |
|         |                     | reaction (can   | (insomnia, nausea, |
|         | itchiness,          | be serious)     | vomiting, anxiety, |
|         | dizziness, muscle   |                 | headache,          |
|         | weakness, headache, | Common but      | abdominal pain,    |
|         | flatulence, nausea, | usually mild    | muscle aches,      |
|         | anxiety, and        | and             | rash, dizziness,   |
|         | insomnia            | self-limiting:  | fatigue,           |
|         |                     | drowsiness,     | constipation, and  |
|         | Less common, but    | metallic taste, | chills)            |
|         | more serious:       | headache,       |                    |
|         |                     | impotence, and  | Less common, but   |
|         | depression and      | acne            | more serious:      |
|         | suicide risk        |                 | potential liver    |
|         |                     | Less common,    | toxicity           |
|         |                     | but more        | (especially at     |
|         |                     | serious: liver  | high doses) and    |
|         |                     | toxicity,       | suicidal ideation  |
|         |                     | peripheral      |                    |
|         |                     | neuropathy,     |                    |
|         |                     | psychosis, and  |                    |
|         |                     | delirium        |                    |
+---------+---------------------+-----------------+--------------------+
| **Cont  | Hypersensitivity to | H               | Hypersensitivity   |
| raindi- | the drug; severe    | ypersensitivity | to the drug, any   |
| cations | renal (kidney)      | to the drug,    | use of narcotic    |
| and     | impairment          | significant     | analgesics, liver  |
| Cau     | (creatinine         | liver disease,  | disease, and acute |
| tions** | clearance \<30      | alcohol still   | opioid withdrawal  |
|         | mL/min)             | in system,      |                    |
|         |                     | psychosis,      | FDA pregnancy      |
|         | Dosage may be       | coronary artery | category C\*       |
|         | modified for        | disease,        |                    |
|         | moderate renal      | paraldehyde     |                    |
|         | impairment          | use, diabetes,  |                    |
|         | (creatinine         | and severe      |                    |
|         | clearance 30--50    | metronidazole   |                    |
|         | mL/min)             | use             |                    |
|         |                     |                 |                    |
|         | Use with older      | FDA pregnancy   |                    |
|         | adults or with      | category C\*    |                    |
|         | patients with       |                 |                    |
|         | depression only     |                 |                    |
|         | when potential      |                 |                    |
|         | benefits justify    |                 |                    |
|         | potential risk      |                 |                    |
|         |                     |                 |                    |
|         | FDA pregnancy       |                 |                    |
|         | category C\*        |                 |                    |
+---------+---------------------+-----------------+--------------------+

\* FDA pregnancy category C: Animal studies have indicated potential
fetal risk OR have not been conducted and no or insufficient human
studies have been done. The drug should be used with pregnant or
lactating women only when potential benefits justify potential risk to
the fetus or infant.

**Disulfiram,** used to treat alcohol dependence for decades, is an
aversive medication that inhibits aldehyde dehydrogenase and leads to
increased levels of acetaldehyde. When a person taking disulfiram drinks
alcohol, the increased acetaldehyde causes severe physical reactions
such as facial flushing, nausea, vomiting, low blood pressure, headache,
and weakness. Disulfiram does not reduce craving or normalize brain
functioning, as acamprosate and naltrexone are believed to do. Instead,
disulfiram's effectiveness depends on the patient's reluctance to suffer
the aversive effects of drinking when on disulfiram.

**Naltrexone** (an opioid antagonist) blocks opioid receptors, leading
to reductions in craving and in the reinforcing effects of alcohol.
Unlike naltrexone, acamprosate does not affect the action or subjective
effects of alcohol (Brasser et al. 2004).

Patients with liver damage usually cannot use either naltrexone or
disulfiram. However, because acamprosate is not metabolized in the
liver, patients with liver damage can safely take the medication.

Preliminary evidence suggests that treatment outcomes improve when
acamprosate is combined with naltrexone or with disulfiram, particularly
for patients who responded poorly to therapy with any of these
medications alone (Besson et al. 1998; Kiefer and Wiedemann 2003; Kiefer
et al. 2003). Combination therapy also has been found to be safe. No
specific protocol for combination therapy has been established as yet,
but the results of a large national study, sponsored by the National
Institute on Alcohol Abuse and Alcoholism, will be available soon. The
study, Combining Medications and Behavioral Interventions (COMBINE),
examines the effects of naltrexone and acamprosate and two psychosocial
therapies, alone and in various combinations.

**Are there side effects or drug interactions with acamprosate?**

The most common side effects experienced by people taking acamprosate
are diarrhea, insomnia, anxiety, muscle weakness, nausea, itchiness, and
dizziness. Uncommon, but serious, side effects include depression and
suicidal thoughts. Most side effects are usually mild and transient,
lessening or disappearing within the first few weeks of treatment.

Acamprosate has not been found to be associated with any significant
drug (including alcohol) interactions and does not affect the action of
coadministered disulfiram, diazepam, nordiazepam, imipramine,
desipramine, selective serotonin reuptake inhibitors, naltrexone, or
naltrexol. No adjustment of dosage is recommended in patients taking
these other medications.

**Can acamprosate be used for detoxification?**

Research on the effectiveness of acamprosate in treating the symptoms of
acute withdrawal has been inconclusive, and FDA has not approved its use
for this purpose. However, patients who are already taking acamprosate
and who relapse may be medically withdrawn from alcohol without
discontinuing acamprosate.

**How safe is acamprosate?**

Acamprosate is not addicting and appears to have no potential for abuse;
patients maintained on the drug have developed no known tolerance for or
dependence on it. It also carries little overdose risk. Even at
overdoses up to 56 grams (a normal daily dose is 2 grams), acamprosate
was generally well tolerated by patients (Thomson Healthcare, Inc.
2005).

Because acamprosate is not metabolized by the liver, it can be used by
individuals with liver disease. Because acamprosate is excreted
primarily from the kidneys, patients with severe renal impairment
(creatinine clearance \<30 mL/min) should not use acamprosate. Those
with moderate renal impairment (creatinine clearance 30--50 mL/min) may
be able to take the medication with dosage adjustments and careful
monitoring.

Patients should be told to be cautious about driving or operating heavy
machinery until they know how acamprosate will affect their ability to
engage in these activities and until they have adjusted to any effects
of the drug.

In clinical trials, suicidal events (suicidal ideation, attempted
suicides, completed suicides), although rare, were more common in
acamprosate-treated participants than in participants receiving placebo.
Patients should be monitored for symptoms of depression or suicidal
thinking. Families and caregivers should be informed of the need to
monitor their family members for these signs and report their occurrence
to the substance abuse treatment counselor or prescribing professional.

Use of acamprosate during pregnancy has not been studied with humans.
Animal studies of acamprosate and pregnancy have found some potential
fetal risk. The potential risk of taking acamprosate during pregnancy
should be balanced with the potential benefits (considering the known
adverse effects of alcohol, particularly the risk of fetal alcohol
syndrome).

The use of acamprosate by older adults or by children has not been
studied. Because of the higher risk of diminished renal function among
older adults, acamprosate should be used with caution with this
population.

**Campral Dosage and Timing**

-   The recommended dosage of Campral is two 333 mg tablets three times
    a day, with or without food.

-   Treatment with acamprosate should be initiated as soon as possible
    after alcohol withdrawal and should be maintained if the patient
    relapses.

-   Treatment duration at this dosage ranged from 3 to 12 months in
    clinical trials.

-   The manufacturer recommends treatment duration of 1 year.

**How can treatment providers incorporate acamprosate into their
programs?**

Treatment program staff should be well educated about acamprosate and
its effects and be able to educate clients about the medication.
Acamprosate is a prescription medication, so treatment providers need to
be able to provide the medication and medically monitor the patient,
either on site or through relationships with medical professionals in
the community.

Treatment providers should assess patients' clinical appropriateness for
acamprosate. Patients who have been in treatment multiple times but have
been unable to sustain abstinence or those for whom disulfiram or
naltrexone or both have not been effective may be particularly
appropriate candidates for acamprosate. However, given the medication's
good safety profile, patients new to treatment also may be considered
good candidates for acamprosate therapy. A good candidate also is
interested in trying the medication and willing and able to take it
regularly as prescribed.

Motivation is an important factor. Clinical trials found that
participants receiving acamprosate who were motivated and committed to
total abstinence at the start of treatment had lower relapse risk than
less motivated participants (FDA Psychopharmacologic Drugs Advisory
Committee 2002). Less motivated patients are those whose personal goals,
for instance, allow for slips, controlled drinking, other modified
alcohol consumption, or other substance abuse. Research has not
documented the effectiveness of acamprosate with patients who use
multiple substances in addition to alcohol.

Researchers also have looked at whether certain clinical characteristics
(e.g., age of onset of alcohol use disorder, level of craving, gender,
family history of alcohol use) might predict which individuals are more
likely than others to abstain from alcohol successfully on acamprosate.
This research did not find a relationship between patient
characteristics and successful acamprosate therapy (Verheul et al.
2005). Any patient who is found to be both medically and motivationally
appropriate for acamprosate therapy and wants to try the medication
should be given the opportunity.

Once the treatment provider and patient decide that acamprosate may
help, the patient should be referred to a person who can prescribe it.
The prescribing professional should assess the patient's medical
appropriateness for therapy with acamprosate by conducting a medical
examination, including laboratory tests to obtain baseline readings of
kidney function.

Medications for alcohol use disorders do not replace counseling.
Individuals taking acamprosate should be expected to participate fully
in a treatment program's activities, including attending 12-Step or
mutual-help group meetings. In addition, they may need ongoing
motivational counseling specifically geared to helping them comply with
a drug regimen.

Regular communication between treatment providers and the prescribing
medical professional is essential. In particular, treatment providers
need to communicate information concerning the patient to the
prescribing professional such as

-   Reported or detected drinking or drug use episodes

-   Patient concerns about side effects

-   Issues affecting the patient's safety (suicidal ideation, reported
    or observed increase in levels of depression or anxiety, or
    significant physical complaints)

-   Medication compliance issues

-   Expressed desire to stop taking the medication

Treatment providers should encourage patients to talk directly to their
prescribing professionals about these and other issues or questions they
may have.

**How long should an individual take acamprosate?**

The manufacturer of acamprosate recommends that acamprosate therapy be
continued for 1 year (the effectiveness and safety of the medication
have not been evaluated for periods of use longer than a year). Given
that guideline, the length of time a particular patient takes
acamprosate will be determined, ideally, with input from the prescribing
professional, the treatment provider, and the patient. Discontinuation
of acamprosate may be considered once a patient has achieved stable
abstinence from alcohol, reports diminished craving, and has established
a sound plan and support for ongoing recovery. Acamprosate therapy also
may be discontinued if a patient is not compliant with the medication
regimen. Acamprosate should not be discontinued just because a patient
slips or relapses.

**What To Tell the Patient**

Treatment program staff can support patients taking acamprosate by
educating them about the drug, including

-   Informing them about the benefits and limitations of the medication

-   Informing them that it can take 5 to 8 days before acamprosate is
    fully effective

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-   Stressing the importance of taking the medication as prescribed

-   Encouraging them to talk to their prescribing professional about the
    duration of acamprosate therapy

-   Encouraging them to talk to their prescribing professional about
    other medications they are taking

-   Encouraging them to report side effects of the drug and explaining
    that most of these resolve fairly quickly

-   Encouraging women to inform all treatment providers immediately if
    they become pregnant during therapy, if they are trying to become
    pregnant, or if they are breast-feeding

-   Stressing the importance of continuing counseling and 12-Step or
    mutual-help group participation

-   Stressing the need for caution in driving or operating heavy
    machinery until they are certain that acamprosate has no adverse
    effects on their participation in these activities and they have
    adjusted to the drug

-   Advising them to continue taking the medication if a slip or relapse
    occurs and to inform their counselor and prescribing professional
    immediately

**References**

Besson, J.; Aeby, F.; Kasas, A.; Lehert, P.; and Potgieter, A. Combined
efficacy of acamprosate and disulfiram in the treatment of alcoholism: A
controlled study. *Alcoholism: Clinical and Experimental Research*
22(3):573--579, 1998.

Brasser, S.M.; McCaul, M.E.; and Houtsmuller, E.J. Alcohol effects
during acamprosate treatment: A dose-response study in humans.
*Alcoholism: Clinical and Experimental Research* 28(7):1074--1083, 2004.

FDA Psychopharmacologic Drugs Advisory Committee, May 10, 2002.
*Briefing Document for Acamprosate 333 mg Tablets, April 3, 2002.* Lipha
Pharmaceuticals, Inc.: Darmstadt, Germany, 2002.
www.fda.gov/ohrms/dockets/ac/02/Briefing/3857b1_01_Lipha.pdf \[accessed
June 8, 2005\].

Kiefer, F.; Holger, J.; Tarnaske, T.; Helwig, H.; Briken, P.; Holzbach,
R.; Kampf, P.; Stracke, R.; Baehr, M.; Naber, D.; and Wiedemann, K.
Comparing and combining naltrexone and acamprosate in relapse prevention
of alcoholism. *Archives of General Psychiatry* 60(1):92--99, 2003.

Kiefer, F., and Wiedemann, K. Combined therapy: What does acamprosate
and naltrexone combination tell us? *Alcohol and Alcoholism*
39(6):542--547, 2003.

Mann, K.; Lehert, P.; and Morgan, M.Y. The efficacy of acamprosate in
the maintenance of abstinence in alcohol-dependent individuals: Results
of a meta-analysis. *Alcohol Clinical and Experimental Research*
28(1):51--63, 2004.

Tempesta, E.; Janiri, L.; Bignamini, A.; Chabac, S.; and Potgieter, A.
Acamprosate and relapse prevention in the treatment of alcohol
dependence: A placebo-controlled study. *Alcohol* *and Alcoholism*
35(2):202--209, 2000.

Thomson Healthcare, Inc. *Physicians' Desk Reference*, 59th Edition.
Montvale, NJ: Thomson PDR, 2005, p. 3430.

Verheul, R.; Lehert, P.; Geerlings, P.J.; Koeter, M.W.; and van den
Brink, W. Predictors of acamprosate efficacy: Results from a pooled
analysis of seven European trials including 1,485 alcohol-dependent
patients. *Psychopharmacology (Berl)* 178(2--3):167--173, 2005.

**Resources for Additional Information**

Substance Abuse and Mental Health Services Administration (SAMHSA)

1 Choke Cherry Road

Room 8-1054

Rockville, MD 20857

Phone: 240-276-2130 (Office of Communications)

Web: [www.samhsa.gov](http://www.samhsa.gov/)

National Clearinghouse for Alcohol and Drug Information (NCADI)

Phone: 800-729-6686

Español: 877-767-8432

TDD: 800-487-4889

Web: www.ncadi.samhsa.gov

National Institute on Alcohol Abuse and Alcoholism

(NIAAA)

5635 Fishers Lane, MSC 9304\
Bethesda, Maryland 20892-9304

Web: [www.niaaa.nih.gov](http://www.niaaa.nih.gov/)

U.S. Food and Drug Administration (FDA)

5600 Fishers Lane

Rockville, MD 20857-0001

Phone: 888-INFO-FDA (888-463-6332)

Web: [www.fda.gov](http://www.fda.gov/)

***Selected Publications***

Center for Substance Abuse Treatment. *Naltrexone and Alcoholism
Treatment*. Treatment Improvement Protocol (TIP) Series 28. DHHS
Publication No. (SMA) 98-3206. Rockville, MD: Substance Abuse and Mental
Health Services Administration, 1998 (available through NCADI).

Miller, W.R. (ed.) *COMBINE Monograph Series, Volume 1. Combined
Behavioral Intervention Manual: A Clinical Research Guide for Therapists
Treating People With Alcohol Abuse and Dependence*. DHHS Publication No.
(NIH) 04-5288. Bethesda, MD: National Institute on Alcohol Abuse and
Alcoholism (NIAAA), 2004 (available through NIAAA).

NIAAA. *Helping Patients Who Drink Too Much: A Clinician's Guide,* 2005
Edition. Bethesda, MD: NIAAA, in development (will be available through
NIAAA).

Pettinati, H.M.; Weiss, R.D.; Miller, W.R.; Donovan, D.; Ernst, D.B.;
and Rounsaville, B.J. *COMBINE* *Monograph Series, Volume 2. Medical
Management Treatment Manual: A Clinical Research Guide for Medically
Trained Clinicians Providing Pharmacotherapy as Part of the Treatment
for Alcohol Dependence.* DHHS Publication No. (NIH) 04-5289. Bethesda,
MD: NIAAA, 2004 (available through NIAAA).

### Substance Abuse Treatment Advisory

### 

*Substance Abuse Treatment Advisory*published on an as-needed basis for
treatment providerswas written and produced under contract number
270-04-7049 by the Knowledge Application Program (KAP), a Joint Venture
of Johnson, Bassin & Shaw, Inc., and The CDM Group, Inc., for the Center
for Substance Abuse Treatment (CSAT), Substance Abuse and Mental Health
Services Administration (SAMHSA), U.S. Department of Health and Human
Services (HHS). Christina Currier serves as the Government Project
Officer for the *Substance Abuse Treatment Advisory*. The content of
this publication does not necessarily reflect the views or policies of
SAMHSA or HHS.

**Public Domain Notice:** All material appearing in this report is in
the public domain and may be reproduced or copied without permission;
citation of the source is appreciated. However, this publication may not
be reproduced or distributed for a fee without the specific, written
authorization of the Office of Communications, SAMHSA, HHS.

**Electronic Access and Copies of Publication:** This publication can be
accessed electronically through the Internet at www.kap.samhsa.gov.
Additional free print copies can be ordered from SAMHSA's NCADI at
800-729-6686.

**Recommended Citation:** Center for Substance Abuse Treatment.
Acamprosate: A new medication for alcohol use disorders. *Substance
Abuse Treatment Advisory.* Volume 4, Issue 1. Fall 2005.

National Clearinghouse for Alcohol and Drug Information

Substance Abuse and Mental Health Services Administration

U.S. Department of Health and Human Services

7079 Oakland Mills Road

Columbia, MD 21046

DHHS Publication No. (SMA) 05-4114

NCADI Publication No. MS974

Printed 2005