Journal of Psychosocial Nursing and Mental Health Services

Psychopharmacology 

Baclofen for the Treatment of Alcohol Dependence

Robert H. Howland, MD

Abstract

The amino acid gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the nervous system. The mesolimbic dopamine system is a major component of the brain’s reward pathways, and GABA neurons are part of this system, decreasing the activity of dopamine neurons through the inhibitory effects of GABA-B receptors. Because the mesolimbic dopamine system has been linked to the reinforcing effects of alcohol and other drugs of abuse, baclofen (Lioresal®, Gablofen®), a GABA-B receptor agonist drug, has been investigated in preclinical studies as a potential treatment for addictions. Baclofen reduces the reinforcing effects of alcohol and other drugs in animals, providing justification for clinical studies in human beings. Two open-label and two placebo-controlled studies in humans found that baclofen was effective for reducing alcohol craving and intake, but one placebo-controlled study found no benefit for baclofen. Baclofen is a safe and well-tolerated novel drug treatment for alcohol dependence.

Abstract

The amino acid gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the nervous system. The mesolimbic dopamine system is a major component of the brain’s reward pathways, and GABA neurons are part of this system, decreasing the activity of dopamine neurons through the inhibitory effects of GABA-B receptors. Because the mesolimbic dopamine system has been linked to the reinforcing effects of alcohol and other drugs of abuse, baclofen (Lioresal®, Gablofen®), a GABA-B receptor agonist drug, has been investigated in preclinical studies as a potential treatment for addictions. Baclofen reduces the reinforcing effects of alcohol and other drugs in animals, providing justification for clinical studies in human beings. Two open-label and two placebo-controlled studies in humans found that baclofen was effective for reducing alcohol craving and intake, but one placebo-controlled study found no benefit for baclofen. Baclofen is a safe and well-tolerated novel drug treatment for alcohol dependence.

Naltrexone (ReVia®), acamprosate (Campral®), and disulfiram (Antabuse®) are the only drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol dependence. Because alcohol dependence is a major public health problem, there is an obvious need for other effective therapies. In this article, I will review the use of baclofen (Lioresal®, Gablofen®), approved by the FDA for the treatment of spasticity, as a drug treatment for alcohol dependence.

What is Baclofen?

The amino acid gamma-aminobutyric acid (GABA), first discovered in the early 1950s, is the major inhibitory neurotransmitter in the nervous system (Froestl, 2001). GABA receptor systems are the target of a wide range of drugs active in the brain, including anti-anxiety, sedative-hypnotic, general anesthetic, and anti-convulsant drugs. GABA also modulates the activity of other neurotransmitters in various regions of the nervous system. The main GABA receptor complexes are referred to as GABA-A, GABA-B, and GABA-C. The GABA-A receptor complex is the most clinically important, and it is composed of at least five subunits. Benzodiazepine receptor agonist drugs (BzRAs) work by binding to GABA-A receptors. The two BzRA drug classes are benzodiazepine and non-benzodiazepine drugs. Benzodiazepine drugs (e.g., lorazepam [Ativan®]) bind nonspecifically to the GABA-A receptor complex. Non-benzodiazepine BzRA drugs (e.g., zolpidem [Ambien®]), which are chemically unrelated to benzodiazepine drugs, bind more selectively to specific GABA-A receptor subunits. The GABA-C receptor (also known as the GABA-A-rho receptor) is composed of rho subunits related to GABA-A subunits, but the GABA-C receptor is not sensitive to the binding of benzodiazepine drugs or baclofen. The GABA-C receptor is highly expressed in the retina, where it has been studied.

Baclofen is a derivative analogue of GABA that was first synthesized in 1962 as a potential treatment for epilepsy. Its effect on seizure suppression was disappointing, but it was noted to reduce muscle spasticity. The GABA-B receptor was discovered and characterized in 1980, when it was determined that baclofen did not bind to the GABA-A receptor complex. The GABA-B receptor is considered primarily an inhibitory receptor, since it acts to stop neurons from firing and releasing neurotransmitters. They are found in the central and peripheral autonomic nervous system. Baclofen is a GABA-B receptor agonist. Hence, by activating GABA-B receptors, baclofen will inhibit the activity of neurons that have these receptors. This pharmacological action explains why baclofen is able to treat muscular spasticity. This effect can be achieved by administering baclofen orally or intrathecally (i.e., directly into spinal fluid).

The mesolimbic dopamine system is a major component of the brain’s reward pathways, and GABA neurons are part of this system, decreasing the activity of dopamine neurons through the inhibitory effects of GABA-B receptors. Because the mesolimbic dopamine system has been linked to the reinforcing effects of alcohol and other drugs of abuse, baclofen and other investigational GABA-B receptor agonist drugs have been investigated in preclinical studies as potential treatments for addictions (Cousins, Roberts, & de Wit, 2002). Baclofen reduces the reinforcing effects of alcohol and other drugs in animals, providing a justification for clinical studies in human beings.

Clinical Studies of Baclofen for Alcohol Dependence

In an open-label, 30-day study, Addolorato et al. (2000) investigated the effect of baclofen on craving for alcohol, alcohol consumption, and abstinence from alcohol in 10 men with alcoholism. Baclofen was started at 15 mg per day for the first 3 days and then increased to 30 mg per day for the remainder of the study. Nine men completed the study. Seven maintained abstinence throughout the study, and 2 continued to drink alcohol, although they substantially reduced their daily consumption during the first week. Average craving was significantly reduced from the first week through the entire study period, and obsessional thinking about alcohol disappeared. Liver enzyme measures of alcohol abuse were significantly decreased by study endpoint. Baclofen tolerability was fairly good in all participants. Side effects included headache, vertigo, nausea, constipation, diarrhea, abdominal pain, hypotension, increased sleepiness, and tiredness. No participants exhibited any craving for baclofen.

Flannery et al. (2004) conducted a 12-week, open-label study investigating the effect of baclofen on drinking, craving, and subclinical anxiety and depressive symptoms in 12 alcohol-dependent men and women. Participants took baclofen 30 mg per day throughout the study and received four sessions of motivational enhancement therapy. Four participants completed the 12-week study, whereas 8 dropped out prematurely (2 because of side effects, 2 for personal reasons, and 4 for lack of efficacy). Overall, statistically significant reductions were achieved in the number of drinks per day and the number of heavy-drinking days, and an increase in the number of abstinent days. Significant decreases in anxiety and alcohol craving were observed. Baclofen was reasonably well tolerated, with no serious adverse events. One participant who dropped out because of side effects reported drowsiness, sedation, fatigue, confusion, and dizziness, while the second reported drowsiness, sedation, insomnia, constipation, and depression.

In the first double-blind, randomized controlled study, Addolorato, Caputo, Capristo, Domenicali, et al. (2002) investigated baclofen versus placebo on alcohol intake, abstinence from alcohol, alcohol craving, and changes in depressive and anxiety symptoms in 39 alcohol-dependent participants. Baclofen was started at 15 mg per day for the first 3 days and then increased to 30 mg per day for the subsequent 27 days of the study. Compared with placebo, a higher percentage of participants taking baclofen were completely abstinent from alcohol, and there were a higher number of cumulative abstinence days throughout the study in the baclofen group. Alcohol craving and intake were reduced in the baclofen group compared with placebo. A decrease in anxiety was found in the baclofen group compared with placebo, but no significant difference in depression. Baclofen was well tolerated, and no participants discontinued due to side effects. Observed side effects were sleepiness, tiredness, and vertigo. Baclofen craving was not observed.

In a larger 12-week, randomized controlled study, Addolorato et al. (2007) investigated baclofen versus placebo in 84 men and women with alcohol dependence and liver cirrhosis. Primary outcome was proportion of participants achieving and maintaining alcohol abstinence, as measured by total alcohol abstinence and cumulative days of abstinence. Relapse was defined as alcohol intake of more than four drinks per day or overall consumption of 14 or more drinks per week over a period of at least 4 weeks. A secondary outcome was alcohol craving. Baclofen was started at 15 mg per day for the first 3 days and then increased to 30 mg per day for the duration of the study. Of the 42 baclofen-treated participants, 30 (71%) achieved and maintained abstinence, a proportion significantly greater than the 12 of 42 (29%) placebo-treated participants. Cumulative days of abstinence were significantly greater for baclofen (63) than for placebo (31). Baclofen significantly reduced craving scores compared with placebo. Fewer baclofen-treated participants (14%) dropped out of the study compared with placebo (31%), but this difference was not statistically significant. Reported side effects were headache, tiredness, vertigo, and sleepiness for baclofen, and headache, tiredness, and vertigo for placebo. No liver effects were observed, and no differences in liver enzymes were found between groups.

Garbutt, Kampov-Polevoy, Gallop, Kalka-Juhl, and Flannery (2010) conducted a 12-week, randomized placebo-controlled study of baclofen 30 mg per day in 80 men and women with alcohol dependence. All participants also received eight sessions of a psychosocial treatment. The primary outcome measure was the percentage of heavy drinking days. Secondary outcomes included several other drinking outcomes, anxiety levels, and alcohol craving. No significant differences were found between groups on the primary and secondary outcomes, except that baclofen was associated with a significant reduction in anxiety. There were no significant differences in the proportion of participants completing the study (baclofen, 70%; placebo, 80%). Baclofen was well tolerated, with only 2 participants stopping it due to adverse events. Drowsiness occurred in 28% of baclofen participants (versus 10% for placebo), whereas headache occurred in 10% of placebo participants (versus 3% for baclofen). There were no serious adverse events.

Clinical Use of Baclofen

For the treatment of spasticity, the recommended starting dose of baclofen is 15 mg per day, and it can be increased by 15 mg every 3 days to a maximum recommended dose of 80 mg per day. The published studies for alcohol dependence used starting doses of 15 to 30 mg per day and were limited to 30 mg per day. In two reports, doses up to 400 mg per day have been used for alcohol dependence (Pastor, Jones, & Currie, 2012; Rigal, Alexandre-Dubroeucq, de Beaurepaire, Le Jeunne, & Jaury, 2012). Although high-dose baclofen was safe and well tolerated in these reports, the safety and efficacy of such high doses has not been systematically investigated in controlled studies. Baclofen is typically given in three to four divided doses because it has a short half-life (approximately 2 to 4 hours).

Side effects include sedation, fatigue, lethargy, headache, nausea, constipation, dizziness, hypotension, and urinary hesitancy or retention. Potentially serious adverse effects include delirium and seizures, although these are rare and may be more likely with intrathecal than oral use. Abrupt discontinuation after long-term use can be associated with a withdrawal syndrome, which could include symptoms such as anxiety, agitation, insomnia, confusion, delirium, psychosis, muscle rigidity, fever, autonomic instability, and seizures. This kind of withdrawal syndrome appears similar to what would be expected with abrupt withdrawal from benzodiazepine drugs or alcohol. Consistent with this, baclofen was successfully used to rapidly suppress severe alcohol withdrawal symptoms in 5 patients (Addolorato, Caputo, Capristo, Janiri, et al., 2002). Tapering baclofen is recommended if the drug is to be discontinued.

That baclofen is relatively well tolerated and not associated with serious adverse events among patients who are actively drinking or using large amounts of alcohol, who take various psychotropic drugs, or who have liver disease is reassuring (Evans & Bisaga, 2009). A review of 31 published reports of baclofen overdoses described only two deaths from among 107 patients (Weißhaar et al., 2012). Baclofen does not undergo extensive liver metabolism and does not affect metabolic enzymes. Approximately 70% to 80% of baclofen is excreted unchanged through the kidneys. Dosage changes are not required for patients with liver disease, but patients with impaired renal function should take lower doses and be monitored more closely for adverse effects. Baclofen has sometimes been used as a “fun drug” for possible euphoric effects (Weißhaar et al., 2012), but studies in patients with alcohol dependence found no evidence for baclofen craving or abuse. Nevertheless, its use should still be monitored for signs of misuse or abuse.

Conclusion

Baclofen is a GABA-B receptor agonist drug that is a promising approach to treatment for alcohol dependence. In my opinion, even though baclofen is not approved by the FDA for this indication, I believe it would be clinically appropriate to consider using it off label for patients who have not had a satisfactory response to available FDA-approved medications. Therefore, nurses should be familiar with the pharmacology and clinical profile of this novel drug.

References

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Authors

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author has disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

Posted Online: September 17, 2012

10.3928/02793695-20120906-92

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