Baclofen for alcohol Dependence and Withdrawl

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J Clin Psychopharmacol. 2012 Apr;32(2):266-8.High-dose baclofen for treatment-resistant alcohol dependence.Pastor A, Jones DM, Currie J.SourceDepartment of Addiction Medicine, St Vincent's Hospital, Melbourne, Australia. Abstract

Alcohol dependence is associated with a wide array of physical and psychiatric complications and is a major cause of morbidity and mortality worldwide. Recent randomized trials of baclofen, with a total daily dose 30 mg administered in 3 divided doses, have supported its efficacy in reducing craving and promoting abstinence from alcohol. Individual case studies support a possible increased effect at higher doses for treatment-resistantpatients. Here, we report on 4 alcohol-dependent patients resistant to standard treatments who responded to higher doses of baclofen ranging from 75 to 125 mg daily. Further research into the use of high-dose baclofen for treatment-resistant alcohol dependence is warranted. PMID: 22367662

These 4 patients who did not respond to standard medications (or to baclofen at 30 mg daily) achieved abstinence on doses of baclofen up to 125 mg daily.  This adds to Ameisen's self reported (and self prescribed!) case report[1] where he was able to stay sober after baclofen doses up to 270 mg daily.  France has noted a 20% increase in sales of baclofen since Ameisen's book was published[2].

Garbutt's 2010 randomized trial [3] of 80 patients at 10 mg TID did not show a significant benefit over placebo, but a trial in patients with cirrhosis [4] at the same dose showed marked benefit with treated patients having 71% abstinence vs 29% with placebo. Addorato [5] also notes a slight increase in efficacy with 20 TID vs 10 TID [4].

Treatment of alcohol withdrawal?

A 2011 randomized trial [6] of 31 patients hospitalized for alcohol withdrawal gave baclofen 10 TID vs placebo for "72 hours or until discharge, whichever was shorter" and additional lorazepam for CIWA-Ar scores higher than 10. 

 The cumulative dose of lorazepam administered to the 31 subjects ranged from 0 to 1035 mg in the 72 hours following randomization, with a range of 1 to 1035 mg in the placebo group and 0 to 39 mg in the baclofen group. The 8 subjects who received the highest doses of lorazepam (20 mg or more) included 1 of the 18 subjects who received baclofen and 7 of the 13 subjects who received placebo (P = 0.004). Only 4 subjects required >50 mg of lorazepam over the 72 hours; all 4 of these were patients in the placebo group (P = 0.023).

Cochrane in 2011 finds the evidence is insufficient.

Should we use baclofen?

The addition of baclofen to our current regimen for alcohol withdrawal is worthy of study.  Since it is also a GABAergic medication, I find it's ability to reduce the need for lorazepam is less compelling than when the same is accomplished by anti-convulsants or other non GABA medications.  It would be interesting to see if the incidence of DTs or length of stay if reduced. 

High dose baclofen maintenance for treatment of alcohol dependence is a different question, and a more important one.  I am thinking of this as substitution therapy, similar to methadone maintenance.  Baclofen does create physical dependence and can patients can experience withdrawal not much different than alcohol or benzodiazepine withdrawal. 

I think of baclofen as a drug that is not typically abused: that patients don't obtain it illicitly, lose control of how much they are taking or escalate doses inappropriately.  In this context I'm not sure how to interpret these case reports of success with very high dose use.  If Dr. Ameisen had self prescribed diazepam or oxycodone in this same fashion we would likely consider this part of the disease of addiction.   The case reports do seem to imply that patients are functioning well.  The fact that these reported patients are not drinking suggests progress in managing the addictive process. 

We have a model of maintenance agonist therapy with methadone that is proven to be effective and a sense (without clinical trials) that benzodiazepine treatment only worsens alcohol dependence.  Where would high dose baclofen fit in to this picture?  I have an instinctive hesitation to use GABA drugs due to concern of impairing a patient's judgement.  On the other hand we see patients dying of ongoing alcohol use.  It might be reasonable to consider high dose baclofen in patients who have failed other therapies, where tolerance is high and function is low. In some sense it would seem impossible that baclofen could in any way make these patients worse.

At least we could interpret the current state of literature of supporting higher doses of baclofen, if it is to be used for the treatment of alcohol dependence. 

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[1] Alcohol Alcohol. 2005 Mar-Apr;40(2):147-50. Epub 2004 Dec 13.

Complete and prolonged suppression of symptoms and consequences of alcohol-dependence using high-dose baclofen: a self-case report of a physician. Ameisen O. PMID: 15596425 

[2]Addiction. 2012 Apr;107(4):848-9. Epub 2012 Feb 11.  

Alcohol-dependence: the current French craze for baclofen. Rolland B PMID:  22324452

[3]

Alcohol Clin Exp Res. 2010 Nov;34(11):1849-57.  

Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo-controlled trial.  Garbutt JC  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965272/?tool=pubmed

[4] Lancet. 2007 Dec 8;370(9603):1915-22.  

Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study.  Addolorato G PMID: 18068515

[5] Alcohol Alcohol. 2011 May-Jun;46(3):312-7. Epub 2011 Mar 17.
Dose-response effect of baclofen in reducing daily alcohol intake in alcohol dependence: 
secondary analysis of a randomized, double-blind, placebo-controlled trial. Addolorato G PMID: 21414953

[6] J Hosp Med. 2011 Oct;6(8):469-74. 

Treating alcohol withdrawal with oral baclofen: a randomized, double-blind, placebo-controlled trial.  Lyon JE PMID: 21990176

British Association for Psychopharmacology updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity


This is an exhaustive review.  Print it out, sit down in a comfy chair and spend some time with it's 40 pages (not counting 14 pages of citations).  Should be required reading for the addiction specialist.  The full text is free at http://jop.sagepub.com/content/early/2012/05/15/0269881112444324.full.pdf+html


Here are some interesting (to me) gems: 

Wernkicke's and thiamine replacement

It  has been suggested that a presumptive diagnosis of WE should be made for any patient with a  history of alcohol dependence who shows one or more of the following: evidence of ophthalmoplegia, ataxia, acute confusion, memory disturbance, unexplained hypotension, hypothermia, coma, or unconsciousness.

Patients commonly deemed ‘at risk’ of developing WE during a hospital admission or a planned detoxification are those whose drinking has exceeded 15 units per day [=8.5 US standard drinks] for a month or more and where there is evidence of recent weight loss or vomiting or diarrhoea or malnutrition or peripheral neuropathy or chronic ill health.

In healthy uncomplicated alcohol-dependent/heavy drinkers (i.e. those at low risk), oral thiamine >300 mg/day should be given during detoxification.If patient is at high risk of WE (e.g. malnourished, unwell) prophylactic parenteral treatment should be given, using 250 mg thiamine i.m. or i.v. once daily for 3–5 days or until no further improvement is seenIf WE is suspected or established, parenteral thiamine (i.m. or i.v.) of >500 mg should be given for 3–5 days, followed by >250 mg once daily for a further 3–5 days depending on response

Enthusiasm for phamacotherapy of alcohol dependence

We endorse the recommendation that pharmacotherapy should be the default position, such that the decision not to prescribe is made actively for those patients presenting with harmful alcohol use or abuse that have not benefited from psychosocial interventions and for everyone with dependence, rather than only thinking of medication for more complex patients. 

QTc in methadone vs buprenorphine

In a study of the prevalence of corrected QT (QTc) interval prolongation during methadone and buprenorphine treatment, 4.6% of subjects on methadone had corrected QT intervals > 500 ms, 15% > 470 ms and 28.9% > 450 ms. All subjects on buprenorphine had QTc < 450 ms. There was a positive dose-dependent association between QTc interval and methadone dose. All eight patients with QTc > 500 ms were prescribed 120 mg or more of methadone

Benzodiazepine taper facilitated by melatonin also valproate, trazodone, paroxetine

Four of the pharmacotherapies showed significant effects on benzodiazepine discontinuation rates in single studies. Garfinkel et al. (1999) reported discontinuation rates of 77% with the addition of melatonin compared with 25% with gradual dose reduction alone. Rickels et al. (1999) added sodium valproate, trazodone or placebo to a benzodiazepine taper. At 5 weeks post-taper, 79% of sodium valproate and 67% of trazodone, but only 31% of placebo patients were benzodiazepine free. These differences were not maintained at 12 weeks post-taper. Adjunctive paroxetine in patients without major depression increased discontinuation rates compared with gradual dose reduction alone (46% vs. 17%) (Nakao et al., 2006) 

Antabuse for cocaine dependence
There is a lot I had forgotten about the role of disulfiram for cocaine dependence and the combination of disulfiram & naltrexone for combined alcohol / cocaine dependence


Buproprion a nicotine blocker?

The atypical antidepressant bupropion has been well studied and is licensed as an aid to smoking cessation. It has dopaminergic and adrenergic actions, and also appears to act as an antagonist at the nicotinic acetylcholinergic receptor

Naltrexone improves mood

Lastly, although it is theoretically possible for naltrexone to worsen mood, this has not been seen clinically. Recent studies in newly abstinent heroin addicts have not found naltrexone induction and/or maintenance to worsen mood, but instead to improve it