Journal of Clinical Psychopharmacology--Baclofen

[Ne/Neva Eva]

There are four cases of people who titrated up to between 75mg and 125mg of baclofen a day. They all started at 30mg/day and titrated up over a period of about 4 weeks. Three of the 4 titrated down. One relapsed when he did, so he went back up. They all also used other medications. (Campral and Nal)

I'll post an attachment on the Consolidated Bac thread, too.


High-Dose Baclofen for Treatment-Resistant Alcohol Dependence
Adam Pastor, BA, MBBS, David Martyn Lloyd Jones, MBChB, MRCGP, FRACGP, FAChAM, and Jon Currie, MBBS, PhD, FRACP, FAChAM

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-resistant patients. 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.

Key Words: baclofen, alcohol dependence treatment, alcohol dependence, high-dose baclofen
(J Clin Psychopharmacol 2012;32: 266Y268)
Alcohol consumption is a major cause of preventable mor- bidity and mortality worldwide, and alcohol dependence is associated with an array of physical and psychiatric complica- tions.1 Symptomatic treatment of the alcohol withdrawal syn- drome followed by ongoing individual or group psychological support has traditionally been the mainstay of treatment for al- cohol dependence; however, sustained improvement rates are low and relapses common.2 Recent advances in our understand- ing of the neuroscience of addiction have led to the development and use of an increasing range of pharmacotherapeutic agents that promote abstinence with substantially improved outcomes for patients with alcohol dependence.3,4 Naltrexone, acamprosate, and disulfiram5Y7 are widely used; and a number of other agents including baclofen, topiramate, and ondansetron are accumulat- ing evidence for their clinical effectiveness.3,4 These agents exert their effects at sites implicated in the etiology of craving and mod- ulate neurotransmitters that include dopamine, F-aminobutyric acid (GABA), glutamate, and serotonin.
Baclofen, a GABA-B agonist, is widely used for symp- tomatic relief of muscle spasticity related to multiple sclerosis and spinal conditions, where it is commonly titrated to total daily maintenance doses between 30 and 100 mg administered in 2 to 3 divided doses.8 Of note, considerably higher doses have also been used with good effect.8 Recent studies have suggested that baclofen may also assist in the maintenance of abstinence from alcohol through the modulation of GABAergic neurons in the ventral tegmental area and limbic system,9 stabilizing dopami- nergic neurons with a clinical reduction in craving.
From the Department of Addiction Medicine, St Vincent’s Hospital, Melbourne, Australia. Received December 21, 2010; accepted after revision December 19, 2011. Reprints: Adam Pastor, BA, MBBS, Department of Addiction Medicine,
St Vincent’s Hospital, Melbourne, Fitzroy 3065, Australia
(e-mail: adampastor@yahoo.com). Copyright * 2012 by Lippincott Williams & Wilkins ISSN: 0271-0749 DOI: 10.1097/JCP.0b013e31824929b2
266 Journal of Clinical Psychopharmacology Copyright ? 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Preclinical data10 and 2 unblinded open-label trials sup- port the effect of baclofen on reducing heavy drinking.11,12 Two blinded randomized clinical trials by Addolorato et al13,14 showed a significant effect of baclofen on reducing craving for alcohol and improving abstinence-related outcomes; however, a trial by Garbutt et al15 did not show any positive effect on drinking outcomes. These trials have all used a total daily dose of 30 mg, which was chosen based on the open clinical studies and represents the minimum therapeutic dose recommended by the drug manufacturer to avoid adverse effects.14
A translational model of treatment of substance dependence based on animal studies using high-dose baclofen to completely suppress craving was proposed by Ameisen16 in 2005 and was accompanied by a case study using a total daily dose of 270 mg soon reduced to 120 mg.17 Other single-case studies following this model have also have been published.18,19 A further study was also published indicating that large doses of alcohol could be taken safely in the presence of up to 80 mg of baclofen.20 Con- sidering the safe and efficacious use of high doses of baclofen for comfort care of neurological conditions and its safety with con- current alcohol administration, using high-dose baclofen may have merit in a subgroup of patients with otherwise treatment- resistant alcohol dependence.
We report on the following 4 successful cases (Table 1) on using high-dose baclofen for alcohol dependence in patients who remained treatment resistant to other modalities including a total daily dose of 30 mg of baclofen prescribed in combination with other anticraving medications. With regard to safety, none of the 4 patients reported a history of epilepsy or cardiac dis- ease. A thorough physical examination was performed; and liver function, renal function, and basic hematologic parameters were evaluated at the commencement of treatment before attaining informed consent.
Baclofen was increased from a total daily dose of 30 mg by 12.5 to 25 mg each week as tolerated and until craving was suppressed. Doses were divided twice or 3 times daily depend- ing on patient’s preference and compliance. Each patient was medically reviewed with regard to adverse effects at least weekly during the titration phase and fortnightly once stabilized. After a minimum of 3 months of stabilization, baclofen was then re- duced to the lowest effective dose to minimize the risk of adverse effects, or a significant withdrawal syndrome should the baclo- fen be abruptly ceased.21
Case 1
A 43-year-old woman, employed, with 4 children, and with a 15-year history of depression and alcohol dependence attended an outpatient clinic. She was taking 150 mg of sertraline and regularly attending Alcoholics Anonymous.
She reported becoming a ‘‘heavy drinker’’ in her 30s with escalating use over the last 4 years after a divorce. At presen- tation, she reported drinking a bottle of wine daily (80 g alcohol) with the addition of a 750-mL bottle of spirits daily (220 g alcohol) on weekends. She had significant withdrawal symp- toms when trying to cease drinking and reported high levels of
Journal of Clinical Psychopharmacology & Volume 32, Number 2, April 2012

[Ne/Neva Eva]

Journal of Clinical Psychopharmacology--Baclofen

craving when not drinking. She had had a single period of so- briety lasting 6 weeks approximately 1 year before presentation, with no other periods of abstinence in the previous 4 years.
She initially received both counseling and pharmacological support with naltrexone and acamprosate but did not tolerate acamprosate owing to persistent diarrhea. After a month of ab- stinence, she reported daily cravings of severe intensity and 2 episodes of drinking greater than 80 g of alcohol within a 2-hour period. Baclofen, to a total daily dose of 30 mg, was added with no effect on her craving after 3 weeks. The baclofen dose was then titrated over 4 weeks to 75 mg with a dramatic suppres- sion of cravings, and she maintained abstinence from alcohol for the following 3 months. The baclofen dose was then reduced to a total daily dose of 50 mg, and she has achieved more than 9 months of abstinence, no cravings, stable mood, and excellent social functioning.
Case 2
A 31-year-old male factory worker with an 11-year history of alcohol dependence attended outpatients after being diag- nosed by his neurologist with an alcohol-related bilateral upper and lower limb peripheral neuropathy. He was drinking 2 bottles of wine daily (160 g alcohol) and had 4 previous charges of driving under influence, been involved in a number of physical fights, had and persistent episodes of absenteeism from work.
He described cravings lasting 30 minutes occurring up to 5 times each day. He was commenced on acamprosate and naltrexone but did not tolerate naltrexone owing to unremitting headaches. Topiramate was then introduced but not tolerated owing to dizziness. He had not found counseling useful in the past but did read a number of motivational self-help books. Six weeks after commencement of treatment, he drank up to 8 bottles of beer (120 g of alcohol) each day for 3 days. Baclofen, up to a total daily dose of 30 mg, was introduced, but cravings persisted 1 month after its introduction.
Over the coming 5 weeks, the baclofen dose was titrated up to 87.5 mg, with a substantial suppression of cravings, and he became abstinent. After 6 months of continuous abstinence, his baclofen was slowly reduced to 50 mg without a reemergence of cravings. He has now completed 9 months without any al- cohol intake associated with a stabilization of his peripheral neuropathy.
Case 3
A 46-year-old male baker with type 2 diabetes, dyslipidemia, asthma, depression, and alcohol dependence attended outpatients.
* 2012 Lippincott Williams & Wilkins Copyright ? 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
He was first diagnosed with alcohol dependence at age 26 and reported drinking a bottle of spirits daily (220 g of alcohol) for the 2 years before presentation. He reported significant cue-induced cravings, being unable to walk past a bottle shop without buy- ing alcohol. He began individual counseling and pharmaco- therapy involving naltrexone, acamprosate, and a total daily dose of 30 mg of baclofen. Despite this treatment and his stated aim of being abstinent from alcohol, he continued low-level drinking and complained of ongoing cue-induced cravings.
After 3 months of reduced drinking, he relapsed to his pre- vious heavy daily use for 6 weeks and ceased his medications. After re-presenting, his other anticraving agents were ceased and his baclofen dose was titrated over 6 weeks to 100 mg. A validated measure of alcohol craving, the Obsessive-Compulsive Drinking Scale,22 had dropped from 39 pretreatment to 9 after stabilization, and he achieved abstinence.
After 7 months of abstinence, the patient’s dose of baclo- fen was gradually reduced. When it reached a total daily dose of 50 mg, he reported an increase in craving and relapsed to daily intake of a bottle of spirits (220 g of alcohol). He was admitted to a residential withdrawal unit, and during his admission, the dose of baclofen was increased to 100 mg.
After the increase in his baclofen dose, the cravings were suppressed, and he maintained abstinence for 5 months. He de- scribes some daytime fatigue but does not wish to reduce his current dose of baclofen.
Case 4
A 36-year-old man with bipolar disorder, managed with olanzapine and citalopram, attended outpatients after a number of minor criminal offences committed when intoxicated. He re- ported drinking a carton of beer on a single occasion each week (360 g of alcohol) and described feeling anxious and experienc- ing craving on alcohol-free days. This had been a regular pattern since age 16, and his longest period without alcohol since that time had been 6 weeks.
He had been prescribed naltrexone in the past, with no effect on his drinking, but had some benefit from acamprosate. He was commenced on acamprosate and a total daily dose of 30 mg of baclofen with minimal effect on his binge drinking, which con- tinued to occur on a weekly basis. After a trial of 3 months of treatment, his dose was increased over 6 weeks to 125 mg daily after which he ceased drinking alcohol for 3 months. He relapsed to binge drinking twice weekly for 1 month, which was associated with a depressive episode, which was then followed by a further 7 months of abstinence.
Journal of Clinical Psychopharmacology 267

[Ne/Neva Eva]

Journal of Clinical Psychopharmacology--Baclofen

The aforementioned case studies demonstrate that high- dose baclofen may benefit patients with alcohol dependence, with all of the patients reporting a sustained period of abstinence after an upward titration of their baclofen. The reported mech- anism was a suppression of craving, and the further use of val- idated clinical tools to measure craving would be valuable in the future to document this effect.
By titrating baclofen slowly, there were few adverse effects, and the drug was generally well tolerated. Transient mild symp- toms occurred during dose reductions in 2 of the 4 cases. All the patients have been retained in intensive medical treatment for more than 9 months, with cases 1 and 3 continuing counseling or 12 step-based supports in addition to pharmacotherapy.
After a period of stable abstinence, an attempt was made in cases 1 to 3 to reduce baclofen doses. Two of the patients, cases 1 and 2, had long periods of stability, and a dose reduction to lower maintenance doses was possible. This suggests that in some patients, higher doses of baclofen may only be necessary in the first 3 to 6 months after cessation of alcohol. This partially mitigates against concerns of using high-dose baclofen for long periods. The patient in case 3 had a significant return of cravings and a relapse to heavy drinking when baclofen was reduced, necessitating a reinstatement of higher doses.
Whereas it is impossible to rule out a placebo effect for the aforementioned cases, each had a long history of failed treat- ments and demonstrated a sustained period of improvement associated with suppression of craving on high-dose baclofen. Because most of the patients continued other anticraving med- ications, it is unclear whether baclofen may work cumulatively or even synergistically with other medications aimed at cravings or other psychiatric symptoms. The concomitant use of other medications may have also partially concealed the effectiveness of baclofen, and there was no attempt at reducing or ceasing concomitant anticraving medications while on baclofen. It is also unclear from the length of this study whether tolerance to the anticraving effect of baclofen may develop over a longer period of treatment. As with many treatments for addiction, the length of time required for treatment may have considerable interindividual variability.
Although only a small group, there is already considerable heterogeneity with regard to sex, age, motivations, and pattern of drinking. The variety of cases presented argues against easy matching of clinical typologies with baclofen treatment and raises a number of questions regarding optimal dose, delivery of care, and length of treatment.
In summary, these case studies suggest that doses of baclofen greater than a total daily dose of 30 mg may suppress craving in patients with alcohol dependence who have not responded to lower doses or other anticraving medications. Furthermore, high- quality research into the use of high-dose baclofen for alcohol dependence is warranted to confirm these findings.
AUTHOR DISCLOSURE INFORMATION
The authors declare no conflicts of interest.

[Ne/Neva Eva]

Journal of Clinical Psychopharmacology--Baclofen

I can't figure out how to post the table, but I will...