02/26/19

More Harm Than Good with Baclofen

In October of 2018 French health authorities approved the use of a muscle relaxant known as baclofen as a medication-assisted treatment (MAT) for alcoholism. In the U.S., it is approved to treat muscle spasms caused by conditions such as multiple sclerosis or spinal cord injuries. But a French-American cardiologist names Olivier Ameisen self-treated his own compulsive drinking with high doses of baclofen and then wrote a book about his experiences: The End of My Addiction. His reasoning behind the book title was that since baclofen stopped his symptoms of craving and obsessing over alcohol, he was “cured” of alcoholism.

I wrote a three-part article, “The End of Alcoholism? “ (Part 1, Part 2, Part 3), about Ameisen and his use of baclofen as a MAT for alcoholism three years ago. Read that article for more information on Ameisen and his so-called “cure.” My primary concern discussed then was the known withdrawal syndrome related to baclofen use. Similar to medications used to “treat” opioid use disorders (buprenorphine and methadone) and anxiety or panic attacks (benzodiazepines like: Ativan, Klonopin, Xanax) the physical and psychological dependency that develops is a hidden adverse effect. The medications work so effectively that the growing dependency is either minimized or goes unnoticed. Only when and if the individual attempts to taper off of the drugs do people realize what has happened.

The Prescribers’ Digital Reference warns that confusion, hallucinations, seizures and other psychiatric disturbances have occurred with abrupt discontinuation (withdrawal) of baclofen. They recommended a gradual reduction over 2 weeks or more. Listed severe adverse reactions included: coma, stroke, seizures, suicidal ideation, and others. Milder and more frequent adverse reactions included: drowsiness, weakness, dizziness, headache, and others. There is a very long list of noted drug interactions, many of which are CNS (central nervous system) depressants like benzodiazepines and opioids.

The Medical Xpress press release announcement of France’s approval of baclofen did indicate officials warned the drug could have harmful side effects and limited its maximum recommended dosage to 80 milligrams. This was down from the 300-milligram dose that had been used previously by Ameisen and others. The French version of the U.S.’s FDA (ANSM) said that while there was not definitive proof baclofen was efficient in treating alcoholism, it has shown “clinical benefits in some patients.” The ANSM director said that refusing the drug “did not seem reasonable to us given the needs and the seriousness of alcoholism, and the fact that tens of thousands of people are taking the medicine for this treatment.”

In November of 2018 the British medical journal The Lancet published an editorial article by Agabio et al., “Baclofen for the treatment of alcohol use disorder: the Cagliari Statement.” The consensus statement was named after the town in Italy where the GABA_B Receptor Conference was held on May 25, 2018. Agabio et al. said they believed baclofen was a “promising pharmacotherapy for alcohol use disorder, but it’s superiority over placebo has not been established yet.” More research needed to be done.

Despite the absence of consistent evidence of efficacy, baclofen is frequently used off-label to treat alcohol use disorder, especially in Australia and some European countries. The use of baclofen for clinical research and in medical practice varies substantially, because of differences in treatment provision for alcohol use disorder, clinical experience, and country-specific regulations and culture.

Three recently published meta-analyses were cited and commented on in “Baclofen for the treatment of alcohol use disorder: the Cagliari Statement.” Agabio et al. said the studies did not draw definitive conclusions on the efficacy of baclofen to treat alcohol use disorder. One meta-analysis (Bschor et al.) did not find baclofen to be superior over placebo on the primary outcomes of each study. The other two meta-analyses (Rose and Jones; Pierce et al.) found baclofen increased the number of abstinent patients and time to first drink when compared to placebo. “Chiefly, all three meta-analyses found overall a small effect size and substantial heterogeneity among studies.”

Bschor et al. found a small, but not statistically significant superiority of baclofen over placebo. They questioned the utility of baclofen in the long-term treatment of alcohol use disorder at both normal and high doses. “While the confidence intervals indicate that marginally harmful or moderately beneficial effects of baclofen remain a possibility, the most likely effect size is slightly above placebo effects.”

Rose and Jones said baclofen was associated with higher rates of abstinence than placebo. But there was no superior effect of baclofen on increasing the number of abstinent days or decreasing heavy drinking, craving, anxiety or depression. “These results suggest that the current increasing use of baclofen as a treatment for alcohol use disorders is premature.”

Commenting on her study for Healio, Abigail Rose said many of the trials in her study were under-powered. There were also differences in how the trials reported data on adverse events. “Although the most recent trials were larger and still failed to find an effect of baclofen. Importantly, we don’t yet fully understand baclofen’s pharmacokinetics and how this may have an impact on therapeutic effect.”

Pierce et al. found that low dose baclofen (LDB 30-60 mg) showed better efficacy than high dose baclofen (HDB >60 mg daily). Tolerability of HDB was low, but serious adverse events were rare. The effects of baclofen were stronger when daily alcohol intake was higher. “Baclofen seems to be effective in the treatment of AD, especially among heavy drinkers. HDB is not necessarily more effective than LDB with low tolerability of HDB being an import limitation.”

Naudet and Braillon reflected on Agabio et al.’s article in the same issue of The Lancet, “Baclofen and alcohol in France.” They said the promotion of the off-label use of baclofen was not appropriate, “especially when evidence points to a negative benefit:harm ratio.” They noted where the ANSM published an evidence-based assessment “from a Temporary Special Scientific Committee of independent experts who concluded that the benefit:harm ratio of baclofen in alcohol use disorder was negative.” After two days of public hearings, the ANSM concluded that it supported the use of baclofen in alcohol-dependent patients, but limited the marketing authorization for baclofen proposed in the application of Ethypharm Pharmaceuticals to France. Then on October 23, 2018 the ANSM approved the use of baclofen for alcohol use disorder.

This decision seems to ignore the evidence summarised by the Temporary Special Scientific Committee. Evidence opposing the use of baclofen includes findings from a pharmacoepidemiological study on 277,790 patients who were treated with baclofen between 2009 and 2015. Compared with 117,720 people who used the approved treatments for alcohol disorders (acamprosate, naltrexone, or nalmefene), the group of 47,614 people who were prescribed baclofen for an off-label use had higher mortality at any dose of baclofen. . . . Importantly, this increased risk was dose related.

Referring to the Bschor et al. and Rose & Jones studies, Naudet and Braillon said the finding that baclofen may increase abstinence was largely driven by two small, short-term studies, while the two largest trials failed to show that baclofen was effective. “No other effects on treatment efficacy were observed.” Further, the Temporary Special Scientific Committee focused on two relatively large randomized controlled trials of baclofen versus placebo. In the analyses for one of the studies submitted for baclofen’s approval by ANSM, Ethpharm changed the primary outcome measure. The results of this study are still unpublished in the peer-reviewed literature even though it was completed in October of 2015.

Preliminary results presented at conferences showed a two times increase in mortality in the baclofen group and that 19 of 162 patients in the baclofen group and 60 of 158 in the placebo group received open-label baclofen before the end of the study. Although the study was funded by the French Department of Health, the sponsor (Paris Public Hospital Authority) contractually transmitted data to Ethypharm. The analyses that were done for the purpose of approval were performed by Ethypharm, and the primary outcome was changed.

Replying to Naudet and Braillon on behalf of the Cagliari group, Agabio, Sinclair and Leggio said the Cagliari Statement did not promote the off-label use of baclofen. Rather, since the off-label use of baclofen happens, they wanted to provide “objective statements on the available evidence and clinical use of baclofen in alcohol use disorder.” They thought their statements could be useful to clinicians using baclofen for patients with alcohol use disorder and by scientists planning baclofen-related research in alcohol use disorder. Protecting patients’ safety was paramount and the recent pharmacoepidemiological work mentioned by Naudet and Braillon was important. “The Cagliari Statement highlights the risks related to baclofen use, emphasises that side-effects and safety concerns might be dose dependent, and provides several safety-related statements and recommendations.”

So despite the French approval of baclofen as MAT, it does not seem the FDA should also approve it for use in the U.S. market. In fact, it appears the benefit:harm ratio suggests baclofen would do more harm than good if approved as a MAT in the U.S.

11/21/17

Cunning, Baffling, Powerful

Vincent Dole was one of the three physicians who originated methadone as a maintenance drug treatment for heroin addiction in the 1960s. Rather unexpectedly, he was asked to serve as a Class A, non-alcoholic, trustee for the General Service Board of Alcoholics Anonymous. He thought they had made a mistake so before accepting the position, he discussed his research into “chemotherapy for narcotic addiction” with executives of the A.A. Fellowship. They didn’t see any problem or conflict of interest with his appointment and Dr. Dole served as a trustee for A.A. for eleven years, from April of 1965 until April of 1975.

At one point in his tenure as a trustee, he served as a co-chair for the General Service Board. In his farewell letter to the A.A. GSO, printed in the August-September issue of Box 4-5-9, the newsletter from the General Service Office of A.A., he said he would always remain identified with A.A. “My heart is with the Fellowship.”

Like most in A.A., I have gained more in the association than I have been able to give. Especially, it has been a privilege to witness the power of love when focused and unsentimental. I have seen that: Salvation is found in helping others; help stems from knowledge, humility, compassion, and toughness; success is possible.My greatest concern for the future of A.A. is that the principle of personal service might be eroded by money and professionalism. Fortunately, most of the membership of A.A., especially the oldtimers, know that A.A. cannot be commercialized. It is not a trade union of professional counselors or an agency hustling for a budget. The mysterious wisdom of A.A. will discover how to cooperate in reaching out to sick alcoholics while maintaining its Traditions.

In a 1991 article he wrote for the journal Alcoholism, “Addiction as a Public Health Problem,” Dr. Dole said that throughout his time as a trustee he was puzzled by why he specifically was asked to serve. He ended by assuming he had been “brought in as a smoke alarm, a canary in the mine” to guard against “the Fellowship being distorted by aggressive person with dogmatic opinions.” Then, in the late 1960s, he believed a more specific reason emerged, not long before Bill W.’s death. An excerpt from that article is available here: “The Methadone/AA Link.”

A more specific answer, however, emerged in the late 1960s, not long before Bill’s death. At the last trustee meeting that we both attended, he spoke to me of his deep concern for the alcoholics who are not reached by AA, and for those who enter and drop out and never return. Always the good shepherd, he was thinking about the many sheep who are lost in the dark world of alcoholism. He suggested that in my future research I should look for an analogue of methadone, a medicine that would relieve the alcoholic’s sometimes irresistible craving and enable him to continue his progress in AA toward social and emotional recovery, following the Twelve Steps. I was moved by his concern, and in fact subsequently undertook such a study.

Dr. Dole went on to say he unsuccessfully sought to find that analogue in his laboratory until it closed in 1991. But he thought the work had just begun. Other laboratories and investigators would continue to work on the analogue problem. “With the rapid advance in neurosciences, I believe that Bill’s vision of adjunctive chemotherapy for alcoholics will be realized in the coming decade.”

Since Dr. Dole made that optimistic prediction, several different medications have been used as a harm reduction strategy for individuals with alcohol dependence or alcohol use disorders. Two opioid antagonists, nalmefene and naltrexone and three drugs acting on the gamma-aminobutyric acid (GABA)ergic system (baclofen, acamprosate and toprimate) has been used formally or informally to reduce alcohol consumption or maintain abstinence. Recently in the journal Addiction, Palpacuer et al. did a meta-analysis of 32 double-blind randomized controlled trials of these five medications. The studies were published between 1994 and 2015, and had a combination of 6,036 patients between them. They concluded:

There is currently no high-grade evidence for pharmacological treatment to control drinking using nalmefene, naltrexone, acamprosate, baclofen or topiramate in patients with alcohol dependence or alcohol use disorder. Some treatments show low to medium efficacy in reducing drinking across a range of studies with a high risk of bias. None demonstrates any benefit on health outcomes.

There was no evidence of any significant reduction in serious adverse events or mortality. Studies that sought to assess the efficacy of these medications as maintenance drugs, similar to how methadone is used, “were inadequate to investigate” whether they reduced serious adverse events. “In addition, any pharmacological approach that might benefit patients by reducing their alcohol consumption might also harm them because of safety issues.” As a result, the researchers advocated for long-term mega-trials exploring health outcomes.

To conclude, our results suggest that no treatment currently has high-grade evidence for pharmacologically controlled drinking in the treatment of patients suffering from alcohol dependence or alcohol use disorders. At best, some showed low to medium efficacy in reducing drinking, but across a range of studies with a high risk of bias. Although based on all available data in the public domain, this meta-analysis found no evidence of any benefit of the use of drugs aiming for a controlled drinking strategy on health outcomes. We invite researchers and stakeholders to set up a coherent agenda to demonstrate that pharmacologically controlled drinking can be translated into genuine harm reduction for patients. From the clinical perspective, while this new approach is often presented as a ‘paradigm shift’ in terms of therapeutics, doctors and patients should be informed that the critical examination of the pros and cons of the evidence clearly questions the current guidelines that promote drugs in this indication.

Reporting for The Guardian, Sarah Boseley further noted that one of the reasons for the inconclusive findings in Palpacuer et al. was because of the high drop out rates in the studies. “So many people dropped out of the trials that 26 of the 32 studies – 81% of them – had unclear or incomplete outcome data.” The lead author for the study, Clément Palpacuer, said the report did not mean the drugs weren’t effective. “It means we don’t yet know if they are effective. To know that, we need more studies.” There have also been concerns raised about the drugs by some studies already.

Bosley cited Fitzgerald et al., a review of the trial evidence used to approve nalmefene for use in the NHS. The researchers said at best, there was only modest evidence of efficacy in reducing alcohol consumption. This was despite stacking the deck in how the data was analyzed for approval of the drug.

Important weaknesses in nalmefene trial registration, design, analysis and reporting hamper efforts to understand if and how it can contribute to treating alcohol problems in general practice or elsewhere. The efficacy of nalmefene appears uncertain; a judgement of possible limited efficacy in an unusually defined and highly specific post‐hoc subgroup should not provide the basis for licensing or recommending a drug.

There are issues noted with baclofen as well. A co-author of Fitzgerald et al. noted one French study raised concerns with the safety of baclofen, with more deaths in the treatment group (7 of 162) than the placebo group (3 of 158). A further study by France’s medicines safety agency drew attention to additional adverse effects: “In particular, the risk of intoxication, epilepsy and unexplained death [on the death certificate] increases with the dosage of baclofen.” See “Sure Cure for Drunkenness” and “A ‘Cure’ for Alcoholism” and “The End of Alcoholism?” Part 1, Part 2 and Part 3 for more concerns with baclofen and nalmefene.

Vincent Dole’s search for a methadone analogue or adjunctive chemotherapy for alcoholism is unlikely to be successful. As Carleton Erickson pointed out in The Science of Addiction, alcohol is different than other drugs. He said: “Unlike other drugs, alcohol has no specific receptor to activate in the brain.” Cocaine works on the dopamine transporter. Heroin and other opioids work on the opioid receptor; and marijuana works on the cannabinoid receptor. “Alcohol is known to affect the GABA receptor, the NMDA receptor, and probably others.”

There isn’t a hand-in-glove fit between a receptor and alcohol as there is with the opioid receptor and heroin or other opioids. So there isn’t a medication that can single handedly block alcohol as there is with heroin and other opioids. As Bill W. knew from personal experience, alcohol is cunning, baffling and powerful.

10/5/15

The End of Alcoholism? Part 3

“One of the first duties of the physician is to educate the masses not to take medicine.” Sir William Osler, physician

Olivier Ameisen wrote in The End of My Addiction that thoughts about an addictive substance could insinuate themselves into an addict’s consciousness and quickly preoccupy the whole mind with anxiety about how to get it. “This is a harrowing experience mentally and emotionally as well as physically, because it is charges with shame and self-loathing for even experiencing the craving.” Cravings could propel him into a trance-like state. He would set out to buy liquor, feeling as if someone else was controlling his body. “When craving defeated me, I could only hope, pray, and strive to do a better job of resisting it the next day.”

Ameisen was “a French-American male physician with alcohol dependence and comorbid pre-existing anxiety disorder.” He said he had been plagued by anxious feelings of inadequacy throughout his life. He’d been seeing therapists for a long time before he started drinking. They were never much help with his anxiety. “Nor was the Xanax they prescribed me.” So he turned to alcohol.

I was terrified of living without alcohol. Without it, I would be an anxious wreck. Admitting my problem drinking to most of my friends and my colleagues terrified me too. I feared being ostracized, and since I felt that drinking should be under my control I felt ostracism would be justified.

He told every physician and therapist he saw that his fundamental problem was anxiety, “which expressed itself in chronic muscle tension, and which intensifying to a panic state, triggered the overwhelming need to drink for relief.” None of the addiction professionals took him seriously. So he looked around to prescribe his own treatment. He thus disregarded another observation of the Canadian physician, William Osler: “A physician who treats himself has a fool for a patient.”

An old girlfriend sent him a copy of a New York Times article that discussed baclofen reduced craving with cocaine, but he was in the midst of a binge and misplaced the copy. He eventually contacted the doctor mentioned in the article and asked her about baclofen. Although he was encouraged by the conversation, his alcohol treatment specialist and psychiatrist weren’t interested in discussing an unproven medication. In early February of 2002 he began doing an internet research into baclofen. Panic was his most crippling symptom, so he searched first under “baclofen panic.” He found several reported studies, including the 2000 study by Addolorato, “Ability of baclofen in reducing alcohol craving and intake.”

Ameisen developed a theory that there is a “threshold dose” of baclofen needed to break the cycle of craving, preoccupation and obsessive thoughts with alcoholism. And he decided to try out the theory on himself. He began his self-medicated treatment with baclofen on January 9, 2004. See “The End of Alcoholism? Part 1” for a fuller description of this process. Ameisen did attempt social, controlled drinking, about fifteen months after establishing alcohol abstinence by taking baclofen. But he said he preferred not drinking. James Medd in The Guardian suggested that “He can now drink socially—an idea entirely counter to the teachings of AA and most other therapies.”

Ameisen saw anxiety as his primary disorder, with his drinking as a way to self-medicate his anxiety. Additionally, he held on to a belief that he should be able to control his drinking: “I should be able to control my urge to drink. . . . Since I felt that drinking should be under my control, I felt ostracism would be justified.” Even though he reportedly went to hundreds of Alcoholics Anonymous (A.A.) meetings, if he held onto a belief that he should be able to control his drinking, he would not be able to effectively use A.A. to remain abstinent, because he didn’t entirely accept their first Step: “We admitted that we were powerless over alcohol, and that out lives had become unmanageable.”

Other medical professionals were concerned with his use of high dose baclofen. Jonathan Crick, the psychiatrist who is the editor-in-chief of Alcohol and Alcoholism, said he’s been encouraged with his own treatment of 50 patients with baclofen, but won’t use the high doses of Ameisen’s method. He stays under 100 mg a day. “I do actually have some concerns about unwanted effects in large doses. . . . This is a drug which is active in the brain, and there are some concerns about some unwanted effects of higher doses.”

I also wonder if he turned a blind eye to some of the concerns raised about baclofen in the literature. He saw it as essential to his own ability to manage anxiety, cravings, and to refrain from compulsive, out of control drinking.

There have been a series of studies reporting what has been called a “baclofen withdrawal syndrome.” A 1981 article, Complication of Baclofen Withdrawal, reported that three patients taking baclofen on a long-term basis experienced hallucinogens and/or seizures with abrupt reduction of their dose or discontinuation of baclofen therapy. A 1998 article, “Prolonged Severe Withdrawal Symptoms,” reported that an abrupt decrease or too rapid taper off baclofen could result in a withdrawal syndrome manifesting hallucinations, delirium, seizures and high fever.

A 2005 study, “Delirium Associated with Baclofen Withdrawal,” reviewed 23 published cases of psychiatric symptoms with baclofen withdrawal. Delirium, but not other symptoms was found to arise from abrupt baclofen withdrawal. The delirium appeared to be greater in individuals who received chronic baclofen therapy. A 2001 case study reported on the case of a man with neuroleptic malignant-like syndrome, with disorientation, signs of autonomic dysfunction and rigidity from abruptly stopping his long-term baclofen treatment. “He improved markedly after the reintroduction of baclofen.”

In contrast to published studies saying that baclofen helped with alcohol withdrawal, a Cochrane review published in May of 2015, “Baclofen for alcohol withdrawal syndrome,” concluded that the evidence for recommending baclofen for alcohol withdrawal syndrome was insufficient. “We therefore need more well-designed RCTs to prove its efficacy and safety.”

A 2013 article assessed the potential to confuse baclofen withdrawal for alcohol withdrawal. The authors said the clinical and psychopharmacological overlap between acute intoxication and the withdrawal symptoms of baclofen, alcohol and benzodiazepines could lead to diagnostic uncertainty. “In every case of unexplained confusion, agitation, hallucinations, seizures, and psychosis occurring in patients with current drinking, both AWS and BWS should be systematically considered.”

A small study by Franchitto et al. in 2013 did a retrospective study of the medical records for 12 individuals diagnosed with alcohol dependence who had overdosed on baclofen. The median dose of ingested baclofen was estimated at 340 mg. Ten had a previous suicide attempt. Three had co-ingested benzodiazepines. The “classic” effects of baclofen overdose associated with neurotransmitter inhibitory effects were evident:

Impaired consciousness or coma, generalized muscular hypotonia with absent limb reflexes, respiratory depression, seizures, hemodynamic changes and cardiac abnormalities such as supraventricular tachycardias, premature atrial contractions and first-degree heart block.

Four patients were in coma before admission, and required intubation and respiratory support. Coma after a baclofen overdose may persist for several days because of the drugs’ depression of neuronal activity in the central nervous system. Nevertheless, the authors concluded that consistent with other reports, “most patients with baclofen overdose had a good outcome with adequate supportive care.”

There have been reports of heart problems and even mania. A 2014 case report concluded that cardiac arrest occurred with baclofen withdrawal syndrome. A 2014 article concluded that baclofen-induced manic symptoms could appear in individuals regardless of a history of bipolar or mood disorders. The question to be raised about the use of baclofen for alcohol use disorders is what effects does it have on the brain? To the extent that these effects correspond to the effects of alcohol, or any other potentially “addictive” substance, its use in substance misuse treatment is a double-edged sword.

A 2015 study by Rigal et al. reviewed the records of 146 patients who used baclofen to treat their alcohol use disorder. Ninety (78%) reported at least one adverse effect. The most frequently reported adverse effect was a disruption of the wake-sleep cycle in 73 patients (63%). “Persistent adverse effects occurred in 62 patients (53%).” There were 8 patients who had adverse effects that led them to stop taking baclofen. Women reported more adverse events than men. “High-dose baclofen exposes patients with alcohol disorders to many adverse effects. Generally persistent, some adverse effects appear at low doses and may be dangerous.”

The evidence seems clear for a baclofen withdrawal syndrome. There is a state of tolerance or dependence that develops with long term, high dose use. Are patients given baclofen informed of the potential for them to develop a dependency upon this medication? My concern is this dependency is a “sleeper” symptom that initially goes largely unnoticed as with medications used to “treat” opioid use disorders—buprenorphine, and methadone. This same problem with dependency also exists with benzodiazepines prescribed for anxiety or sleep disturbance. They initially work so effectively that the dependency, if it’s noticed at all, is minimized. Only after it becomes seriously entrenched physically and psychologically do people realize what has happened.

So where might all of this lead? Baclofen is a generic drug with no potential for a pharmaceutical company to patent, and thus become a highly profitable product for them. So pharmaceutical companies are largely not interested in developing baclofen as a treatment for addictions. However, there is a prodrug version of baclofen called arbaclofen palcarbil that was initially in development by XenoPort as a treatment for GERD and spasticity due to multiple sclerosis. In May of 2013, XenoPort announced that Phase 3 clinical trials for arbaclofen palcarbil were unsuccessful and they decided to terminate further investment in the program.

In May of 2014, Reckitt Benckiser Pharmaceuticals and XenoPort announced they had entered into a joint license agreement, where Reckitt Benckiser will have the exclusive rights to develop and commercialize arbaclofen palcarbil as a treatment for alcohol use disorder.ClinicalTrials.gov indicated that a Phase 2 study by Reckitt Benckiser was scheduled to begin in September of 2015 and should be completed by April of 2016. The purpose of this clinical trial is to determine the maximum tolerated dose of arbaclofen palcarbil in treating alcohol use disorder.

Reckitt Benckiser appears to be looking for a replacement blockbuster product since its opioid treatment drug, Suboxone, went generic. Before losing its patent rights, Suboxone had become a billion dollar drug for Reckitt Benckiser, rising to the 25th best selling drug of 2010, according to drugs.com. The existing research on baclofen gives us a pretty good idea on what the future holds for any arbaclofen palcarbil product. Also, the potential population for a maintenance drug for alcohol use disorder is significantly larger than there was for an opioid maintenance drug. If Reckitt Benckiser can successfully move arbaclofen palcarbil through the FDA approval gauntlet, we will see a patented knock off product of baclofen on the market to treat alcohol use disorder in a few years.

Suboxone made another top drug list in 2013. It was listed as the #2 most abused prescription drug of 2013 by Genetic Engineering & Biotechnology News. Hopefully, any arbaclofen palcarbil product will not repeat that ‘achievement’ for Reckitt Benckiser.

09/28/15

The End of Alcoholism? Part 2

Within an introductory “Note to the Reader,” to his book, The End of My Addiction, Olivier Ameisen said: “By completely suppressing my addiction, baclofen saved my life. I believe it can save and improve the lives of many others by completely suppressing their addictions, and I have written this book to that end.” He ended his note with a caution that his book was not a self-help manual or a guide to self-treatment. Baclofen, a prescription drug, “should be taken only as prescribed … and closely monitored by a licensed physician.” Yet his book is a detailed discussion of how he did exactly the opposite of everything he had just cautioned others not to do.

There had been some ongoing research into the potential of baclofen as a treatment for alcohol use disorders (see the References for Ameisen’s Alcohol and Alcoholism article) before Ameisen wrote his book. But Ameisen’s personal experimentation and its description in his book brought it to the attention of the public and sparked further interest in researching the potential of baclofen to treat addiction. “The End of Alcoholism? Part 1” looks in more detail at that story. Here I want to explore some of the research supportive of using baclofen in treating alcohol use disorders.

Giovanni Addolorato of the Catholic University of Rome was one of the initial baclofen researchers Ameisen read. Eventually they began to correspond and shared their interest its potential to treat alcoholism. A sampling of Addolorato’s published research studies looks at the ability of baclofen to reduce cravings and alcohol intake (2000); the suppression of alcohol withdrawal syndrome with baclofen (2002); a comparison of baclofen to diazepam in treating alcohol withdrawal (2006); the effectiveness of baclofen in maintaining abstinence with patients with cirrhosis of the liver (2007). Addolorato found baclofen to be effective in reducing craving and alcohol intake; it was comparable to diazepam in treating withdrawal; and it promoted abstinence—even in alcohol-dependent patients with cirrhosis of the liver.

Colombo et al. (2002) found that baclofen inhibited the drinking behavior of selectively bred alcohol-preferring rats. Baclofen is a known GABA(B) receptor and the results suggested that the GABA(B) receptor was involved in the disclosure and experience of the psychopharmacological effects of alcohol.

William Bucknam published a case study in 2007 to investigate whether baclofen-induced suppression to consume alcohol in animals could be transposed to humans. The patient, Mr. A., wanted to be able to control his drinking not establish and maintain abstinence. He “experienced a satisfactory response to high-dose baclofen that [was] sustained over ten months without significant side-effect.”

Lorenzo Leggio (2009) suggested that baclofen “represents a promising medication in the treatment of alcohol-dependent subjects.” It demonstrated an ability to reduce alcohol craving and intake. So it could be useful for promoting abstinence “as well as relieving alcohol withdrawal syndromes.”

In 2012 Renaud de Beaurepaire published a 2-year observational study of 100 individuals using baclofen. Initially 132 individuals were included in the study, but 32 were excluded for various reasons. These reasons included: not providing feedback after their first visit, stopping their use of baclofen because of adverse drug effects, and not being motivated to stop drinking. The effects of baclofen in the first three months were not included in the study, “because the effect of the treatment during this period does not represent the full potential of the drug.” (So what was going on in the initial three months that might give an unfavorable view of baclofen, I wonder?) The participants were evaluated before treatment with baclofen and then at 3, 6, 12 and 24 months to fit into three categories: low risk, medium risk and high risk.

In the “at low risk” category, patients experienced a suppression of craving, and their complete control over drinking was effortless. In the “at medium risk” category, patients experienced a clear decrease in craving but, for various reasons (in general, too strong an attachment to their drinking habits associated with an incomplete motivation to cease drinking), they were not able to control completely their drinking compulsions. In the “at high risk” category, patients either experienced an insufficient reduction of craving, or, although they experienced a significant decrease in craving, after a period of decrease in drinking, relapsed in their addiction. The risk category was defined according to the control over drinking during the last 4 weeks [before the evaluation].

Fifty-nine percent of the participants had one or more concomitant psychiatric disorders, including: 53% with anxiety disorder, 34% with depression, 18% with bipolar disorder, 42% with a sleep disorder, 11% with another addiction (mostly cannabis), 8% with psychosis, and 5% with an eating disorder.

At the end of the first visit, participants were told they could drink as usual. Using baclofen was expected to suppress the motivation to drink. No additional therapeutic intervention other than baclofen was given or suggested.

The doses ranged from 20 mg to 330 mg, with an average dose of 147 mg. Eighty-eight percent of the participants reported at least one undesirable side effect. The five most frequently reported were: fatigue or sleepiness (64%); insomnia (31%); dizziness (21%); tingling or abnormal sensations (18%); nausea or vomiting (17%). There were several others, including: weight loss, memory loss, mental confusion, hypomania, dysphoria (a state of profound unease or dissatisfaction). De Beaurepaire assessed these side effects as “always benign.” However, eleven individuals discontinued treatment because they could not tolerate the side effects. And 20 participants did not reach an optimum dose because of the worsening of side effects.

The study reported that 92% reported a decrease in their motivation to drink at one time or another during the follow up time period. About half reported that at sufficient doses of baclofen, they had “a complete and effortless control” of alcohol craving. All participants were rated “at high risk” initially, but about half were rated “at low risk” at 3, 6, 12, and 24 months of follow up.

De Beaurepaire concluded that baclofen was very effective in treating alcohol dependence, particularly in reducing the motivation to drink. High doses were often necessary to obtain an optimum effect. The principle limitations seemed to be the side effects, the absence of a strong willingness in some to stop drinking, and co-occurring psychiatric illness—with the possibility that the concomitant use of psychotropic medications was a factor. “Baclofen should be considered a major help for drinking cessation, but other factors (psychological and environmental) are likely to play an important role with many patients.”

Ameisen sees baclofen as essentially a miracle cure for alcoholism. “So far it seems to work in all types except for one … and that’s people who turn up once and don’t come again.” He admits that no medication works effectively for everyone, and that includes baclofen. It’s not one size fits all; “you have to refine it.” There is a parallel here to methadone maintenance for opioid addiction. Ameisen’s “threshold dose,” refining the dosage until it’s high enough to eliminate cravings, sounds like raising a person’s methadone dose until they don’t want to get high anymore.

But the miracle cure claims of his treatment have provoked skepticism. Dr. Nicholas Pace, a clinical professor of medicine at New York University said: “I have studied alcoholism for the past 40 years, and there is no single magic bullet. This is a complex disease, and you can’t just flip one switch. The idea that an alcoholic can drink socially is simply a lot of bull.”

Ameisen said this kind of reaction from addiction professionals is because they feel threatened. “If baclofen works, then their specialism is going to fall apart.” But James Medd, writing for The Guardian suggested there could be another reason. This isn’t the first time someone claimed they found a cure for alcoholism. Barbiturates, benzodiazepines like Valium and antidepressants such as Prozac were hyped at one time as an end to addiction. Naltrexone has also been proposed as a “cure” for alcoholism in the Sinclair Method (See A “Cure” for Alcoholism).

At least for Ameisen, baclofen seems to have turned his life around. He reportedly had over nine years without drinking compulsively. There are several studies being done to investigate the treatment potential of baclofen. Here is sample a of some of those listed on clinicaltrials.gov. Assistance Publique – Hôpitaux de Paris (study 8) is completing a study to show the effectiveness of a year of baclofen treatment to that of a placebo. It was planned to increase the dose to a maximum of 300mg daily. In case of intolerance, the dosage would be decreased. Essentia Health (study 9) is investingating the use of baclofen to prevent the symptoms of Alcohol Withdrawal Syndrome. The University of North Carolina at Chapel Hill (study 14) is investigating whether a 90mg dose of baclofen is effective and safe with individuals with alcohol dependence.

While there are some potential benefits with baclofen in treating alcohol use disorders, there are some clear adverse effects as well. We will look closer at those side effects in Part 3. Amiesen did not describe or dwell on the adverse effects with baclofen. Perhaps this was because he came to it when his own fight against alcoholism was at the point that he thought he was going to die from it. He had a blind spot to its negative effects because baclofen became the miracle drug that saved his life. As a physician writing a book on baclofen he cautioned his readers to not self-treat with baclofen. As an active binge drinker he was desperate to find something—anything—that would put an end to his addiction and did it anyway.

09/21/15

The End of Alcoholism? Part 1

There is an existing generic medication called baclofen, a muscle relaxant, which has been primarily used to treat spasticity and multiple sclerosis. Now it is in the early research stages as a treatment for alcoholism. Olivier Ameisen, a French-American cardiologist used himself as guinea pig in testing baclofen to treat his own alcoholism. He said that baclofen saved his life by freeing him of all cravings for alcohol and suppressing his addiction. He’s written several journal articles and a book, The End of My Addiction, describing his active drinking and how baclofen helped him stop. Ameisen died of a heart attack on July 18, 2013, but his “discovery” lives on. Let’s see if it is a miracle treatment; or not.

First we will summarize his experiences by looking at The End of My Addiction and an article he wrote for the journal, Alcohol and Alcoholism about nine months after his “complete liberation from symptoms of alcohol dependence.” Afterwards, we will look at some of what the research literature has to say about baclofen.

Ameisen said he began to struggle with symptoms of alcohol dependence in the 1990s. In his struggles to stop drinking, he had numerous emergency hospitalizations, emergency room visits, detoxifications, and years of both inpatient and outpatient rehabilitation services. Because of his persistent and strong cravings for alcohol he tried disulfiram (Antabuse), but drank on it. He tried Naltrexone and acamprosate, which didn’t stop his cravings or his relapses. He achieved periods of prolonged abstinence, but always struggled with cravings and a preoccupation with alcohol.

He attended Alcoholics Anonymous—sometimes as often as two, three or four meetings a day. He had a sponsor and a home group. Twice he did a “90 in 90,” attending ninety meetings in ninety days. He achieved prolonged periods of abstinence, but continued to relapse. By his estimate, he attended roughly 700 meetings a year, over a period of 7 years between 1997 and 2004. But until he began using baclofen to treat himself, he was unable to maintain abstinence.

Ameisen noted that physicians are notoriously bad patients “who often inhibit their recovery by trying to run their own cases.” And he seems to have been one of the worst. Long before he experimented with baclofen, he preferred to administer his own detox at home after his binges. He objected to CPH (the Committee for Physician Health of the New York Medical Society) refusal for him to continue using benzodiazepines for his anxiety. “Being denied a standard medication for severe anxiety, the condition that triggered and fueled my craving for alcohol, was at best counterproductive and at worst callous and cruel.”

He moved back to France in 1999, where he continued to drink off and on; and continued to seek help to stop his drinking. His binge cycles became shorter and shorter. A treating psychiatrist told him he was afraid he would not live much longer. In the midst of a binge, a friend from New York sent him an article on baclofen treatment for cocaine craving she saw in the New York Times. He was in the midst of a binge and misplaced it. A year later in November 2001 he remembered the article and had the friend track it down and send him another copy. Thus began his investigation and growing belief that baclofen could be a treatment for his alcoholism.

He contacted the doctor mentioned in the New York Times article. In February of 2002 he bought a PC and began to search the internet for information on “baclofen and panic.” He added “baclofen anxiety;” and finally baclofen alcohol.” This led him to a 2000 research article written by an Italian researcher, Giovanni Addolorato on the ability of baclofen to reduce alcohol craving and intake. Ameisen checked with a neurologist friend who told him it was a safe drug; not addictive (Baclofen is not a controlled substance, but can impair thinking or reactions. Withdrawal can result in seizures and hallucinations in some long term users). He decided to order some baclofen and try it on himself. In The End of My Addiction, Ameisen wrote:

Until this point, I had steadfastly tried to be a good patient and had avoided benig my own physician, but it seemed to me that in order to save my life from alcoholism, I had no choice but to risk walking out onto a tightrope without the normal safety net of another physician’s supervision.

This seems to be an inconsistent memory by Ameisen. He had been acting as his own doctor from the time of preferring his own detox at home. Nevertheless, he started using baclofen on March 22, 2002 and gradually increased his dose to 180 mg daily. He found some immediate relief of his muscular tension. He slept better and felt calmer. But he continued to binge drink and he continued to do research into baclofen. Eventually he saw an animal study that suggested even higher doses of baclofen could suppress cocaine intake in rats addicted to cocaine. “The more I learned, the more I came to believe that at a high enough dose of baclofen, I too could reach a point where I would lose the motivation to consume alcohol.”

Then on January 8, 2004, he decided it was now or never. “If I continued to follow my doctor’s advice and the conventional treatments for alcoholism, I was going to keep lapsing into binges and eventually die from drinking. I had to take my treatment into my own hands.”

From the first day, he reported his anxiety was substantially reduced and his sleep became restful. By the 37th day on 270 mg of baclofen, “I experienced no craving or desire for alcohol for the first time in my alcoholic life.” He reported that even in a restaurant with friends, he was indifferent to people drinking. Drowsiness became an inconvenient side effect, so he tapered his dose down to 120 mg per day from days 49-63 of his abstinence from alcohol. He stabilized at that dose, with occasional additions of 40 mg as needed in stressful situations.

At first he avoided situations and places where alcohol was present. But then believed he did not have to be concerned about this. Even when socializing with friends who were drinking, he had no cravings for alcohol. He realized he was “completely and effortlessly indifferent” to alcohol. He was encouraged by a friend and physician to write a paper of his self experiment, which was eventually published in the journal Alcohol and Alcoholism. In the article he said:

At the end of my ninth month of complete liberation from symptoms of alcohol dependence, I remain indifferent to alcohol. Abstinence has become natural to me. I no longer plan my life around alcohol. Alcohol thoughts no longer occur. . . . I no longer suffer anticipatory anxiety of relapse, of embarrassing or dangerous alcohol-related situations. I am no longer depressed about having an incurable stigmatizing disease.

Eventually he wondered if he was vulnerable to relapse. “Would one drink plunge me back into the hell of alcoholism?” So in May of 2005, sixteen months after his abstinence with baclofen, he decided to put his recovery to the test with three successive challenges.

First, while continuing his maintenance dose of 120 mg of baclofen, he had three standard drinks over a few hours at a social gathering. He didn’t guzzle his first drink. He also didn’t finish his third drink. The second test was increasing his alcohol intake to five standard drinks over a six-hour span. Again, he had no urge to drink rapidly and experienced only a mild euphoria. But the following afternoon, he had a serious craving that he said an additional dose of 40 mg of baclofen suppressed within an hour.

His final test was to consume a massive amount of alcohol; similar to that he ingested during active relapse. Over an evening, he drank about 600 milliliters of Scotch. The next day he had a mild hangover, but no cravings. “It was good to discover that with baclofen I could drink in a nondependent way.” On occasions he said he would have a glass or two of champagne or a mixed drink. But he preferred to not drink. In a 2010 article for The Guardian, James Medd, reported Ameisen can now even drink socially. “I became disease free-free,” he said.

After his “self-case report” was published in Alcohol and Alcoholism, it didn’t cause much professional excitement. “But he found that potential patients were much more interested.” After two unsuccessful years of trying to work up interest within the medical system, Ameisen decided to write The End of My Addiction, published in France as Le Dernier Verre (The Last Glass). Small groups using high-dose baclofen sprung up around doctors who adopted Ameisen’s ideas and who were willing to prescribe baclofen off-label. Interest in researching the potential treatment benefits of baclofen also began to occur.

Ameisen did begin to gather some research and media interest in his treatment method with baclofen. Here is a 2009 video of Diane Sawyer interviewing him after the publication of his book. Ameisen began to correspond with George Koob in 2005, who would become the Director of the NIAAA, the National Institute on Alcohol and Alcoholism in January of 2014. He reported agreeing to act as a consultant to a prospective study Koob planned to do on baclofen. There was a mention in a report by the Committee on the Neurobiology of Addictive Disorders (where Koob was the Committee Chair before moving to the NIAAA) that baclofen could block alcohol self-administration in rats. Here is a link to Koob’s 2007 published study.

Ameisen was not the first person to theorize baclofen could be useful in the treatment of alcoholism. But his self-experimentation and the publication of his results spurred an interest in baclofen. His theories may or may not be ultimately demonstrated as valid. But what is clear is that while he claimed baclofen ended his cravings for and addiction to alcohol, it didn’t end his drinking. Ameisen believes that “In addiction the symptoms ARE the disease.” So he sees suppressing his symptoms as “curing” his alcoholism. Since he doesn’t have cravings and doesn’t obsess over alcohol and drinking, he’s “cured.”

But what are the long-term consequences of high-dose baclofen treatment for alcoholism? It isn’t listed as a controlled substance, but there is a baclofen withdrawal syndrome and high dose users are discouraged from rapid tapering or withdrawal. So is there a slow developing physical dependency or dysregulation of the GABA system in the brain from long term use of baclofen? Is taking a dose of a drug daily to not drink alcohol really a cure for alcoholism? Ameisen asserted that he has yet to find a patient where it hasn’t been a success. But is that the whole story? Ameisen’s death came before there was an answer to these questions.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: baclofen

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The End of Alcoholism? Part 2

The End of Alcoholism? Part 1