Abstract. individuals dealing with Alcohol Use Disorder (AUD), but agree on the need to solve this

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2 Abstract The existing literature disagrees in terms of treatment options and alternatives for individuals dealing with Alcohol Use Disorder (AUD), but agree on the need to solve this public health concern. This paper seeks to first understand the disease and the drugs available for its treatment and secondly reviews the guidelines and regulations that either restrict or encourage the market authorization (MA) of a drug. Those will be the foundations for suggesting the implementation of a temporary recommendation for use of the Baclofen in the treatment of AUD. A review of positive and negative outcomes from peer-reviewed Randomized Controlled Trials (RCT) is provided to demonstrate Baclofen s success in the treatment of AUD and support the implementation of a temporary recommendation for use (TRU) in the United States. Keywords: Alcohol Use DisorderGamma Aminobutyric Acid (GABA) Baclofen Temporary Recommendation for Use (TRU) ii

3 Acknowledgements: UNC Gillings School of Global Public Health; The Public Health Leadership Program at the Gillings School of Global Public Health; Professor Lori Evarts from the Gillings School of Global Public Health for her continuous support; Dr Krupitsky for initiating this incredible journey; Dr Ameisen for lobbying for the Baclofen in the treatment of AUD; Dr. Garbutt for his contribution in treatment options for recovering addicts; Dr. Thorp for his contribution in this present report as a second reader and a leader in recovery treatment facilities; My wife for her multiple contributions to this project. I want to dedicate this paper to Dr Olivier Ameisen who passed in 2013 after leading the case of Baclofen in the treatment of AUD and to all those individuals who fight addictions on a daily basis. iii

4 Table of Contents Introduction 1 Methodology 1 Biological Description of AUD 2 Existing AUD treatment options in the United States 7 FDA Guidance 7 FDA Approved Medications in the Treatment of AUD 8 Drugs Currently Under Investigation in the Treatment of AUD 14 Negative outcomes observed in RCTs 20 American Trials 20 French Trial 20 Israeli Trial 21 Hypotheses for negative observations in RCT 21 Prominent Ongoing Trials 24 French RCT 24 American RCTs 24 Regulations and Processes for Drug Approval 26 FDA Regulations in the United States 26 EMA and the ANSM Regulations in France 29 Discussion 31 Implementing a TRU in the United States 31 Positive outcomes observed in RCTs and case reports 32 Comparison of Costs of Drugs in the United States 37 Creating a coalition 38 The Principle of Beneficence 39 iv

5 Appendices Page 1. DSM-5 criteria to be diagnosed with AUD Long-term implications of AUD List of FDA approved manufacturers for the distribution of generic Baclofen in the United States Summary of trials with positive outcomes Summary of trials with negative outcomes Summary of ongoing trials 56 v

6 List of Figures Figure 1: Flow of ethanol in the body Page 3 Figure 2: GABA s role in the synaptic cleft Page 4 Figure 3: How alcohol releases dopamine Page 5 Figure 4: Summary of biology related to alcohol intake Page 6 Figure 5: Drugs approved by the US FDA to treat AUD Page 8 Figure 6: How Disulfiram works Page 10 Figure 7: How Naltrexone works Page 11 Figure 8: How Acomprosate works Page 13 Figure 9: Baclofen From its discovery to present time Page 17 Figure 10: How Baclofen works Page 18 Figure 11: Evolution of baclofen s sales in France Page 31 Figure 12: IBIS Page 39 vi

7 List of Abbreviations ADH ALDH ANDA ANSM AUD BAC BRENDA CNS DSM EMA FDA GABA GSK HDB HSL IBIS IND MA NCBI NDA Alcohol Dehydrogenase Aldehyde Dehydrogenase Abbreviated New Drug Application The French National Agency for Medicines and Health Products Safety Alcohol Use Disorder Blood Alcohol Content Biopsychosocial evaluation, Report to the patient on assessment, Empathic understanding of the patient s situation, Needs collaboratively identified by the patient and treatment provider, Direct advice to the patient on how to meet those needs, Assess reaction of the patient to advice and adjust as necessary for best care Central Nervous System Diagnostic and Statistical Manual European Medicines Agency Food and Drug Administration Gamma Aminobutyric Acid GlaxoSmithKline High Dose Baclofen Health Sciences Library International Baclofen Intervention Study Investigational New Drug Market Authorization National Center for Biotechnology Information New Drug Application vii

8 NIH NMDA RCT TRU t.i.d National Institutes of Health N-methyl-D-aspartate receptor Randomized Controlled Trial Temporary Recommendation for Use Three times per day viii

9 Introduction According to the National Institute on Alcohol Abuse and Alcoholism, over 17 million Americans over 18 years of age are currently identified as having an alcohol use disorder (AUD). (Alcohol Facts and Statistics, 2014) AUD is an internationally recognized medical condition that can be attributed to anyone who meets any two of the eleven criteria established by the Diagnostic and Statistical Manual, fifth edition (DSM- 5). (Appendix 1) In 2010, Lim and colleagues reported that [g]lobally, alcohol misuse is the fifth leading risk factor for premature death and disability; among people between the ages of 15 to 49, it is the first. (as cited in Alcohol Facts and Statistics, 2014) In the United States, alcohol is responsible for 88,000 preventable deaths annually. (Alcohol Facts and Statistics, 2014) AUD leads to diseases such as cirrhosis, hepatitis, cancer, and type 2 diabetes as shown in Appendix 2. (A-Team Alcohol Services, n.d.) This paper will examine Baclofen as a drug to treat alcohol addiction, focusing on the reduction of cravings and anxiety. Information from published medical results of human trials will be discussed. It should be noted that this paper will not examine AUD treatments that address alcohol withdrawal since this would constitute another area of study. Methodology Review of online literature was accomplished using PubMed and NCBI electronic databases, followed by Google Scholar searches through the University of North Carolina s Health Sciences Library (HSL). Keyword searches included combinations of 1

10 the following: alcoholism, Baclofen, dependence, addiction, clinical trial, treatment, AUD, and review. Since the treatment of AUD with Baclofen varies by country, no limitation in terms of place and time was applied for this research. Unpublished works, inaccessible articles due to registration or subscription services, and articles not available in English were not included. Since review was part of the inclusion criteria, meta-analysis and systematic reviews were selected based on relevancy. Multiple professional domains including the National Institutes of Health (NIH), the Food and Drug Administration (FDA), ClinicalTrials.gov, and the French National Agency for Medicines and Health Products Safety (ANSM), were searched for relevant data. The literature review was supplemented with cited sources within the publications identified, as well as included grey literature. Biological Description of AUD When an individual drinks alcohol, the body will first metabolize the ethanol (main molecule found in alcoholic beverages) and before any other nutrient because the ethanol cannot be stored in the body. Upon intake of alcohol, the fluid goes straight to the stomach and then the small intestine where up to 20% and 80%, respectively, of its content will be absorbed into the bloodstream. (Altounian, 2014) After being absorbed into the bloodstream, the ethanol goes to the liver as illustrated in Figure 1. (Duke University - How does ethanol get to the lungs?, n.d.)the liver can only metabolize ethanol at a rate of about one ounce of hard liquor per hour. (Alcohol Alert, 1997) The leftover alcohol in the stomach will travel in cycles through the body (Figure 1) until the liver s enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) 2

11 - can take care of it and break the remaining ethanol down to the detoxified molecule acetate that will eventually return into the bloodstream. (Duke University - How does ethanol get to the lungs?, n.d.) This process of oxidation in the liver is responsible for the detoxification of the drug in the body. While the excess ethanol travels through the body, it goes to the lungs via the right side of the heart. (Duke University - How does ethanol get to the lungs?, n.d.) At that point, about 5% of the alcoholic content is exhaled by the lungs. (Duke University - How does ethanol get to the lungs?, n.d.) The remaining ethanol will travel to the central nervous system (brain and spinal cord) and then eventually finds its way back to the liver where more ethanol will be oxidized. (Duke University - How does ethanol get to the lungs?, n.d.) Figure 1: Flow of ethanol in the body Source: Duke University - How does ethanol get to the lungs? (n.d.) Adapted from the There are billions of cells in the nervous system, called neurons, communicating with one another via chemical signaling (neurotransmitters, represented by the red dots 3

12 on Figure 2). (Benzodiazepines: How they provide their anxiolytic and hypnotic effects, 2012) In a healthy individual, Gamma-Aminobutyric Acid (GABA), an inhibitory neurotransmitter (molecule that inhibits the generation of a signal in between neuron cells), only will let a certain amount of negatively charged ions to pass through it after it binds to the postsynaptic neuron as illustrated in Figure 2. (Benzodiazepines: How they provide their anxiolytic and hypnotic effects, 2012) Figure 2: GABA s role in the synaptic cleft Source: Benzodiazepines: How they provide their anxiolytic and hypnotic effects. (2012). After consuming an alcoholic beverage, the ethanol binds to the GABA receptor at the postsynaptic neuron and allows more activity going through. Within minutes of alcohol intake, the individual will start feeling its effects on the brain as the larger than normal intake of negatively charged ions going through the GABA receptors will stimulate the release of beta-endorphins (another kind of neurotransmitter). (Altounian, 2014) Those beta-endorphin molecules will travel across the synapse and bind to postsynaptic receptors, releasing the dopamine molecules that make individuals feel good. (Figure 3) Dopamine is now known to be the most addicting property of alcohol. It belongs to the mesolymbic reward pathway of the brain, an interconnected circuit of 4

13 neuron cells where the signals travel in loop to achieve a desire of satisfaction. (Altounian, 2014) Figure 3: How alcohol releases dopamine Source: Naltrexone, 2014; Naltrexone With Without Prescription!,(n.d.) Dopamine s main characteristic is that it needs a continuously increasing intake of alcohol to keep its effects steady since the GABA receptors, key to the release of dopamine, become desensitized over time. (Altounian, 2014) Concurrently, the molecules of alcohol will suppress the release of an excitatory neurotransmitter, the glutamate, which in turn will slow down the brain activity. (DiSalvo, 2012) The alcoholic therefore will increase his or her intake of alcohol in a quest to keep this good feeling going. A larger intake of alcohol results in proportionally less absorption of the molecules into the bloodstream and more damage to the liver as more alcohol needs to 5

14 be metabolized before being excreted. (Altounian, 2014) In the liver, the alcohol molecule is broken down and converted into acetaldehyde and then acetic acid. Retention of acetaldehyde during the acetaldehyde dehydrogenase is what individuals feel as a hangover. Figure 4 provides a summary of the biology related to the intake of alcohol. Figure 4: Summary of biology related to alcohol intake: Alcohol Intake CNS Stomach & Small Intestines Respectively 20 and 80% of fluid absorbed & released in bloodstream (increases blood pressure) Increases activity of GABA-b receptors Brain Suppresses release of excitatory neurotransmitter glutamate Liver is responsible for about 90% of elimination of alcohol in body (can metabolize <1 oz of hard liquor per hour) Lungs exhale about 5% of alcoholic content (detected by breathalyzers) Sweat, feces, milk, & saliva eliminate < 5% of all alcoholic content Triggers release of betaendorphins Triggers release of dopamine through mesolimbic pathway Slows down brain activity Ethanol Enzyme alcohol dehydrogenase (ADH) acetaldehyde Enzyme aldehyde dehydrogenase (ALDH) acetic acid (= acetate) Kidneys eliminate about 5% of the ethanol in urine (ethanol suppresses action of diuretic vasopressin, which results in the drinker loosing more water than usual) Calms down & relaxes the individual (this is how Xanax works) Source: based on aforementioned methodology An individual s Blood Alcohol Content (BAC) increases when the body absorbs alcohol faster than it can eliminate it. (Zakhari, n.d.) Binge drinking therefore increases the potential for overdose of acetaldehyde that accumulates in the liver (as well as an 6

15 accumulation of the fatty acids that are no longer the liver s priority for metabolism). (Zakhari, n.d.) Binge drinking is also associated with the retention of alcohol in the stomach that induces vomiting. (Zakhari, n.d.) FDA Guidance Existing AUD treatment options in the United States Clinical trials lacked consistent guidance for defining and recruiting patients with AUD. Most scientists refer to the DSM models, fourth and fifth editions, to recruit their patients, but other characteristics such as the length of the study vary. In the United States several clinical trials have been conducted but varying endpoints were used to determine outcomes, not allowing for aggregation of efficacy and safety results across trials. In February 2015, the FDA therefore published draft guidance for industry on the approval of medications for the treatment of alcoholism and the population of those with AUD. This guidance is currently being reviewed and updated by stakeholders involved in the treatment of alcoholism. (US Department of Health and Human Services et al, 2015) The focus of this governmental paper is as follows. We are issuing this guidance to better communicate our current thinking on the appropriate endpoints for clinical trials of drugs to treat alcoholism, and to apprise sponsors of possible alternatives to abstinence-based endpoints, which have often been considered an unattainable threshold in the clinical trial setting, and which may be considered a hindrance to clinical development for drugs to treat alcoholism. (US Department of Health and Human Services et al, 2015, p. 1) With this important aspect in mind, the draft guidance also suggests: We believe analyses of existing data also support the use of another valid surrogate endpoint defined by a pattern of reduced drinking, described as no heavy drinking days. Heavy drinking days are defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as days when the patient consumes more than four standard drinks (men) or more than three standard drinks 7

16 (women). Standard drinks are defined in the United States as containing 14 grams of alcohol, such as would be found in a standard shot of hard liquor, a 12 ounce bottle of beer, or a 5-ounce glass of wine. An analysis of the proportion of patients who attain and sustain a pattern of drinking that never exceeds the heavy drinking definitions may be appropriate.... DAAAP s current recommendation is for trials of 6 months duration, with a primary endpoint of the proportion of patients who do not have any heavy drinking days during the observation period (percent no heavy drinking days). (US Department of Health and Human Services et al, 2015, p. 2-3) The FDA has approved drugs for the American market for the treatment of AUD. The next section will describe both approved and off-label drugs for the treatment of AUD in the United States. FDA approved medications in the treatment of AUD As of the writing of this paper, three drugs -- Disulfiram, Naltrexone, and Acamprosate are approved by FDA for the treatment of AUD as shown in Figure 5. Figure 5: Drugs approved by the US FDA to treat AUD 8

17 Source: FDA-approved Pharmacological Treatments for Alcohol Dependence (Wilkins, n.d) Disulfiram The generic drug Disulfiram, first introduced by Danish scientists to North America in 1949, received its FDA approval for the treatment of AUD in (Kragh, 2008) This drug has no labeling authorization other than for AUD treatment. Disulfiram (brand name is Antabuse) works in the liver by inhibiting the process of alcohol dehydrogenase in which acetaldehyde accumulates at an average of a tenfold compared to the regular metabolism of alcohol without the drug. (Figure 6) The patient outcome is an adverse reaction when the drug encounters alcohol with symptoms ranging from nausea to vomiting, and headaches. Even though Disulfiram is often prescribed, it is limited due to non-compliant patients who do not take their medicine to be able to drink. Recently, the European market saw the emergence of an Antabuse implant that goes under the skin to increase compliance with treatment. This form of Antabuse has not yet been proposed to the FDA for the treatment of AUD in the United States. (Weighing The Pros And Cons Of Antabuse For Alcoholics, 2014) The FDA approved recommended daily dose is from 125 mg up to 500 mg per day, which can damage the liver if taken on a regular basis (Incorporating Alcohol Pharmacotherapies Into Medical Practice Chapter 3 - Disulfiram, 2009). Figure 6: How Disulfiram works 9

18 Source: Disulfiram: An aversion-based Pharmacotherapy (Wilkins, n.d) The positive aspects of using Disulfiram as a medication in the treatment of AUD include over sixty years worth of evidence based results and the fact that the drug does deter the patient from taking alcohol. On the other hand, the drug does not stop the cravings nor does it normalize the brain activity. Additionally, by initiating an adverse reaction, the drug faces the issue of compliance and the potential interaction from nonintentional ingestion of food containing alcohol. The major disadvantage for this medication is that it only works at high doses, putting additional stress on the liver and therefore is not compatible with patients with hepatic concerns. Naltrexone hydrochloride Vivitrol (brand name) was approved by the FDA in (Vivitrol, n.d.) This drug has no labeling authorization other than for AUD treatment. This medication acts on the 10

19 brain by binding to GABA receptors at the postsynaptic neurons in order to inhibit the activity of endorphins and release of dopamine as illustrated in Figure 7. (Wilkins, n.d ) Inhibiting this activity results in decreased cravings for alcohol and makes the use of alcohol less rewarding by decreasing the effects of euphoria. (Incorporating Alcohol Pharmacotherapies Into Medical Practice - Chapter 4 Oral Naltrexone, 2009) Figure 7: How Naltrexone works Source: Naltrexone Modulates the Activity of Endogenous Opioids (Wilkins, n.d) The recommended dose is 50 mg daily for 12 consecutive weeks. (Naltrexone - FDA prescribing information, side effects and uses, 2014) Until 2006 when the FDA approved the extended-release injectable Naltrexone, Naltrexone in tablets was facing issues with compliance in outpatient treatment settings, due to the disease taking over the individual s behavior. Injectable Naltrexone only requires one shot of 380 mg a month, increasing patient adherence to a treatment plan. (Incorporating Alcohol 11

20 Pharmacotherapies Into Medical Practice - Chapter 5 - Extended-Release Injectable Naltrexone, 2009) A placebo controlled, outpatient, double blind clinical trial, involving 104 cases, found a 51% abstention rate (versus 23% for the Placebo) and a relapse rate at 31% (compared to 60% for the Placebo). (Naltrexone - FDA prescribing information, side effects and uses, 2014) An advantage of Naltrexone is that the drug does not induce an adverse reaction, but instead blocks brain receptors to remove the feeling of pleasure from alcohol. It was also associated with lower patient cravings compared to the patients in the placebo group. (Naltrexone - FDA prescribing information, side effects and uses, 2014) Thompson concluded that Naltrexone has a greater effect on reducing relapse to heavy drinking than it does on maintaining abstinence. (Thompson, 2014) The label also includes a warning for hepatotoxicity. (Vivitrol, n.d.) Since most patients with AUD have liver issues, Krishnan-Sarin and colleagues noted the potential risk of hepatotoxicity at high doses requires caution when treating patients with liver disease. Naltrexone is not indicated in the treatment of AUD in those with a coaddiction to opiates since the drug is an opiate antagonist. (Krishnan-Sarin et al, n.d.) Acamprosate calcium Campral (brand name) was approved by the FDA for the treatment of AUD in 2004 and works in the brain by modulating and normalizing brain activity. (FDA - Drug Approval Package, n.d.) Acamprosate specifically targets levels of glutamate and GABA receptors, responsible for the release of NMDA, as illustrated in Figure 8. (Wilkins, n.d) NMDA are glutamate receptors that increase over time in alcoholic patients. However, Reilly and colleagues concluded Acamprosate does not 12

21 significantly modulate the function of these receptors and ion channels at clinically relevant concentrations. Thus, the clinical effectiveness of Acamprosate in the treatment of alcoholism is not likely due to direct effects on these receptors or ion channels. (Reilly et al, 2008, p. 1) The drug is primarily used for the treatment of withdrawals. When the patient is withdrawing from alcohol, there is an increase in activity of neurotransmitters, which the drug Acamprosate helps to regulate. (Krishnan- Sarin et al, n.d.) Figure 8: How Acamprosate works Source: Acamprosate Modulates the Activity of Glutamate (Wilkins, n.d) Campral is not known to cause alcohol aversion and does not cause a disulfiram-like reaction as a result of ethanol ingestion, and the drug s efficacy was supported by three out of four placebo controlled studies. (Campral [Acamprosate Calcium] Delayed-Release Tablets, n.d, p. 2) Of importance is that the drug is not 13

22 metabolized in the liver but in the kidneys affording a treatment option for patients with liver cirrhosis, but not in those with renal impairment. (Campral [Acamprosate Calcium] Delayed-Release Tablets, n.d) Since this medication does not reproduce the ill effects of Disulfiram, Acamprosate does not deter alcohol consumption but is promoted for alcohol abstinence. (Mann et al., 2004; Kranzler and Gage 2008) Drugs currently under investigation in the treatment of AUD To date, and as noted by Krishnan-Sarin et al, the FDA approved medications in the treatment of AUD have modest efficacy, and there is a great need for newer medications that target different neurochemical systems and which could be used either as adjunctive treatments or to treat subpopulations of drinkers. Furthermore, it also is important to improve current treatment options by understanding and incorporating differences in how people with certain genes respond to medication (i.e., pharmacogenetic differences). (Krishnan-Sarin et al, n.d., p. 1) NIH recently published a list of drugs that are being researched for the treatment of AUD. These potential therapies are Varenicline, Gabapentin, Topiramate, Ondansetron, Nalmefene, and Baclofen. (NIH - Research on Promising Medications not approved by the U.S. Food and Drug Administration [FDA]) to Treat Alcohol Use Disorder (AUD), n.d.) Other medications being investigated in preliminary animal trials include Ezogabine that has shown some positive results. (Knapp et al, 2014) Varenicline Chantix (brand name) was approved by the FDA in 2006 for smoking cessation treatment. (Chantix - Highlights of Prescribing Information, 2014) Varenicline belongs to the nicotinic agonist medicines, which recently showed promise for AUD treatment 14

23 though definite results are not published. (Krishnan-Sarin et al, n.d) The FDA recently corrected the drug s labeling by noting that those taking Chantix experiencing increases intoxicating effects of alcohol Some cases described unusual and sometimes aggressive behavior, and were often accompanied by amnesia for the events. (Chantix - Highlights of Prescribing Information, 2014, p. 3) Therefore, this noted interaction with alcohol limits its use for AUD treatment to a sub-population already sober prior to enrolling in a treatment plan. Gabapentin Neurontin (brand name) was approved by the FDA for the treatment of epilepsy, seizures, and pain management of shingles or the herpes virus in (Gabapentin - FDA prescribing information, side effects and uses, 2015) A recent dose-ranging clinical trial that was funded by NIH showed promising results in the treatment of AUD. (Mason et al, 2014) Mason s team showed that "Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile." (Mason et al, 2014) Its use for the treatment of AUD has not been reviewed and approved by the FDA as of the writing of this paper. At present, a contraindication exists: Using gabapentin together with ethanol can increase nervous system side effects such as dizziness, drowsiness, and difficulty concentrating. Some people may also experience impairment in thinking and judgment. You should avoid or limit the use of alcohol while being treated with gabapentin. (Gabapentin - FDA prescribing information, side effects and uses, 2015, p. Gabapentin and Alcohol / Food Interactions ) Since Gabapentin is absorbed and not metabolized, patients with severe renal dysfunction should not take the medication. Gabapentin is another GABA drug of interest working in a similar way to Baclofen. The results of a 150 patient clinical trial 15

24 showed similar or greater positive outcomes when compared to existing FDA approved treatments for alcohol dependence. (as cited in NIH-funded study finds that gabapentin may treat alcohol dependence, 2013) Topiramate Topiramate, an anti-seizure medication, received its FDA approval in (Topiramate - FDA prescribing information, side effects and uses, 2014) The drug acts on both GABA-a and glutamate receptors in the brain. (NIH - Research on Promising Medications (not approved by the U.S. Food and Drug Administration [FDA]) to Treat Alcohol Use Disorder (AUD), n.d.) Ondansetron Zofran (brand name) was first approved by the FDA in 1991 and the generic form followed in (Ondansetron - FDA Approved Drug Products, n.d.) According to Johnson et al. and Kranzler et al., both teams who conducted similar studies and were cited by Krishnan-Sarin and colleagues in a NIH document found, Clinical trials of this medication have shown efficacy in reducing drinking behavior, especially in drinkers with early-onset (type B) alcoholism. (Johnson et al., 2000; Kranzler et al., 2003, as cited in Krishnan-Sarin et al, n.d) This information would imply a targeting of this product to those diagnosed with early-onset alcoholism. Nalmefene Nalmefene was authorized by the European Medicine Agency in 2013 to treat AUD. However, it is not FDA approved for the treatment of AUD. (Nalmefene - EPAR summary for the public, 2012) The drug works by attaching to certain opioid receptors in the brain and thereby reduces the urge to drink. It however, is contraindicated in 16

25 Dr Dave Roberts (Carleton University) started working on Baclofen for treatment of AUD after one of his students hypothesized the benefits of the drug in the case of AUD. First RCT done in Italy. Started in 10/2003 and ended in 11/ alcohol-dependent patients with liver cirrhosis were referred to the Institute of Internal Medicine, Rome, Italy. 84 were randomly allocated either oral baclofen or placebo for 12 weeks. (Addolorato et al., 2007) Positive outcomes were noticed. Dr. Olivier Ameisen publishes the positive outcomes of his own trial in the book The End of my Addiction. Dr James Garbutt (UNC Chapel Hill) runs a second RCT on Baclofen with higher dosages, as recommended by European findings. Project started in 11/2013 and will be complete in 12/2017. Estimated enrollment: 120 individuals. Swiss chemist Heinrich Keberle synthezises the drug for treatment of epilepsy Franco-American Dr. Olivier Ameisen performs a trial with Baclofen on himself to treat his own AUD. Dr James Garbutt (UNC Chapel Hill) runs a RCT on Baclofen, following FDA guidelines. Found no significant evidence, but admitted that the dosage at 30 mg might have been too low to observe noticeable results. The French Government orders a RCT for $920,000, lead by Dr. Philippe Jaury (Paris Descartes University). Trial started in 05/2012 and will last until 02/2015. The French Health Authorities decided to give a Temporary Recommendation for Use (TRU) to the Baclofen in the treatment of AUD. those who use opioids and [i]t must also not be used in patients with severe liver or kidney impairment or a recent history of acute alcohol withdrawal syndrome. (Nalmefene - EPAR summary for the public, 2012, p. 2,3) Baclofen Baclofen is a potential drug for the treatment of AUD. Since its first discovery in 1962 for the treatment of epilepsy, the drug has shown promise for recovering addicts suffering from AUD. Figure 9 shows the timeline from the molecule s discovery in 1962 to its TRU in France in Figure 9: Baclofen From its discovery to present time Baclofen in Treatment of AUD s

26 Approved by FDA in 1977 for the treatment of spasticity, the generic drug Baclofen (former brand name was Lioresal) works in the CNS by mimicking the naturally occurring inhibitors GABA-b neurotransmitters. (Brennan et al, 2013) The synthetic drug binds to GABA receptors at the postsynaptic neuron so that alcohol molecules have no or fewer binding sites and less stimuli results from this action. Less activity (neurotransmitters) going through those binding sites translates into a decrease in activity in the nerves that control muscle contraction and relaxation. (Brennan et al, 2013) In a healthy individual, GABA-b (only GABA-b neurotransmitters seem to have the desired effect with Baclofen) are sufficiently present to keep that individual calm and relaxed by causing the activity of other nerves to decrease. (Brennan et al, 2013) A patient lacking those GABA-b neurotransmitters will begin to feel the effects of anxiety and possibly feel his or her muscles involuntarily contracting, which is the case in multiple sclerosis for which Baclofen has demonstrated the ability to address (Figure 10) Figure 10: How Baclofen works Source: Alcoholism 'cured' By Baclofen - Spinal Cord Injury Health Issues, n.d. The FDA suggests a recommended maintenance dosage for the treatment of muscle spasms not to exceed 80 mg per day. (FDA Approved Drugs - KEMSTRO - NDA , 2003) Baclofen is not FDA approved for the treatment of AUD. It has been 18

27 suggested that this drug would not be efficacious in the treatment of AUD at a dose equal to or lower than 80 mg per day, since doses exceeding 250 or 300 mg/day are often necessary to produce a state of complete indifference to alcohol. (DeBeaurepaire, 2014, Introduction) While treating his own AUD, Dr Olivier Ameisen was taking a maintenance dose of up to 270 mg per day. (Rolland, et al, 2012, p. 1) Similar results were observed by Dr Garbutt when his first American trial in 2007 studied the use of Baclofen at a dosage of 30 mg per day. This study did not demonstrate support for Baclofen in the treatment of AUD. (Garbutt et al, 2010) However, Garbutt et al concluded, Baclofen was associated with a significant reduction in state anxiety (F(1,73)=5.39, p=0.02). (Garbutt et al, 2010, p. 1) Ezogabine Potiga (brand name) was approved by the FDA for the treatment of seizure disorders in (Potiga - FDA Approved Drug Products, n.d.) A recent study lead by researchers at Boston University School of Medicine found positive outcomes with Ezogabine in the treatment of AUD. (Knapp et al, 2014) However, its use for the treatment of AUD has not been reviewed by the FDA. Psychiatric drugs Physicians might prescribe other pharmaceutical drugs in the treatment of AUD, especially when it comes to dual-diagnosis including a psychiatric aspect. Such medicines include diazepam (valium) or amitriptyline (antidepressant). (Krupitsky et al, 1993) Those drugs can be taken concurrently with most prescribed AUD medicines. To date, only one study has evaluated the effectiveness of diazepam, amitriptyline, and Baclofen. (Krupitsky et al, 1993) Results of investigations showed that Baclofen is an 19

28 effective drug for affective disturbances in alcoholic patients, with efficacy superior to placebo and equal to diazepam and amitriptyline. (Krupitsky et al, 1993, p.157) Negative outcomes observed in RCT and study cases Despite encouraging studies performed worldwide, the replication of confirmatory positive outcomes has failed to confirm the efficacy of Baclofen in the treatment of AUD. Some of the most influential studies are described below. Those trials with negative outcomes are listed chronologically. American Trial For his first trial, Dr Garbutt, affiliated with the University of North Carolina at Chapel Hill, intended to reproduce the Italian trials lead by Dr Addolorato to confirm the positive outcomes observed at a dosage of 30 mg per day. His aim was to test the efficacy and tolerability of baclofen in alcohol dependence in the United States. (Garbutt et al, 2010, p. 1849) The study screened 121 individuals to obtain 80 randomized subjects (balanced for gender) and followed them for twelve consecutive weeks. (Garbutt et al, 2010) His findings did not support Dr Addolorato s outcomes as he stated: Despite encouraging preclinical data and prior positive clinical trials with baclofen in Italy, the current trial did not find evidence that baclofen is superior to placebo in the treatment of alcohol dependence. (Garbutt et al, 2010, p. 1849) French Meta-analysis A meta-analysis undertaken by French scientist Dr Lesouef from the French Pharmacology and Therapeutic Society, confirmed the results found by Dr Garbutt. (Lesouef et al, 2014) His aim was "to estimate the efficacy of baclofen on the 20

29 maintenance of abstinence and the decrease of craving in alcohol-dependent patients. (Lesouef et al, 2014) He found that treatment with a low dosage of Baclofen (30 mg per day) [c]ompared to placebo, baclofen was associated with a significant increase of 179% in the percentage of abstinent patients at the end of the trial, without heterogeneity. For secondary outcome measures, based on a random-effect model, no significant effect of baclofen was observed compared to placebo. (Lesouef, et al, 2014) Israeli Trial Dr Ponizovsky, from the Sha'ar Menashe Mental Health Center at the Bruce Rappaport Medical Faculty in Haifa, Israel, undertook a multi-site, placebo controlled clinical trial with the aim to test the efficacy and tolerability of baclofen in alcohol dependent patients in Israel. (Ponizovsky, et al, 2014, p. 24) Sixty-four patients were randomized to receive either baclofen 50 mg/day (n=32) or placebo (n=32), from which a total of 62% completed (72% in the baclofen group and 53% in the placebo group) the 12-week trial and 37% completed the 52-week follow-up (34% baclofen; 41% placebo). (Ponizovsky, et al, 2014) Dr Ponizovsky concluded that [a] significant reduction in levels of distress, depression and craving and improved HRQL occurred for both arms and that [u]nlike previous positive trials in Italy, and similarly to a negative trial in the USA, we found no evidence of superiority of baclofen over placebo in the treatment of alcohol dependence. However, the high placebo response undermines the validity of this conclusion. (Ponizovsky, et al, 2014, p. 24) Bias in the selection of patients Hypotheses for negative observations in RCTs 21

30 Dr. Leggio reported that the Italian study recruited patients with more severe AUD than the study conducted in the US. These differences suggest that baclofen may be more potent and effective in the treatment of severe AUD, rather than moderate AUD. (Leggio et al., 2010 as cited in Agabio & Colombo, 2014, p.7) Even if this held true, it would seem that Italian patients would therefore require higher dosages than the minimal 10 mg t.i.d to show an overall improvement of their health. Most of the patients recruited by the clinical trials discussed are patients who have tried other treatment options including FDA approved Disulfiram, Naltrexone, and Acamprosate, with or without a combination of other drugs and/or therapies to treat their AUD. I hypothesize that some of these patients might also have developed some immunity and resistance to treatment options including Baclofen - with their drinking habits. Length of study participant treatment Most clinical studies discussed in this paper that evaluated the efficacy of Baclofen in the treatment of AUD, lasted 12 weeks (=84 days). As reported by Dr Ameisen himself in the journal Alcohol and Alcoholism, it took him at least 37 days to titrate to the dose of 270 mg/day, based on a starting dose of 15 mg/day with increments of 20 mg/day every third day. (Ameisen, 2004, p.148) In fact, Dr. Ameisen may have reached a plateau for a while based on increasing side-effects and thereby increasing the timing by which he reached the maximal dosage of 270 mg/day. (Ameisen, 2004, p.147) Also, after noticing that side-effects outweigh the benefits of the Baclofen, Dr Ameisen decreased his intake of the Baclofen, but did it slowly to avoid any symptom of withdrawal. (Ameisen, 2004, p.148) In his case, he reached a 22

31 maintenance dosage of 120 mg/day at 9 weeks while still experiencing alcohol cravings for which he temporarily increased his daily intake by 40 mg and stabilized his behavior with no additional intake of Baclofen at week 12. (Ameisen, 2004, p.148) Thus, I suggest that upcoming trials and interventions shall last more than 12 weeks in order to further study Bacolfen s efficacy and safety for the treatment of AUD. Dosage Dosage factors to consider in the use of the Baclofen include the following: typology of the patient (severe versus moderate AUD), inpatient versus outpatient, gender, comorbid mental disorder, renal function (since Baclofen is discarded via the kidney). For example, inpatient study participants may be able to undergo stronger treatments and are more inclined to be compliant with the drug intake. Outpatient participants have greater access to alcohol and can be less compliant with their drug intake as there is no one to supervise their compliance. Further one should not undergo large dose increments without close medical supervision. In addition, the half-life of Baclofen is short lived, requiring patients to take the drug on a t.i.d. (3 times per day) protocol. As Dr. DeBeaurepaire suggested, "Significant relationships were found between the amount in grams of alcohol taken before treatment and the maximal dose of baclofen required, and between the existence of a mental disorder and a lesser effect of baclofen." (DeBeaurepaire, 2012, p.103) This finding coincides with Dr Addolorato s findings reported in AUD is a chronic disease that quite often is associated with mental disorders. There might be a different assimilation of the drug when mixed with other psychotic drugs. Also, as Wilder stated in an earlier publication, people with mental disorders 23

32 often show a bad compliance with treatments. (as cited in DeBeaurepaire, 2012, p. 103) DeBeaurepaire concluded, Potential limitations in the effectiveness of baclofen include the coexistence of a mental disorder, the concomitant use of other psychotropic drugs, a lack of real motivation in patients to stop drinking, and the impossibility to reach the optimal dose of baclofen because of unbearable side-effects (sometimes possibly related to too sharp a protocol of dose escalation). (DeBeaurepaire, 2012, p.103) Prominent Ongoing Trials Since the previous trials have been challenged, ongoing trials are taking into account the identified flaws to further investigate the efficacy of Baclofen in the treatment of AUD. French RCT An ongoing trial is being led by Dr. Philippe Jaury from Assistance Publique in Hôpitaux de Paris, France. His aim is to show the effectiveness to a year of baclofen compared to placebo, on the proportion of patients with a low risk alcohol consumption or no, according to the WHO standards. (Jaury, 2015) The study plan is to enroll 330 adults. Enrollment began in May 2012 and recruitment has concluded. Study participants were followed for 12 months, with the participants in the baclofen treatment group receiving up to 300 mg per day (that can be titrated down as medically indicated) to test the efficacy of high dose Baclofen in the treatment of AUD. (Jaury, 2015) American RCTs Dr Garbutt s trial Dr Garbutt, who first led a clinical trial to replicate Dr Addolorato s outcomes (results published in 2010), has undertaken another trial to test high dose Baclofen (HDB) in the treatment of AUD. His aim is to 24

33 test the hypothesis that a robust dose of baclofen (90 mg/day) has efficacy and is safe in individuals with alcohol dependence. Furthermore, the proposal will test whether an indicator of physical dependence, i.e. drinks/drinking day, predicts response to baclofen. Additionally, the proposal will examine the anti-anxiety effects of baclofen within an alcohol dependent population and ascertain whether baseline levels of anxiety predict response to baclofen. (Garbutt, 2014) The clinical trial has an estimated enrollment of 120 adults. Recruitment began in November 2013 and is continuing as of the writing of this paper. The study s overall estimated completion date is October (Garbutt, 2014) One of the pitfalls to consider in this study is the root definition of HDB. In this study, Dr Garbutt is administering doses up to 90 mg per day before decreasing the dosage to match the threshold of tolerance of the side-effects for the patients. (Garbutt, 2014) In a recent publication, Dr DeBeaurepaire mentioned that drug summaries recommend not exceeding the daily dose of mg, which agrees with the FDA labeling of Baclofen for the treatment of spasticity. (DeBeaurepaire, 2014) Anything above this dosage would be considered HDB, although long-term studies have shown that doses exceeding 250 or 300 mg/day are often necessary to produce a state of complete indifference to alcohol. (DeBeaurepaire, 2014, p. 143) For this reason, the French Health Safety Agency released a recommendation allowing for the prescription of baclofen to be given up to 300 mg/day, but not beyond, for the treatment of alcohol dependence (French Ministerial decree of June 13, 2014). (DeBeaurepaire, 2014, p.143) Dr Leggio s trial Another American study has been undertaken by Dr Leggio for the NIH. (Leggio, 2014) This clinical trial s aim is to see if baclofen is safe and helpful for people who have alcoholism and high anxiety levels." The study plans to enroll 132 adults (ages 21 25

34 to 65). Enrollment began in December 2012 and the overall study completion is targeted for September (Leggio, 2014) This study is unique as note by Leggio: The present project proposes investigating baclofen using a design similar to that used in the previous pilot study (thus, an already validated paradigm), thus representing not only the first study testing baclofen in alcoholic individuals with high anxiety levels, but also the first study investigating baclofen s biobehavioral mechanisms in such a population for which baclofen may hypothetically show a very robust effect. (Leggio, 2014) Regulations and processes for drug approval FDA regulations in the United States In the United States, the FDA has not considered the approval of the Baclofen in the treatment of AUD. Conflicting efficacy results compounded with side-effects that include drowsiness, dizziness, and memory trouble as observed in RCTs do not support the efficacy of Baclofen to expand its labeling for the treatment of AUD. (Ponizovsky et al, 2014, p.24) How to get the FDA s approval? The FDA's Center for Drug Evaluation and Research (CDER) s mission is to ensure that drugs marketed in this country are safe and effective. (FDA - How Drugs are Developed and Approved, 2014) The CDER is composed of representative members of the diverse medical professions, including physicians, pharmacists, chemists, biostatisticians, to name a few. Their mission is to review Investigational New Drugs (IND) applications and New Drug Applications (NDA) submitted by the drug s pharmaceutical sponsor. (FDA - How Drugs are Developed and Approved, 2014) The sponsor will have to wait for the CDER s review and approval before starting clinical trials or undertaking the marketing of the drug for a new indication (e.g., AUD). 26

35 IND (Investigational New Drug) After researchers proved the efficacy of a molecule in the treatment of a specific medical condition on animals, a physician can make a request to the FDA to further investigate the compound through a pre-clinical human study. (FDA - Investigational New Drug (IND) Application, 2014) The sponsor will request an IND and wait 30 days before beginning the trial. (FDA - Investigational New Drug (IND) Application, 2014) During this time frame, the FDA will review the literature provided by the drug s sponsor and can decide to refuse the right to do any human experimentation if they believe the risk of harm to humans is too high. (FDA - Investigational New Drug (IND) Application, 2014) NDA (New Drug Application) In place since 1938, the NDA allows the drug s sponsor to be considered for the sale and marketing of the drug that previously received an IND approval. (FDA - New Drug Application (NDA), 2015) During this process, CDER reviews the scientific evidence that confirms both safety and effectiveness of the medicine for the proposed labeling. CDER can approve or deny the sponsor s request for approval in the American market based on the principle of beneficence. (FDA - New Drug Application (NDA), 2015) Among other key elements reviewed by the FDA, the process of manufacturing the drug also is taken into account as it must match current FDA s standards. (FDA - New Drug Application (NDA), 2015) ANDA (Abbreviated New Drug Application) When the patent of an existing innovator drug comes to expiration, a drug sponsor can make a request to the FDA to market the drug as generic via an ANDA. 27

36 (FDA - Abbreviated New Drug Application (ANDA): Generics, 2014) In its application, the sponsor has to prove that its intended generic drug is bioequivalent, meaning that its composition and biological use are similar to those of the innovator drug. (FDA - Abbreviated New Drug Application (ANDA): Generics, 2014) Off-label use in the United States Physicians are often considered the learned intermediaries in between the manufacturers of the drug and the patients. (Salbu, 1999) Physicians shall respect the description and recommendations of use as presented on the drug s label before prescribing it to their patients. The FDA s labeling requirements, in place since 1938, confers safety to the patient as an end-user of the product. (FDA - New Drug Application (NDA), 2015) If the physician were to prescribe a drug other than for the recommended use that has been approved by the FDA, he or she would do so offlabel. If a manufacturer wants one of their drugs to be considered for use under a different label, meaning a different use, the sponsor would have to submit under the NDA process. (Salbu, 1999) The legal use of Baclofen in the treatment of AUD in the United States would fall into this category. According to Salbu, It would be logistically impracticable, although not technically impossible, for Congress or the FDA to ban the off-label use of drugs. (Salbu, 1999, p.188) To this day, the off-label prescription was permissible before Congress s 1997 liberalizations. (Salbu, 1999, p.190) In fact, the FDA only has legal authority on manufacturers, not physicians. (Salbu, 1999, p.190) Legally, the prescription of an off-label drug without the patient s consent is not considered malpractice. (Salbu, 1999, p.190) Physicians are to abide by their code of 28

37 medical ethics and provide care for their patients in their best interest, which I propose can sometimes include the thoughtful use of an off-label prescription. EMA and ANSM regulations in France In France, Baclofen has recently been authorized for the treatment of AUD under the Temporary Recommendation for Use (TRU) decree. French National Agency for Medicines and Health Products Safety (ANSM) In France, pharmaceutical companies have the choice to either seek national market authorization (MA) through the ANSM or obtain European approval via the European Medicines Agency (EMA), the European FDA equivalent. (Rémuzat et al, 2013) In 2011, two bills drastically changed the conditions of access of pharmaceutical drugs to the market and their conditions for reimbursement. (Rémuzat et al, 2013) Those laws also saw the emergence of the ANSM. (Jeannet & Maraninchi, 2013) Before then, pharmaceutical companies only could have a MA for the French territory through the EMA. (Jeannet & Maraninchi, 2013) The newly created ANSM made it a priority to implement a new framework for off-label prescribing via the emergence of the Temporary Recommendation for Use (TRU). (Rémuzat et al, 2013) Temporary Recommendation for Use In 2014, after noticing the increasing evidence that supports the drug Baclofen in the treatment of AUD, French health authorities decided to regulate its use under a temporary recommendation for use (TRU). In France, when evidence-based trials prove that a drug s benefits outweigh the risks involved, it can receive a Market Authorization (MA) equivalent to the FDA approval for labeling in the United States. (Temporary Recommendation for Use (TRUs), 2012) This MA often only covers the 29

38 diseases for which the drug has proven to be efficacious. In some instances, some medicines are prescribed off-label to fulfill a public health need not covered within the scope of an existing MA. (Temporary Recommendation for Use (TRUs), 2012) Two conditions need to be fulfilled in order for the drug to receive a TRU: there is an unmet therapeutic need and the benefit/risk ratio of the medicine is assumed to be favorable based on the available scientific efficacy and safety data. (Temporary Recommendation for Use (TRUs), 2012) A TRU is temporary as the acronym suggests and has a maximum length of approval of three years. During these three years, public health authorities will gather accumulated data and either dismiss the drug s use or evaluate alternatives such as labeling it for the disease it received a TRU approval. Baclofen fell into this category and is now regulated by the French Public Health authorities under a TRU. Figure 11 shows the drastic increase in sales of Baclofen after the release of the notoriously famous book The End of my Addiction from Dr. Olivier Ameisen in (Figure 11) Figure 11: Evolution of baclofen's sales in France 30

39 Source: Rolland, et al, 2012 Discussion Implementing a TRU in the United States Due to the lengthily and costly process required for a drug to be approved in the United States, one should consider implementing the framework of TRU successfully developed in France a few years ago. In the case of Baclofen, even though the drug might be considered for approval in the treatment of AUD within the next few years, to date, only three prescription drugs are currently legally available to patients suffering from AUD in the United States. For many patients, the drugs Naltrexone, Disulfiram, and Acamprosate are not a treatment option because of the hepatic concerns emanating from ingesting alcohol. For other patients, those treatments have proven to be inefficient and Baclofen could potentially lead them towards the path to recovery. 31

40 Since prescribing off-label is legal in the United States but still not popular, consideration of a TRU would legally protect and encourage physicians to prescribe Baclofen as a treatment option when all others have failed, and while still following the guidelines of the medical code of ethics. Since 88,000 deaths due to alcoholism are preventable each year in the United States, using a TRU to frame the legal distribution of Baclofen would potentially save thousands of American lives before the FDA considers it for labeling authorization for the treatment of AUD. (Alcohol Facts and Statistics, 2014) Positive outcomes observed in RCTs and study cases As noticed in Appendix 4, there have been at least twelve relevant worldwide studies attempting to prove the benefits related to the use of Baclofen for the treatment of AUD. Most of the studies might be limited to broad application due to the inability to detect both statistically and clinically meaningful results due to the small sample sizes. They shall therefore be discussed to provide support of a trend that requires the involvement of more statistically rigorous studies. The following trials are sorted in chronological order. Russian Trial Nearly a decade before Dr Ameisen shared with the rest of the world his discoveries based on self-administered Baclofen in the treatment of his AUD, Dr Krupitsky explored the positive effect of the drug in the context of AUD. Dr. Krupitsky, from the Leningrad Regional Dispensary of Narcology in Russia, was the lead investigator in a clinical trial that involved ninety alcoholic patients with the secondary affective disorders (anxiety, depression). (Krupitsky et al, 1993, p.157) There were four 32

41 study arms in this trial, namely one group of patients receiving 37.5 mg per day of Baclofen, another group receiving diazepam 15 mg per day, a third group receiving amitriptyline 75 mg per day and the last group received a placebo tablet. (Krupitsky et al, 1993) The aim of the study was to identify which drug was more efficient in the treatment of AUD. (Krupitsky et al, 1993) His findings were that baclofen is an effective drug for affective disturbances in alcoholic patients, with efficacy superior to placebo and equal to diazepam and amitriptyline. At the same time baclofen does not have the side-effects and complications of the latter. (Krupitsky et al, 1993, p. 157) Even though those results are encouraging, the methods used in this study do not allow for generalization since there were too few individuals in each group to detect statistically significant differences. Also, the study suffered from another flaw, the fact that it was not a double-blinded experiment. (Krupitsky et al, 1993) Italian Trials Dr. Addolorato et al: 2002 The first European study was lead by the investigator Dr. Addolorato from the Institute of Internal Medicine, Catholic University of Rome in Italy. (Addolorato et al, 2002) This study s aim was to provide a first evaluation of the efficacy of baclofen in inducing and maintaining abstinence and reducing craving for alcohol in alcoholdependent patients in a double-blind placebo-controlled design. (Addolorato et al, 2002, p. 504) In this context, Dr Addolorato recruited 39 alcohol-dependent patients. These patients were administered a dose of 15 mg/day for the first 3 days of the study and 30 mg/day for the subsequent 27 days. (Addolorato et al, 2002, p.505) His findings were as follows: 33

42 A higher percentage of subjects totally abstinent from alcohol and a higher number of cumulative abstinence days throughout the study period were found in the baclofen, compared to the placebo, group. A decrease in the obsessive and compulsive components of craving was found in the baclofen compared to the placebo group; likewise, alcohol intake was reduced in the baclofen group. A decrease in state anxiety was found in the baclofen compared to the placebo group. (Addolorato et al, 2002, p.504). The same way Dr Krupitsky s trial suffered from flaws in the design of his study, Dr Addolorato s first trial included a sample size too small that the results cannot be generalized to a population due to the inability to detect statistically significant along with clinically relevant findings. Dr. Addolorato et al: 2007 Dr. Addolorato s second study was designed to investigate the effectiveness and safety of baclofen in achieving and maintaining alcohol abstinence in patients with liver cirrhosis. (Addolorato, et al, 2007, p. 1915) This trial included 148 alcohol-dependent patients with liver cirrhosis. (Addolorato et al, 2007, p. 1915) The dosage administered remained equal to that of the first trial at 30 mg per day. (Addolorato et al, 2007, p. 1916) The findings followed the same positive trend observed five years prior: Of 42 patients allocated baclofen, 30 (71%) achieved and maintained abstinence compared with 12 (29%) of 42 assigned placebo. (Addolorato, et al, 2007, p. 1915) Though a positive clinical trend was observed, the study was disregarded by most healthcare professionals because of the small cohort used in the study. French Trial A three year investigation, lead by French doctor DeBeaurepaire from Groupe Hospitalier Paul-Guiraud in Villejuif, France included [a] hundred patients with alcohol dependence, resistant to usual treatments. (DeBeaurepaire, 2012, p. 103) Most of the 34

43 study participants were patient referrals from Dr Ameisen s practice. (DeBeaurepaire, 2012) The aim of the study was to examine the long-term effects of baclofen in a large cohort of alcohol-dependent patients compliant to baclofen treatment. (DeBeaurepaire, 2012, p. 1) Dosing ranged from 30 to 330 mg of baclofen per day with an average dose at 147 mg per day. (DeBeaurepaire, 2012, p.3). In his study, Dr DeBeaurepaire admitted that there was a significant relationship between the amount of alcohol (in grams) consumed before treatment and the maximal dose of baclofen needed by patients. (DeBeaurepaire, 2012, p. 3) Dr DeBeaurepaire concluded: Ninety-two patients (92%) reported a decrease in their motivation to drink at one time or another during the follow-up. At baseline, all patients belonged to the WHO at high risk category. At 3 months, 50% of the responses were classified as at low risk, 34% at medium risk, and 16% at high risk ; at 6 months, the percentages were respectively 52, 18, and 27%, they were 48, 15, and 29% at 1 year, and 50, 12, and 25 at 2 years. (DeBeaurepaire, 2012, p. 3) All patients entering the study were for treatment resistant alcoholism, meaning that all patients have been treated before for their alcoholism, in various ways, including medications, hospitalizations, rehab centers, Alcoholics Anonymous, and psychotherapies, and that these treatments failed. (DeBeaurepaire, 2012, p. 2) Even though this clinical trial was the first undertaken at a larger scale, the sample size issue remains since this was a dose ranging study, or considered a Phase II trial by the US FDA. In addition, to ensure that appropriate statistical and clinical significance could be determined, more participants in each group would have been optimal to move this conclusion forward. This clinical trial was reviewed by Dr Addolorato, lead investigator in both the 2002 and the 2007 Italian trials. In fact, Dr Giovanni Addolorato, besides being a researcher with a focus on the pharmacological treatment of alcohol dependence, is the 35

44 Editor of "Frontiers in Addictive Disorders", where Dr DeBeaurepaire s paper got published in (Professor Giovanni Addolorato, n.d.) Australian Trial Another study exploring the use of Baclofen in the treatment of AUD was led by the Australian investigator, Dr. Morley from the NHMRC Centre of Research Excellence in Mental Health and Substance Use, Discipline of Addiction Medicine of the University of Sydney in Australia. (Morley, et al, 2014) The study s aim was To conduct a doubleblind, placebo-controlled randomized clinical trial of baclofen in the treatment of alcohol dependence. (Morley, et al, 2014, p. 654) Sixty-nine individuals were referred to the study, with a total of 42 patients randomized to one of three arms: Baclofen 30 mg/day (n=14); Baclofen 60 mg/day (n=14); Placebo (n=14). Study participants were followed for twelve consecutive weeks. Randomized participants received upward and downward titrations of medicine to reduce the likelihood of side effects. (Morley, et al, 2014, p ) The team s findings were stated as follows: Intention-to-treat analyses revealed that alcohol consumption (heavy drinking days, drinks per drinking day) significantly reduced across all three groups during the treatment period. A post hoc analysis stratifying according to whether there had been a comorbid anxiety disorder, revealed a beneficial effect of baclofen 30 mg/day versus placebo on time to lapse and relapse (P < 0.05). There was also a beneficial effect for baclofen 60 mg/day relative to placebo on time to relapse in this comorbid group (P < 0.05). (Morley, et al, 2014, p.654) Even though this clinical trial might confirm a positive trend observed in prior trials, the "post hoc" analysis was not planned and Morely et al concluded In spite of the small sample for a 3-arm clinical trial, this study suggests a specific role of baclofen in alcohol-dependent individuals with comorbid anxiety. Replication in larger, fullypowered studies is required. (Morley, et al, 2014, p.654) Additionally, the trial only 36

45 lasted twelve weeks, which is under the grace period of three months defined by a 2006 FDA report cited in Dr DeBeaurepaire s paper, where the grace period is an early period in a trial where outcome is not considered in the analysis because the effect of the treatment during this period does not represent the full potential of the drug. (as cited in DeBeaurepaire, 2012) As a reminder, Dr DeBeaurepaire s trial lasted 24 months. (DeBeaurepaire, 2012) Further, it is interesting to notice that Drs Addolorato, Leggio, and Haber, from the Italian RCT in 2007, were also involved in this Australian trial. Comparison of costs of drugs in the United States One can make a case for the support of Baclofen over other drugs for the treatment of AUD in the US from a consumer purchase perspective. The following table shows how Baclofen is less than the daily cost associated with any other treatment for AUD on the American market. Drug s name Maintenance recommended dosages Daily cost* generic drug Acamprosate* mg, 3 times per day $8.40 $10.16 Baclofen: FDA guidelines 40 mg / day $0.53 N/A Dr Garbutt s new American trial 90 mg / day $1.20 Dr. DeBeaurepaire 2014 French trial 300 mg / day $4.00 Disulfiram * mg per day $5.90 $10.65 Daily cost* brand s name drug Ezogabine Gabapentin 200 mg, 3 times per day N/A $ mg, 3 times per day $0.96 $10.47 Naltrexone * 2 50 mg per day $3.80 $ 3.53 * denotes a cost found under the following criteria: this is an out-of-pocket cost to the patient, before taxes, in the cheapest pharmacy found, without coupons. All costs were found per 30 tablets and 37

46 quoted as of 02/10/2015, in the zip code (Chapel Hill, NC). (Prices, Coupons and Information GoodRx, n.d.) * 2 Denotes that the drug is approved by the FDA in the treatment of AUD. As seen above, the generic drug Baclofen is currently five times less expensive than its main competitor Disulfiram in its generic form. Based on the fact that Baclofen exists in a generic form, I have assumed that prices would not rise disproportionally after the drug s FDA approval. I propose that approval of Baclofen for AUD would also relieve insurance companies from large claims resulting from the treatment of addictions. Instead, insurance companies would see a rise in claims in the near future but these would be less expensive claims related to prescriptions for the use of Baclofen in the treatment of AUD. Creating a coalition Another consideration should be brought to light: the creation of a coalition among investigators who research AUD treatments. In fact, by joining forces, investigators could develop a master protocol with calculated sample sizes for a multicenter RCT to demonstrate efficacy of the drug being tested. Such coalition was once proposed by Dr Addolorato when he originally planned as a multisite double-blind placebo-controlled randomized clinical trial to assess the effects of two doses of baclofen (30 mg/day, 60 mg day and placebo) in alcoholism. (Morley et al, 2014) The name of this alliance was the International Baclofen Intervention Study (IBIS) as illustrated in Figure 12. (Morley et al, 2014) Unfortunately, this international effort did not succeed as expected and only half of the participating countries ended up collecting data, rendering the study significantly underpowered. (Morley et al, 2014) Figure 12: IBIS 38

47 Source: Addolorato, 2007 The principle of beneficence Converging evidence suggests that the drug Baclofen fulfills its ambition to stop AUD patients cravings and promote sobriety, as detailed in the studies discussed. I am of the opinion that it is a safe drug that patients with liver issues can take without an established risk to their liver, as opposed to the Disulfiram and other FDA approved drugs. Low dose Baclofen is also safe for patients to take while intending to reduce their intake of alcohol without formally quitting drinking. (Agabio & Colombo, 2014) Also, to date, baclofen has not displayed addictive properties in patients affected by AUD. (Agabio & Colombo, 2014) It should be noted that every patient is different and should be treated as such. Regardless of the known tolerance of the patient to a drug, patients taking HDB should be medically supervised to address the potentially dangerous sideeffects that can arise from overdoses. In fact, the DSM-5 model (Appendix 1) shows several levels of dependence to alcohol. Depending upon the patient s background in 39

48 terms of alcohol abuse, a different dosage would be prescribed. A concomitance of other medications should be considered in the case of AUD and dual-diagnosis. Also, it is widely known that alcoholism is first and foremost a health behavioral issue that should be followed by a psychiatrist and a support group in order to make the success of Baclofen as treatment for AUD attainable. The psychiatrist should keep the patient under observation for the time required to reach an optimal maintenance dose of Baclofen. Recent trials included the BRENDA program, a psychiatric support designed to help individuals in their recovery. (Starosta et al, 2006) At last, the most important component in the success of the drug itself is the desire of the patient to actually quit. Without this ambitious goal and the adherence to the program, I believe that no prescription drug can make a patient quit his or her drug of choice. Any drug prescribed in the treatment of AUD will face some obstacles to its success. A reduced efficacy of baclofen may also theoretically be related to a number of other factors (i.e., genes, environment, motivation, enduring habits, severity of alcohol dependence, severity of side-effects, treatment observance), which remain to be investigated. (DeBeaurepaire, 2012) 40

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56 Appendices Appendix 1: DSM-5 criteria to be diagnosed with AUD Source: Alcohol Use Disorder,

57 Appendix 2: Long-term implications of AUD Source: A-Team Alcohol Services, n.d. 49

58 Appendix 3: List of FDA approved manufacturers for the distribution of generic Baclofen in the United States. Source: FDA Approved Drugs,