ThinkTwice! Treating Alcohol Dependence with Topiramate: A Critical Appraisal Learning Activity JOURNAL ARTICLE TEI PLAIN LANGUAGE ANTHOLOGY

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1 JOURNAL ARTICLE Transformed into part of a plain language anthology Treating Alcohol Dependence with Topiramate: A Critical Appraisal Learning Activity Abstract: This study set out to test a drug, topiramate, to see if it reduced the amount of alcohol people drank. The study was designed as a randomized controlled trial. One group (183 men and women addicted to alcohol) was given the drug (topiramate). Another group (188 men and women addicted to alcohol) was given a pill that looked exactly like the one taken by the first group. This pill, however, did not contain the medicine (placebo). Neither the researchers nor the men and women in the study knew which group patients were in (double-blinded study). This means they did not know who was taking topiramate or who was taking the placebo. Both groups received 15 minute counseling sessions each week. Some people dropped out of the study before it was finished. Dropouts affected the results. Therefore, researchers calculated results two ways. They compare the number of heavy drinking days in each study group. Including dropouts, the number of heavy drinking days was 8.44% less in the topiramate group. Not including dropouts, the number of drinking days was 16.19% less in the topiramate group. Side effects, such as lack of appetite, lack of concentration, and burning/tickling feelings were more common in the topiramate group. Researchers said that topiramate may be a promising treatment for people addicted to alcohol Background: Alcohol addiction, or alcoholism, is a complex disease. The National Institute on Alcohol Abuse and Alcoholism describes four main features. These features are: 1) strong need to drink (craving) 2) not being able to stop drinking once started 3) withdrawal symptoms (upset stomach, sweating, or shakiness) after not drinking 4) need to drink more and more alcohol in order to feel it s effects (tolerance) Alcoholism affects about 18 million Americans. It is serious and dangerous. It can increase risk of certain types of cancer. It damages the brain, liver, and other organs. Alcohol can cause birth defects. It also increases the chance of dying in a car crash or from murder or suicide. How does addiction happen? We feel pleasure (rewards) from eating food and drinking fluids. These things activate our brain reward system. Feeling pleasure makes us want to repeat the behavior that caused it. This is good in the case of food and water, which we need to survive. However, the same feeling of pleasure can be caused by some drugs. Examples include cocaine, marijuana, and alcohol. These drugs activate certain networks of nerves in our brains (circuits). The brain circuits release a chemical (dopamine) that makes us feel good. The brain remembers what caused the pleasure and wants it repeated. The need to take drugs becomes more This article was transformed for age level from the original article, which appeared in the Journal of the American Medical Association (JAMA), vol. 298, October 10, 2007, pp Authors: BA Johnson, N Rosenthal, JA Capece, F Wiegand, L Mao, K Beyers, A McKay, N Ait-Daoud, RF Anton, DA Ciraulo, HR Kranzler, K Mann, SS O Malley, and RM Swift for the Topiramate for Alcoholism Advisory Board and the Topiramate for Alcoholism Study Group.This article is for K 12 educational use only. This transformation follows peer-reviewed format. 1

2 important than anything else. A person addicted to alcohol no longer drinks for pleasure they are physically dependent on it. The need for alcohol becomes all that matters. Addiction is caused by changes in the brain that may be lasting. These changes make it hard to stop taking drugs. The medicine used in this study is called topiramate. Its approved use is to prevent seizures and headaches. Topiramate may do its job by changing brain chemicals. This study tested the drug, topiramate, to see if it also might be used to treat alcohol addiction. Methods: The study design was a randomized, double blind, placebo controlled-trial that took place in 17 study sites across the United States. The study was done between January 27, 2004 and August 4, men and women were included in the study. They were 18 to 65 years of age. All men in the study drank more than 35 drinks per week (average of 5 drinks/day). All women in the study drank more than 28 drinks per week (average of 4 drinks/day). For the study, a drink was 0.5 oz of alcohol (this is the amount of alcohol in a 4 ounce glass of wine or a 10 ounce beer). All had to have a urine test that showed no illegal drugs in their bodies, like cocaine or marijuana. All had to want to stop or lower their drinking. People who applied to the study were not accepted if they had circumstances that could affect the study or cause harm to the person. Some of these situations included serious withdrawal symptoms, more than 4 unsuccessful hospital stays, or receiving psychiatric help. Other factors included taking anti-seizure medicine, being pregnant, or having kidney disease or depression. Institutional Review Boards at all 17 study locations approved the study design. All people in the study signed written informed consent forms. Before they could sign, they had to have breath alcohol levels less than 0.02%. 707 men and women volunteered to take part in the study. 336 did not meet study requirements. 31 decided not to join after learning details of the plan. 40 never followed through on the application process. 371 men and women were placed into two groups by chance (randomized). 183 received the medicine topiramate. 188 received pills that looked identical, but had no active ingredient (placebo). Both groups received 15 minute counseling sessions each week (Figure 1). 2

3 707 Men and Women Screened 336 not eligible in study 371 randomized 4 dropped after enrollment 67 dropped out during study (34 side effects) 183 assigned to take Topiramate and counseling 188 assigned to take placebo and counseling 112 finished study 144 finished study 3 dropped after enrollment 41 dropped out during study (6 side effects) 183 included in main analysis 183 included in safety analysis 188 included in main analysis 188 included in safety analysis Figure 1 Study Profile Participants were given a card for recording the amount of alcohol they drank. The main result (dependent variable) was percentage of heavy drinking days. A heavy drinking day for men was 5 drinks/day or more. For women it was 4 drinks/day or more. Another result was the number of days with no drinking. A blood test measuring alcohol intake was required in addition to the information the people reported. To ensure the drug was safe, vital signs, physical exams, and blood tests were watched carefully. This was done to see if the study drug caused any harmful side effects. While the study was taking place, a separate group, completely independent from the research, looked at the emerging data from time to time. This was done to be sure every person in the study was safe. When some patients dropped out of the study, data about them were missing. As with any study, it would have been better to have no missing data. The amount and pattern of missing data can affect results. Therefore, the researchers had to decide how to handle missing data in their study. To see how missing data affected their results, calculations were done in two ways. The first was to analyze the study with every subject in it, which made the most of all the available information. This approach preserved the effects of patient assignment into groups at the start of the 3

4 study. It was the tougher test of the drug s affect. The second analysis was to focus only on subjects who went all the way through the study and had complete data. This approach gave a best case result. These two approaches were compared to see how much dropouts affected the final results. An expert, who was not involved in the study, checked the calculation of results. The information on number of drinking days was reported by people in the study (self-reported). These people may have been affected by the alcohol they consumed. Therefore, their information was compared to the required blood alcohol test data. Results: The two groups of study participants were similar at the start of the study (Table 1). Table 1. Study Group Characteristics at Start of Study Topiramate Group (n=179) Placebo Group (n=185) Average Age (years) Sex Male Female Race White Black Asian Other Self-Reported Drinking Days Heavy Drinking (%) Days Without Drinking (%) Breath Alcohol (%) By the end of the 14-week study, 67 people in the topiramate group dropped out (36.6%) in contrast, 41 people dropped out of the placebo group (21.8%). In the group that took the medicine, the percentage of heavy drinking days dropped from 81.91% to 43.81%. In the group that took the pills without medicine in them (placebo), the percentage of heavy drinking days dropped from 81.97% to 51.76% (See Figure 2). The percent of days without drinking any alcohol increased from 9.64% to 37.56% in the topiramate group; it also increased from 9.64% to 29.06% in the placebo group. The blood tests verified lower alcohol intake in the group taking the topiramate. The number of side effects was higher in the group taking topiramate (Table 2). 4

5 A Figure 2 Percentage of Heavy Drinking Days (Dropouts Included) Heavy Drinking Days (%) Placebo (n=188) Topiramate (n=183) Study Week B Figure 2 Continued Percentage of Heavy Drinking Days (Dropouts Not Included) Heavy Drinking Days (%) Placebo Topiramate Study Week 5

6 Table 2 Side Effects Side Effect Topiramate Group Placebo Group Discussion of Results: In this (n=183) (n=188) 14-week study, Tingling of skin topiramate appeared Headache to reduce the Tired percentage of heavy Could not concentrate 27 6 drinking days and Memory problems increase the number of days with no Sleepiness drinking (abstinence). Because Nausea people in the study had to meet certain requirements, they may have been healthier than most people addicted to alcohol. Therefore, the results may not apply to all people with alcohol addiction. The study also did not have a long follow-up time to see if people in the study started drinking heavily again. Our conclusion, however, is that topiramate is safe and effective for treating alcoholism. This is important because alcoholism is a serious health problem in the United States. References: National Institute on Alcohol Abuse and Alcoholism, retrieved on May 8, 2009 from National Institute of Drug Abuse, retrieved on April 13, 2009 from Johnson, BA, et al. Topiramate for treating alcohol dependence: A randomized controlled trial. JAMA, 298, Study Disclosure: Dr. Johnson reported being a consultant for Ortho-McNeil Janssen Scientific Affairs, LLC., as did 6 other researchers on the study. This company makes Topiramate, the medicine used in the study. Funding Support for the study: Ortho-McNeil Janssen Scientific Affairs, LLC. provided the medication and funding for this study. Role of Sponsor: Ortho-McNeil Janssen Scientific Affairs, LLC was involved in all phases of the study, from its design through analyzing the results and review of the paper to be published. A separate analysis of the results was done by Daniel O. Scharfstein, who was not employed by Ortho-McNeil Janssen Scientific Affairs, LLC or Dr. Johnson. 6 Measures of Readability for this transformed article (text only): Flesch-Kincaid Grade Level 8.7 Flesch Reading Ease 55.9