Dependence & Withdrawal



Distinguished Faculty award winner, Professor of Human Medicine James Galligan.by James J. Galligan, Ph.D.,
Professor of Pharmacology and Toxicology
and Neuroscience Program Director

Alcoholism is difficult to treat as alcohol can change brain function in an almost permanent way such that cravings for the drug never go away even when the alcoholic is sober. There are many treatment plans which have varying degrees of success but even in alcoholics who have been sober for years, there is always a risk of relapse.

There are several drugs used for the treatment of alcoholism with varying degrees of success. One drug that is very effective in reducing the cravings for alcohol is disulfiram. To understand how this drug works, we need to understand how the body metabolizes alcohol. Alcohol is metabolized in the liver. There are two enzymes responsible for this process: alcohol dehydrogenase and aldehyde dehydrogenase (see figure below). Alcohol dehydrogenase takes one molecule of alcohol and converts it to acetaldehyde. Acetaldehyde is “toxic” as it is responsible for the effects we associate with a hangover (headache, nausea, vomiting). When most people drink moderate amounts of alcohol they do not experience a hangover as the enzyme aldehyde dehydrogenase converts acetaldehyde to acetic acid which is quickly excreted from the body by the kidney. However, when a person consumes large amounts of alcohol, aldehyde dehydrogenase cannot keep up with the amount of acetaldehyde that accumulates and a hangover results. Disulfiram is a drug that inhibits aldehyde dehydrogenase and is used to treat alcoholism. When a person takes disulfiram and drinks alcohol, aldehyde dehydrogenase cannot convert acetaldehyde to acetic acid and acetaldehyde levels build up even with moderate amounts of alcohol consumption. The drinker immediately feels nauseous with a headache and vomiting to follow. This person does not experience any of the “good” effects of alcohol and goes immediately to a hangover. Disulfiram works well in alcoholics trying to stay sober. However, if the alcoholic chooses to stop taking disulfiram it no longer works.

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Perhaps if aldehyde dehydrogenase could be inhibited permanently, this shortcoming could be overcome. This is the strategy being tested by a research group working in Chile in South America. The group led by Dr Juan Asenjo (Director of the Institute for Cell Dynamics and Biotechnology at Universidad de Chile) is preparing to test a “vaccine” that will produce long term inhibition of aldehyde dehydrogenase in an early clinical trial in human subjects. This is not the typical vaccine though. Conventional vaccines are injections of a virus or bacteria that will activate your immune system to produce antibodies against that invader. Usually only small amounts or an inactive form of the virus or bacteria is used. Now your body has an immune memory so that when you are exposed to that invader again, your immune system is prepared to fight off the infection. The Chilean group is proposing a different strategy. They will use a modern molecular biology technique in which a virus containing genetic material that will “knock down” the gene that encodes the aldehyde dehydrogenase protein. The Chilean group reports that this gene knockdown can last up to 9 months. Booster shots would likely be required to maintain the gene knockdown for continued protection against alcoholic relapses.

No data are available in the peer reviewed scientific literature to document the potential effectiveness of the gene knockdown strategy in the treatment of alcoholism. For example, there are no published studies of using this strategy in animal models of chronic alcohol consumption. We await the findings of the early trials of this exciting and hopefully life changing treatment for recovering alcoholics.

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“I don’t need help because if I can’t help myself I can’t be helped.” --Amy Winehouse

“Amy Winehouse found dead at her London flat…autopsy inconclusive…toxicology results expected in two to four weeks.” 

by Jane Maddox, Ph.D., Assistant Professor
Department of Pharmacology and Toxicology

Why do forensic toxicology results take so long? There are several reasons:

Multiple samples must be tested: blood, stomach contents, and urine are commonly first taken, but other tissues such as liver, brain, kidney, and vitreous humor of the eye may also be sampled.

If there are no obvious signs or symptoms linked to specific drugs or toxins observed at the time of death, testing for many different toxic substances must occur.

The tests must identify and quantify a wide repertoire of both legally prescribed drugs and illicit substances to determine if either any single drug or combination of drugs could have been the cause of death.

The initial tests would likely be immunoassays to screen for a wide variety of drugs suspected as the cause of death. These tests use antibodies to detect known drugs, but they can only measure a predetermined set of substances; therefore, if a new or unknown drug has been taken, it can be missed. Other analyses, such as mass spectrometry (that can identify unknown toxic substances) must also be performed.  Mass spectrometry is very sensitive and specific, but it also takes more time to complete.

Once potentially toxic substances have been detected, the concentrations in the sample must be compared with clinical data to determine if the dose, or combination of doses, was high enough to be lethal. In addition, samples may be retested in the same laboratory or sent to a second laboratory for confirmation. Again, these tests take more time. Confirmatory tests are important for several reasons: 1) to ensure scientific integrity of the data, 2) to defend against potential legal issues involved in cause of death, particularly in the case of a celebrity death.

As for the death of Amy Winehouse, it is complicated.

She was alone at the time of death, so no symptoms were observed, and it was reported that no drugs or paraphernalia were found on the premises. Therefore, important clues to direct the toxicology testing were lacking and the search could take some time to complete.

nicotine replacement therapy image

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

Quitting cold turkey is a common regimen for kicking the cigarette smoking/nicotine habit.  Cold turkey does work for many cigarette smokers.  However, there are also many smokers who find that quitting is easy because they have done it hundreds of times.

Nicotine replacement therapy (NRT) is a common treatment for smokers in this latter category.  NRT comes in nasal sprays (very messy), chewing gum and “the patch”.  NRT involves a step down strategy over a 8-12 week period where the smoker gives up cigarettes and initially goes on a high dose nicotine treatment for 2-3 weeks followed by successive 2-3 week nicotine dose reductions.  This strategy is designed to gradually reduce the nicotine dependence and uncomfortable withdrawal symptoms (irritability, craving, disruption of sleep, etc.) until smokers no longer crave nicotine.  Studies have shown that NRT doubles the smoker’s chances of quitting by the end of the 12 week period although the success rate is still not great.  In placebo controlled studies, NRT produces about a 40% success rate while subjects on the placebo treatment quit about 20% of the time.  The big problem is that 80-90% of the quitters relapse in about 1 year. Current Food and Drug Administration (FDA) approval for NRT indicates a maximum 12 week treatment.

Part of the problem with cigarette smoking/nicotine addiction is the behavioral aspect of the addiction.  For example, the post meal coffee and cigarette is a very satisfying experience for smokers and there are strong social reinforcements associated with several smokers sharing this experience.  Studies have shown that even crack cocaine addiction has a strong behavioral-social component to the drug smoking experience and addiction.  So, unless the cigarette smoker changes his or her friends and family the smoker will continue to be exposed to the drug (nicotine)-related cues.

Drug addiction therapists and the FDA are beginning to re-think the 12 week limitation on NRT.  Nicotine raises blood pressure in some individuals but overall the data indicate that nicotine itself is not particularly dangerous to your health.  Cigarette smoking is clearly dangerous to your health as cigarette smoke contains an array of toxic chemicals.

Cigarette smoking is the major cause of lung cancer and it is also a major cause of deadly cardiovascular diseases such as high blood pressure, clogged arteries, heart attacks and strokes.  At this time, the long-term risks of NRT have not been studied in large groups of subjects.  However, the risks of cigarette smoking are unambiguous.  About 20% of Americans are cigarette smokers; this translates into 62 million people who are at great risk for lung cancer and cardiovascular disease which places a huge burden on our healthcare system.  It may be time to permit long-term NRT in an effort to reduce cigarette smoking relapse rates.  Of course this must be done with mechanisms in place to carefully monitor any unanticipated adverse effects that might appear when large numbers of people are using long-term NRT to kick the habit.

by James J. Galligan,  Ph.D., Associate  Chair,
Department of Pharmacology and  Toxicology

Cigarette smoking is one of the most difficult addictions to quit.  This is partly because nicotine so effectively stimulates the brain’s dopamine reward pathway and partly because cigarettes are so accessible.  The costs to individuals and to society associated with nicotine addiction are enormous.  These costs include shortened life spans, reduced quality of life due to a decline in health and also increased healthcare expenses.  There is great interest in developing treatments that would help nicotine addiction subjects to kick the habit.  There are several choices available right now. These include “The Patch”, Zyban/Wellbutrin (buproprion) and Chantix (varenicline).

The Patch is a step down system in which the individual applies nicotine containing patches to the skin.  The nicotine is absorbed from the patch and the nicotine supplied by this approach reduces the craving for cigarettes.  Over several weeks, the individual reduced the “dose” of nicotine until they no longer experience nicotine cravings.

buproprionBuproprion is a complicated drug that acts as an antagonist for the receptors for nicotine and it is a dopamine and norepinephrine reuptake inhibitor.  Buproprion blocks the rewarding actions of nicotine by blocking the nicotinic receptor.  Buproprion also activates the endogenous reward pathway by increasing the availability of norepinephrine and dopamine in this pathway.

Varenicline

Varenicline is also an antagonist of the nicotinic receptor in the reward pathway in the brain.  These drugs all reduce the reward associated with cigarette smoking and this makes it easier to kick the habit.  These drug treatments all have reasonable success rates with up to half of the subjects off cigarettes after 4-12 weeks of treatment.  However, the relapse rate is high after the smoking cessation treatment is stopped and about 90% of people are back on the cigarettes at 1 year.

The problem described above has spurred interest in the development of nicotine vaccines.  This requires multiple nicotine treatments which activate the immune system to produce antibodies against nicotine.  This is an extremely useful strategy as the treated individual becomes immune to the rewarding effects of nicotine.  Antibodies bind to nicotine preventing its movement into the brain where nicotine acts to stimulate the reward system.  Relapse rates would be lower as the individual is permanently immunized against nicotine.  Recent clinical trials of NicVax, a nicotine vaccine, have yielded very positive results (http://www.cnn.com/2010/HEALTH/04/21/nicotine.vaccine.nicvax/index.html) and treated subjects have been able to maintain abstinence much longer than placebo treated groups.

These preliminary results are promising but the outcome of the full trial is still about 1 year away.  If the data from the final study match data from the preliminary results then it may be possible to immunize current cigarette smokers with the goal of getting them to kick the habit in the long-term.

Nathan R. Tykocki
Graduate Student, Pharmacology and Toxicology

I know all-to-well the addictive powers of cigarettes, and trying to quit is a Sisyphean task to say the least.  The hardest thing to overcome are those cravings – the need to have the pleasure caused by lighting up.  But now a new option exists to combat that drive to smoke, and it’s not what you would think.

NicotineNicotine (ironically similar to niacin, an essential human nutrient), can cross the blood-brain barrier and ultimately increase dopamine levels in the reward circuits in the brain.  This increase in dopamine leads to relaxation, euphoria, and the continued urge to smoke.  Repeated nicotine use causes a downregulation of dopamine synthesis, but becomes more sensitive to nicotine’s ability to release dopamine in the reward pathways in the brain.  Thus, the “lows” are lower, the “highs” are higher, and a bad habit rapidly becomes an addiction shared by more than 44 million Americans.

Current pharmaceuticals used to aid in smoking cessation work in the brain in two ways: drugs like bupropion (“Zyban”) that help maintain the levels of dopamine in the brain to prevent the between-smoke “lows”, or those like varenicline (“Chantix”) that decrease the sensitivity to nicotine and prevent the during-smoking “highs”.  While these drugs have been shown clinically to decrease the rate of smoking versus placebo in the short-term, they both come with a myriad of unpleasant side-effects that decreases patient compliance and lower long-term cessation dramatically.  Nausea, vomiting, lethargy, and vivid dreams (and trust me – the dreams can be V-I-V-I-D!!)  make cigarettes seem not-so-bad in comparison.  So what can we do??

Here’s where the new idea comes in.

NicVAX (click image to visit microsite)

Instead of fighting the effects caused by nicotine, a new drug called NicVAX (currently in stage III clinical trials) combats nicotine itself.  In fact, the drug doesn’t work in the brain at all!  According to the company’s website, NicVAX stimulates the body’s immune system to create antibodies against nicotine.  These antibodies will specifically recognize nicotine and bind to it, forming a complex that is too large to cross into the brain and activate the reward centers associated with smoking.  In short: no reward equals decreased smoking.  Because this new drug stimulates the body to produce antibodies against nicotine, it may work much longer than traditional smoking therapies which lose their efficacy relatively rapidly if use is discontinued.  Since it is a vaccine, the body will continue making antibodies to nicotine for 6-12 months after initial drug treatment.  The most interesting bit about this drug is the extremely low incidence of side-effects.  Since it does not work to counter the effects of nicotine in the brain, there are apparently very few psychological side-effects.  This increases patient compliance, and will hopefully lead to greater long-term cessation success.

Now if only there were a jelly doughnut vaccine…

Michael Jackson

Michael Jackson

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

Regardless of the final legal outcomes, it is sad that Michael Jackson was killed by inappropriate use of sedative drugs.  The ruling that his death was a homicide is suggestive of negligence and perhaps poor understanding of how drugs work.

It seems that MJ was taking a number of different drugs to help with his sleeping problems.  His doctor was using lorazepam and midazolam in addition to propofol to help MJ sleep but he was finding that each drug alone or in combination was not producing the desired results.  Lorazepan and midazolam are both Valium like drugs that can be used as anti-anxiety and sedative drugs.  They can be taken in pill form so the safety factor in terms of an overdose is reasonably good.  It is difficult to overdose accidentally.  Propofol can only be administered intravenously, so the risk for an accidental overdose is much greater with this drug.

A pharmacology lesson comes from a discussion of how these drugs work on the brain to produce their sedative effect.  All of these drugs act at receptors for the neurotransmitter GABA. GABA, lorazepam, midazolam and propofol all act to turn off or inhibit neuronal activity.  When we are talking about neurons in the parts of the brain that are responsible for anxiety, this is good as that is where these drugs produce their sedative actions.  However, when the neurons that control breathing or the heart beat are affected that is where an overdose becomes an issue.

It looks like drug tolerance may have played a big role in what happened to MJ.  His physician was administering lorazepam, midazolam and propofol but finding that they were not working well.  This is because each drug acts at the same site and the brain adapts to the continued presence of the drug.  The drugs become less effective over time and more and more drug is required to get to the same therapeutic effect.  As higher and higher doses are given, an overdose becomes more and more likely.

A beneficial strategy would be to use a sedative drug or drugs that act through mechanisms that are different from those used by lorazepam, midazolam and propofol.  There would be no tolerance to the new drugs and lower and safer dose could be used.  Knowledge of this basic pharmacological principle might have reduced the overdose risk for the King of Pop.

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

I am lecturing next week in our graduate level Principles of Pharmacology and Toxicology course (PHM 819).  I will be discussing drug tolerance, dependence and withdrawal.  These are topics usually associated with drug addiction but as I will convey to the class, drug tolerance, dependence and withdrawal are associated with many non-addictive drugs.  My lectures will focus on cellular and molecular mechanisms responsible for tolerance, dependence and withdrawal. We will discuss in great (some say nauseating) detail what happens to individual molecules and cells when they are exposed chronically to drugs.

Questions often posed by the students include: So what? Who cares?  What does this really mean?  How is this useful for using drugs to treat illness?  I admit that these are all good questions.

It is a coincidence then that the Food and Drug Administration has just come out with a News Release (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm172366.htm) that is highly relevant to these questions.  The release is related to a new drug called Onsolis (fentanyl).  Fentanyl is a very strong opioid narcotic that is not easy to use because it is highly potent (only a very little of the drug is needed to produce pain relief or to produce respiratory depression which can be lethal).

The Onsolis preparation of fentanyl is novel in that is contained in a film (like some breath mints) that is placed in the mouth and the drug is absorbed directly from the mouth.  Onsolis is approved for use in chronic pain patients who are taking opiates regularly for pain relief.  Onsolis is for use only for breakthrough pain that is not suppressed by the patient’s normal opiate medication.

Now what does this have to do with PHM 819?  Well because these patients take opiates regularly they are highly tolerant to the effects of opiates.  So a fatal overdose due to respiratory depression is much less likely because these patients are much less sensitive to the respiratory depression caused by opiates.  They also develop tolerance to the pain relieving effects of opiates but because fentanyl is such a strong analgesic, it still provides some relief even in the opiate tolerant patient.

This is a real world application of the principle of drug tolerance and how we can take advantage of this to improve patient health.  This is also a good reason for students to understand drug tolerance, dependence and withdrawal.  Finally, it is a good example of why understanding the mechanisms responsible for drug tolerance is important for drug development and patient care (and not just for passing exams)!

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