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Study seeks safer withdrawal medications

by Dick Peterson
Public Relations
For nearly 40 years a standard treatment to lessen the effects of alcohol withdrawal symptoms has proven to be safe and effective—until now.

Dr. Robert Malcolm

Treatment standards are changing, said Alcohol Research Center clinical investigator Robert Malcolm, M.D. Inpatient venues for alcohol detoxification and control of withdrawal symptoms allowed the careful administration of controlled drugs called benzodiazepines—Valium, Librium, Atavan and others. 

But with the emergence of managed care, where alcoholism treatment is moved to an outpatient setting, the liabilities of using any of the benzodiazepine drugs are profound.

For that reason, Malcolm leads an outpatient study of 160 select men and women from ages 21 to 70 from virtually all socioeconomic and ethnic groups who experience alcohol withdrawal syndrome but are not addicted to any other drugs. Using results from a previous study of a medication called Lorazepam as a point of comparison, his investigation probes the effects of a unique anticonvulsant called gabapentin. 

Study subjects will receive four days of outpatient medication, two days of follow-up, and five days of medical, psychological and physical assessments.

Malcolm's tests will measure the eye blink response to a loud, sudden noise, note the accumulation of withdrawal symptoms, and make subjective assessments of sleep, overall discomfort, anxiety, depression, and the need for additional medications. Included in the comparison will be an evaluation of side effects and safety.

Unlike the benzodiazepines, gabapentin is not a controlled substance, has benign side effects, interacts rarely with other drugs and its interactions with alcohol are limited.

“The benzodiazepines appear to be less satisfactory now than when they were used in the inpatient setting,” Malcolm said. “They impair memory and judgment, and the ability to walk. They interact with alcohol and make driving a car dangerous.”

Malcolm said that control of the withdrawal syndrome that people experience in alcohol detoxification is important. Not only does each successive withdrawal make it more likely that a person addicted to alcohol will return to drinking, the withdrawals become increasingly severe.

Withdrawal side effects can range from headaches, anxiety and tremors in younger, more healthy people to serious, life-threatening conditions like elevated temperature, high blood pressure, irregular heartbeat and convulsions.
 

Mouse model aids in studying intoxication, withdrawal

by Dick Peterson
Public Relations
Fall off the wagon and each time it's a bit harder to get back on. 

We're talking about alcoholism here. Each time a person endures alcohol detoxification, withdrawal symptoms intensify and sobriety becomes even more elusive.

It's the nature of alcohol and how it works on the brain, said Alcohol Research Center investigator Howard Becker, Ph.D., professor of psychiatry, physiology and neuroscience, and co-scientific director. Becker's research probes the effects of alcohol in a search for new treatments to lessen withdrawal side effects and make a return to alcohol dependence less likely.

Dr. Howard Becker

“We've known this for some time,” Becker said. “A review of people who have a medical history of detoxification suggests a worsening of withdrawal symptoms.” 

But the phenomenon is difficult to test in humans, so Becker has developed a model using mice to study chemical and electrical activity in the brain  during alcohol intoxication and during withdrawal. He also measures the amount of work the addicted mice will perform to access alcohol after their detoxification. This way he can measure the effectiveness of various medications thought to lessen withdrawal symptoms and give people a greater degree of power over their alcoholism.

“Using animal models allows for rigorous control over the variables involved,” Becker said. He explained that he is able to expose lab mice to repeated cycles of alcohol exposure and withdrawal and observe the intensification of symptoms over successive withdrawal episodes.

There's a reason for those withdrawal symptoms; it’s tied to the brain's attempt to cope with the alcohol.

Ordinarily, the brain works to maintain a balance of neurotransmitters that both accelerate and restrain brain activity. When alcohol is carried through the blood stream to the brain, it sedates brain activity by enhancing GABA (a primary inhibitory neurotransmitter), and reducing the effects of glutamate (a primary excitatory neurotransmitter).

But that's not the end of it. Following prolonged alcohol exposure, an involuntary mechanism to maintain balance in the brain kicks in—decreasing GABA-inhibition and upregulating glutamate-excitation—the net effect compensates for the sedative effects of the alcohol. While the brain actually adapts to the continued presence of alcohol, the abnormal nature of these changes becomes apparent when drinking is stopped and alcohol leaves the brain during withdrawal.  Now the brain is left in a hyper-excitable state, with a dampened inhibitor (GABA) and enhanced excitability (glutamate) that contribute to withdrawal symptoms.

Repeated cycles of alcohol intoxication and detoxification withdrawal, may magnify these changes and, in the extreme, can lead to brain seizures, Becker said.

As difficult to endure as the symptoms are, medications do exist to help treat the withdrawal, but not without their own side effects.

“There are the benzodiazepines—Valium, Librium and Atavan. They're the most common treatments in the U.S., and are considered safe and effective,” Becker said. “But...”

Becker listed the downside: 

  • They can substitute for alcohol abuse and create dependency  themselves.
  • They can substitute for alcohol abuse and create dependency
  • They produce memory impairment and may even interfere with treatment efforts for recovery from alcohol dependency.
  • And when drugs like Valium and alcohol are combined, which would not be unusual for a person addicted to alcohol, they have an added sedation effect.


“And now with managed care, alcohol detox is being moved into an outpatient venue,” Becker said, “where we can't treat withdrawal complications.”

So he's looking for new treatments that can effectively treat alcohol withdrawal without these side effects and problems. Gabapentin (Neurontin) is one possibility that Becker is testing on mice to see if the drug reverses abnormal chemical and electrical activity in the brain during alcohol withdrawal. Another, Vigabatrin, inhibits enzymes and break down GABA. 

Becker's research also is looking at the link between alcohol dependence and self-administration. He wants to learn how a history of alcohol dependence and withdrawal impacts the possibility of relapse. “As the withdrawals get worse, the relapse rate rises,” he said. A major goal of this research is to identify new treatments that not only treat withdrawal, but also reduce the possibility of relapse.