Drugs for drinkers

Physicians don't always identify patients at risk, especially in certain demographics.

It's a worrisome sign when an expert speaker says a topic is confusing, as Kathleen Finn, MD, FACP, did at the start of her Hospital Medicine 2012 talk on alcohol withdrawal in April.

“I worked at three different hospitals, and at each hospital the addiction specialist told me exactly what I should use [to treat withdrawal] and when I should use it, and all three told me something entirely different,” said Dr. Finn, now a hospitalist at Massachusetts General Hospital in Boston.

Given the conflicting advice, she decided to look into the subject herself, and found only more uncertainty. The American Society of Addiction medicine's evidence-based guidelines rely on studies of patients in detox centers with no co-morbidities. “There are no studies identified which report clinical experience in managing alcohol withdrawal in hospitalized patients with specific co-existing medical disorders,” Dr. Finn reported. “So we are in a data-free zone.”

Unfortunately, quite a lot of hospitalists' patients reside in that zone. “About one in six of your patients have an alcohol use disorder and are at risk for alcohol withdrawal,” she said. Those patients usually fall into one of two groups, the first of which is easy to identify. “We get a lot of patients who are coming in purely for alcohol withdrawal, but we also get the COPDer or the patient with heart disease who also are at risk of alcohol withdrawal.”

To identify the latter group, the CAGE (Cut down, Anger, Guilt, Eye-opener) is the most well-known tool, but the AUDIT-C (which covers how often and how much at a time a patient drinks) is also useful, according to Dr. Finn. “The CAGE questions are behavioral questions and the AUDIT questions are quantity questions,” she said. “I don't think there's one tool that's exact. When you're asking the history, it's probably worth asking both a behavioral and quantity question of patients to try to pick them up.”

Even with these tools available, research has shown that physicians do not identify a very high percentage of patients at risk of alcohol withdrawal, particularly in certain demographics, Dr. Finn said. “We tend to miss women who are white, of higher socioeconomic status and higher education, and we tend to miss the elderly.”

Routine laboratory tests might draw attention to some at-risk patients. “About 30% of chronic abusers of alcohol have hypophosphatemia and 30% have a low magnesium [level],” said Dr. Finn. Alcoholics are also at increased risk of deficiencies in calcium, potassium and vitamin D. “For anyone chronically abusing alcohol, it is helpful to monitor their phosphate and check their vitamin D level,” she said, noting that phosphate may be normal at first and then drop 12 to 36 hours after admission.

Measurement of blood alcohol levels may also be useful in some cases. “One of the reasons alcohol levels can help is because it can tell you about the patient's tolerance. If they're awake and smiling at you with a level of 2,000 mg/L, they have tolerance,” she said. Blood alcohol does not directly predict withdrawal, but tolerance indicates a chronic user, and therefore, an at-risk patient.

So what exactly are these patients at risk of? There are two stages to withdrawal: early (0 to 48 hours after the last drink; includes central nervous system stimulation, adrenergic hyperactivity and hallucinations and seizures) and late (starting any time from 48 hours to five days later; includes delirium tremens, Wernicke's encephalopathy and Korsakoff's syndrome).

“The other way you'll hear people classify alcohol withdrawal is minor and major withdrawal. Minor is early symptoms that are mild and as you move into severe symptoms and seizures and delirium tremens, you call that major withdrawal,” said Dr. Finn.

Because major withdrawal can carry significant risks (the mortality rate from delirium tremens is estimated to be between 0.5% and 8.5%), experts have put some effort into identifying likely sufferers. Risk factors include older age, a history of seizures or delirium tremens, more days since the patient's last drink, heavier and longer drinking, and signs of withdrawal at a blood alcohol level over 100 mg/L.

“But the two biggest risks for developing acute withdrawal or delirium are acute concurrent medical illness, so the patients that we all take care of, and any patients with structural brain issues,” said Dr. Finn.

Hospitalists' patients may also have a higher than average risk of mortality from the condition. “You can still die from delirium tremens. And who dies? Patients who have underlying liver disease, patients who have other medical illnesses, patients who have early [delirium tremens], and people who are transferred to the ICU with pneumonia,” Dr. Finn said.

Medical illnesses also complicate treatment of withdrawal. The Clinical Institute Withdrawal Assessment (CIWA-Ar) is the most frequently used tool to predict withdrawal severity, but it was developed in a healthy younger population. “Is the CIWA scale appropriate for medical patients? We don't know,” she said. “The severity of withdrawal is affected by your concurrent illness. Medical illnesses can affect CIWA scores.”

The CIWA-Ar includes 10 items: nausea and vomiting, tremor, paroxysmal sweats, auditory disturbances, agitation, tactile disturbances, anxiety, visual disturbances, headache, and clouding of sensorium. Note the absence of heart rate and blood pressure from the list, Dr. Finn emphasized. Although both are frequently used in hospitals, neither has been proven to be a good predictor of severe withdrawal, she added.

The CIWA scale was developed to guide dosing of benzodiazepines, which were first prescribed in the 1960s and continue to be the most popular method of treating withdrawal. Four varieties are most commonly used in the U.S.: chlordiazepoxide (Librium), diazepam (Valium), lorazepam (Ativan) and oxazepam (Serax). “The first two are cleared by the liver; the other two are cleared by the kidney. Some people will argue in cirrhotic patients you shouldn't use the ones in the liver and some people will argue that longer-acting (chlordiazepoxide and diazepam) are better because they slowly taper out,” said Dr. Finn.

Research, however, has not found a difference among the long- and short-acting drugs, or even very firm evidence of their effects. A 2010 Cochrane meta-analysis tried to quantify the evidence for benzodiazepines in withdrawal. “They did reduce the risk of seizures, but they were not able to assess whether benzodiazepines reduced the risk of delirium, mortality or withdrawal symptoms,” said Dr. Finn.

The drugs do differ from each other in their dosing. “A milligram of lorazepam is about the same as 5 mg of diazepam, and about the same as 25 mg of chlordiazepoxide,” she said. But the appropriate dose will depend on the patient. “Actual benzo levels in the bloodstream don't correlate with symptoms or its effect on you. It's hard to predict how each person will react individually to benzos, which makes it hard to pick among the four,” Dr. Finn said.

For medical inpatients with co-existing illness, it is also uncertain from the evidence whether fixed-dose or symptomatic usage of benzodiazepines is better. While two studies have shown benefits of symptom-triggered dosing, once again they were conducted in healthy populations in detoxification centers, not medical inpatients, Dr. Finn noted.

“The problem with delirium in the hospital is that it's often multi-factorial. For a patient with pneumonia and alcohol withdrawal you may be giving benzos for the delirium tremens, but is that the appropriate treatment for the delirium from the hypoxia and the infection?” she said.

To further complicate matters, benzodiazepines may also cause or intensify delirium. “As somebody gets older, their risk of developing delirium from benzos goes up,” Dr. Finn said.

Even younger patients can suffer from benzodiazepine intoxication if doses are too high. “The patient starts to develop an agitated delirium, so what does the nurse do? They give more benzos, which move the patient up into stupor. They're now nice and calm, but as that starts to wear off they become agitated again, and you give them more benzo to get them back into the stupor, but the only way to get from stupor back down to normal is to go through that intoxication phase,” Dr. Finn described.

Other problems with benzodiazepine use include resistance (which increases with repeated episodes of withdrawal) and paradoxical reactions. “A lot of patients, especially chronic alcoholics, will start to swing at nurses or pee on the floor, and that is largely because you have now disinhibited their frontal lobes with the benzos you gave,” she said.

There have also been recent shortages of benzodiazepines. “This has forced a lot of folks to go back and look at a lot of the other drugs that have been studied in alcohol withdrawal,” Dr. Finn said. Those alternatives include carbamazepine and clomethiazole (popular choices in Europe), gabapentin, gamma-hydroxybutyrate (GHB), baclofen, corticotropin-releasing hormone (CRH), pregabalin (Lyrica) and phenobarbital.

Phenobarbital has been the subject of recent research. “It makes the benzos much more active,” said Dr. Finn. “People are trying to use phenobarbital with benzos in alcohol withdrawal, to try to reduce the amount of benzo and make it more efficacious.”

Such combination therapy may eventually prove to be the best treatment. “There are a lot of drugs out there,” she said. “The other question is whether we should be using anti-psychotics along with other drugs for delirium tremens. We just don't know what right cocktail mix of these to use.”

But hospitalists could be just the bartenders to figure it out. “This is not a sexy topic like MI or PE. No other society is going to argue with us if we want to take this topic on. This is an area that we as hospitalists treat and probably an area that we should pull together as a society and do some larger multicenter studies,” Dr. Finn concluded.