Alcohol and Benzodiazepine Cross-Tolerance: Why the Two Mask Each Other, and Why Withdrawal From Both Is Managed as One

Cross-tolerance means that a brain adapted to alcohol is also less sensitive to benzodiazepines, and the reverse, because both drugs act on the same receptor, GABA-A. Tolerance is built at the receptor rather than to the drug.

GABA is the brain’s main calming signal, and the GABA-A receptor is where it acts. Alcohol and benzodiazepines both increase that receptor’s effect, which is why both produce calm, sleepiness, poor coordination and, at high enough doses, suppressed breathing. A review from the University of California, Los Angeles, of alcohol use disorder and its treatments notes that benzodiazepines are used to reduce the symptoms of alcohol withdrawal precisely because they act on this system, and that frequent benzodiazepine use produces cross-tolerance, dependence and cross-addiction to alcohol. An earlier review of the receptor pharmacology put it the same way from the other direction: tolerance and cross-tolerance studies show that alcohol’s actions are similar, though not identical, to those of benzodiazepines.

In practice this is why a heavy drinker often needs a larger benzodiazepine dose to feel anything, why someone on a long-term benzodiazepine prescription may find that alcohol seems to do less than it used to, and why neither observation means either drug has become safer.

Source: Alcohol use disorders and current pharmacological therapies: the role of GABA(A) receptors, Liang and Olsen, Acta Pharmacologica Sinica, 2014.

Cross-tolerance makes withdrawal unpredictable because each drug masks withdrawal from the other. A person who stops drinking while still taking a benzodiazepine may feel little, and a person who runs out of the benzodiazepine while drinking may not either, until both are gone at once.

The masking works in both directions. A benzodiazepine is, pharmacologically, the treatment for alcohol withdrawal, so someone taking one every day may cut down on drinking and notice nothing. Alcohol, in turn, blunts benzodiazepine withdrawal for the hours it is on board. What that produces is a person whose dependence is larger than either habit looks, and whose withdrawal arrives on whichever schedule the last drug to leave sets. StatPearls, the peer-reviewed clinical reference, makes two rules of this: when alcohol withdrawal is suspected, a concurrent sedative withdrawal must be ruled out, and physiologic dependence on benzodiazepines is one of the risk factors that takes a person off the list for managing withdrawal at home.

The second complication is kindling. The same reference notes that successive withdrawal episodes tend to increase in severity and lower the seizure threshold, and a person alternating between the two drugs can accumulate withdrawal episodes without ever recognizing them as such. The Librium and alcohol page describes the most common version of this, a prescribed benzodiazepine that was meant to help someone stop drinking and became a second dependence instead.

Source: Alcohol Withdrawal Syndrome, StatPearls, National Library of Medicine.

A combined detox is managed as one withdrawal: a long-acting benzodiazepine at a dose that covers both dependences, with the alcohol withdrawal carried through its peak under that cover. The benzodiazepine is then tapered on a schedule set by the person’s benzodiazepine history rather than the alcohol one.

Cross-tolerance is the reason this works. The American Academy of Family Physicians describes the pharmacologic treatment of alcohol withdrawal as medications that are cross-tolerant with alcohol, with benzodiazepines the agents of choice, given on a fixed schedule or in response to a withdrawal score.

The same drug that treats the alcohol withdrawal is the drug the person is dependent on, so a single long-acting benzodiazepine, diazepam or chlordiazepoxide most often, replaces both. The difference from an alcohol-only detox is what happens after day three. An alcohol-only taper is short. A person who was also dependent on a benzodiazepine cannot be tapered to zero in a week without the seizure risk the FDA’s warning describes, so the taper continues, usually past discharge with an outpatient prescriber, on the gradual, patient-specific schedule the FDA calls for. The benzodiazepine detox page describes that stay and the medications used in benzodiazepine detox page covers the drugs.

Source: Alcohol Withdrawal Syndrome, Bayard et al., American Family Physician, 2004.

Briarwood treats alcohol and benzodiazepine dependence as one withdrawal from the first assessment: a long-acting benzodiazepine covers both, the alcohol peak is carried under nursing observation, and thiamine and fluids are given from admission. The benzodiazepine sets the length of the stay and the taper that follows it.

The admission assessment asks about both drugs separately, because people rarely volunteer the second one: how much alcohol and for how long, which benzodiazepine, at what dose, prescribed or not, and what happened the last time either one stopped. That history decides the starting dose and how closely the first 72 hours are watched.

From there the stay follows the alcohol clock through its peak and then the benzodiazepine clock through the taper, with the outpatient prescriber and the step after detox arranged before discharge so the taper does not end at the door. Medically supervised alcohol detox and benzodiazepine detox describe each half; cost and insurance covers what a stay costs with and without coverage. Admissions is answered at every hour, and the first call is the right place to say that both drugs are in the picture, because the plan is different when they are.