Interdose Withdrawal: The Rollercoaster of Benzodiazepine Dependence

What is interdose withdrawal?

Interdose withdrawal is benzodiazepine withdrawal that arrives between doses, while the medication is still being taken every day and on time. The anxiety, the shakiness, or the pounding heart builds as one dose wears off and settles after the next one is taken. No tablet has been missed, and nothing has been reduced.

The Ashton Manual, written by Professor C. Heather Ashton, describes it in Chapter II as a “mini-withdrawal” that many people feel between each dose of a short-acting benzodiazepine. Its first chapter lists anxiety symptoms between doses among the usual features of people who have become dependent on ordinary prescribed doses.

To a family member, a person watching the clock for the next tablet can look like someone who wants a drug. That is not what is happening. Physical dependence is not addiction. In fact, what the person feels comes from a nervous system that has adapted to a medication and is running short of it for a few hours at a time.

So, why would a medication taken exactly on schedule run short before the next dose is due?

Why does it happen with Xanax and Ativan more than with Valium?

The answer starts with half-life, the time the blood level takes to fall to half its peak after a single dose. Table 1 in the Manual’s first chapter lists 6 to 12 hours for alprazolam (Xanax) and 10 to 20 hours for lorazepam (Ativan). Diazepam (Valium) is listed at 20 to 100 hours, and its active metabolite, the compound the body converts it into, at 36 to 200 hours.

A drug that clears quickly has to be taken several times a day, and Chapter II says its concentration fluctuates with peaks and troughs between each dose. That is the rollercoaster in the title. The blood level climbs after each tablet, crests, and drops toward the next one, several times a day. Another article compares short-acting and long-acting benzodiazepines in more detail.

Yet, half-life alone does not explain it. Benzodiazepines boost the calming signal of gamma-aminobutyric acid (GABA), and the Manual explains that with continued use the receptors that carry that signal become less responsive. A trough that once passed unnoticed now falls below what the adapted nervous system needs. A separate article covers what happens in the brain during benzodiazepine withdrawal.

The pattern can be read off a clock. A person who takes alprazolam at 8 in the morning, 4 in the afternoon, and midnight may start to feel it around noon, 8 in the evening, and 4 in the morning, as the level falls, and the trough, with the worst of it, comes just before the next tablet is due.

The Manual lists clonazepam (Klonopin) at 18 to 50 hours and notes that it is eliminated much faster than diazepam. Some people who take it once or twice a day describe the same pattern late in the interval. The Maudsley Deprescribing Guidelines add that a short-acting sleeping pill taken only at bedtime can leave a person anxious the following day.

What does interdose withdrawal feel like?

Patients often describe a rising unease a few hours after a dose, followed by inner trembling, a racing heart, sweating, tight muscles, and a short temper. Many wake in the small hours with dread or panic, long after the bedtime dose has worn off.

The signature is the timing. Ordinary anxiety rarely keeps a timetable. These symptoms follow the dosing schedule, not the events of the day, and they ease soon after the next dose.

People begin to plan the day around tablets. Many carry them wherever they go, a habit the Manual’s first chapter also lists. A written note of dose times and symptom times, kept for a week or two, makes the pattern plain, and it is worth bringing to the prescriber.

Unfortunately, it is usually mistaken for anxiety getting worse.

Anxiety that returns every afternoon looks like an anxiety disorder that the medication no longer covers. The Maudsley Deprescribing Guidelines warn that withdrawal symptoms during steady treatment, if not recognized, give the impression that the original condition has worsened, which leads to higher doses or added medications. The first chapter of the Ashton Manual records the same result. Tolerance, it says, has often led doctors to increase the dosage or to add another benzodiazepine.

Does a higher dose help? Briefly, yes. The peaks rise, the troughs rise with them, and for a while the afternoons are quiet. Then the nervous system adapts to the new level, and the troughs fall short again, from a greater height.

And, each increase leaves more medication to taper later. Meanwhile, the person has been told that the anxiety is progressing, and may come to believe it.

The opposite mistake is just as common. Some people, alarmed at how much they need the next dose, stretch the hours between tablets, skip one, or stop outright. That only deepens the trough.

The United States Food and Drug Administration (FDA) warned in its 2020 boxed warning update that stopping a benzodiazepine abruptly, or reducing the dose too quickly, can cause withdrawal reactions, including seizures, that can be life-threatening. Call 911 for a seizure or any other medical emergency.

How is interdose withdrawal different from tolerance withdrawal?

The two overlap. Tolerance withdrawal is the broader condition, in which symptoms appear on an unchanged dose because the drug has lost much of its effect. Interdose withdrawal is the form that follows the clock. The Maudsley Deprescribing Guidelines describe tolerance withdrawal as most often seen with short-acting benzodiazepines, where it is often observed as interdose withdrawal.

The difference matters when choosing a remedy. Symptoms that rise and fall with the doses can often be eased by smoothing the blood level. However, symptoms that last all day, even on a long-acting drug such as diazepam, point to tolerance itself, and those call for a slow taper and time.

Fortunately, the first remedy is a steadier blood level.

At this stage, the daily amount stays where it is. The Maudsley Deprescribing Guidelines give two options when interdose symptoms are present before a taper begins. The first is to take the same medication more frequently. The second is to substitute an equivalent dose of a long-acting benzodiazepine, such as diazepam, through a stepwise crossover.

More frequent dosing means the same daily total, divided into smaller doses taken closer together and at fixed times. The peaks are lower, the troughs are shallower, and the nervous system gets a level it can count on. Because this changes how the prescription is written, it is worked out with the prescriber first.

Dr. Mark Leeds, an osteopathic physician and deprescribing specialist in Fort Lauderdale, Florida, treats this stabilization as the first step of care. A taper begun in the middle of a rollercoaster is hard to read, because nobody can tell a reduction symptom from an ordinary trough.

How does a crossover taper to diazepam flatten the ride?

For people coming off potent, short-acting benzodiazepines, Chapter II of the Ashton Manual advises a switch to diazepam. Its slow elimination, Professor Ashton wrote, allows a smooth, gradual fall in blood level. One dose overlaps the next, and the hills flatten into a long, shallow slope.

The switch is not made all at once. The Manual substitutes one dose at a time, usually starting with the evening or night-time dose, and replaces the others one by one at intervals of a few days or a week. At ordinary doses, it sees no need to aim for a reduction during the changeover. From high doses, its example schedules begin some reductions while the switch is still under way.

Professor Ashton also warned that many people have suffered from being switched suddenly to a different, less potent drug at an inadequate dose. The equivalent doses in her Table 1 are approximate and differ between individuals. So, the right amount is found one dose at a time.

This is a framework, not a schedule, and the numbers belong to one patient and one prescriber. A longer article explains why the Ashton Manual recommends switching to diazepam.

While Dr. Leeds uses the crossover where it helps, it is offered, not imposed. The Maudsley Deprescribing Guidelines note that some people find switching difficult or prefer the drug they know. For them, a direct taper with more frequent doses remains an option.

The pace after that belongs to the patient.

Once the blood level is steady, the taper itself can begin. The Manual suggests reductions of up to one tenth of the dose at each step, and the Maudsley Deprescribing Guidelines describe hyperbolic tapering, in which the steps get smaller as the dose gets lower. If a step proves too large, the doctor must slow the taper. If it is going well, patient and doctor may agree to move a little faster, as tolerated.

Dr. Leeds’ practice focuses on medically supervised tapering of benzodiazepines and z-drugs for patients in Florida. It is a concierge practice, every patient sees Dr. Leeds at every visit, and the taper is gradual, patient directed, and measured in months, sometimes longer. A person whose days are run by the clock between doses usually needs a steadier level and a slow way down. Contact the office to ask about stabilizing first and tapering after.

This article is educational. It is not medical advice, and reading it does not create a doctor-patient relationship. Decisions about starting, continuing, or tapering any medication should be made with your own physician.