What Are Paradoxical Reactions to Benzodiazepines, and Why Do Symptoms Get Worse During a Taper?

What is a paradoxical reaction to a benzodiazepine?

A paradoxical reaction is the opposite of what the medication is supposed to do. A benzodiazepine is prescribed to calm anxiety, relax muscles, and bring on sleep. In a paradoxical reaction, the person who takes it becomes agitated, sleepless, or aggressive.

Professor C. Heather Ashton described the reaction in Chapter I of the Ashton Manual. Benzodiazepines, she wrote, “occasionally cause paradoxical excitement with increased anxiety, insomnia, nightmares, hallucinations at the onset of sleep, irritability, hyperactive or aggressive behaviour.” She wrote that these reactions are most frequent in “anxious and aggressive individuals,” in children, and in older adults.

The word to notice is “occasionally.” The dramatic form is not a common event. In the same passage, Professor Ashton wrote that milder increases in irritability and argumentativeness are “much more common,” and that patients and their families often notice them. She suggested that these reactions may come from the release of behavior that is normally held back by social restraint.

A paradoxical reaction is an effect of the drug while the drug is being taken. It is not a withdrawal symptom. So, why does the term come up so often among people who are lowering their dose?

A paradoxical reaction happens on the drug. Withdrawal happens as the drug leaves.

The two are confused because they look alike. Table 1 in Chapter III of the Manual lists the symptoms of benzodiazepine withdrawal, and that list includes insomnia, nightmares, increased anxiety, panic attacks, excitability, rage, aggression, and irritability. Nearly every word on the paradoxical list appears there as well.

What separates them is timing. A paradoxical reaction follows the dose, and it appears while the medication is at work in the body. Withdrawal follows the absence of the medication, and it appears as a dose wears off or in the days after a reduction.

Unfortunately, worsening symptoms are easy to misread from the outside. A family member may decide that the original anxiety has returned, and a clinician who is not familiar with tapering may decide that the patient simply wants more medication. Often, neither is what is happening.

Physical dependence is not addiction. In fact, it is the expected result of taking a benzodiazepine regularly. The United States Food and Drug Administration (FDA) stated in its 2020 boxed-warning update that physical dependence can occur after several days to weeks of steady use, even as prescribed.

Why do symptoms get worse when the dose is going down?

Because that is what withdrawal is. Benzodiazepines strengthen the effect of gamma-aminobutyric acid (GABA), the brain’s main calming signal. Chapter I explains that with regular use, the receptors that carry this signal become less responsive, so the calming effect of both GABA and the medication is reduced.

When the dose comes down, less medication meets a nervous system that has adapted to having it. Professor Ashton wrote in Chapter III that withdrawal reactions “tend to consist of a mirror image of the drugs’ initial effects.” Sleep is replaced by insomnia, calm by anxiety, and relaxed muscles by tension.

A benzodiazepine works like a foot on the brake of a car. Over months, the nervous system compensates by pressing harder on the accelerator, so the car keeps its usual speed. If the foot comes off the brake quickly, the car surges forward. So, the foot comes off the brake slowly.

More anxiety and less sleep after a dose reduction is not a paradox. It is the expected course, and it is information about the pace, which is planned with the prescriber.

The delay can mislead as well. Table 1 in Chapter I gives alprazolam (Xanax) a half-life of 6 to 12 hours and diazepam (Valium) a half-life of 20 to 100 hours, with an active metabolite that lasts longer still. With a short-acting drug, symptoms can begin within hours to a day or two of a reduction. With a long-acting drug, they may not show for several days, so a hard week can be the late result of a cut that seemed to go well.

Why can symptoms rise on a steady dose, or between doses?

Two patterns explain most of it, and neither one involves a reduction.

The first is tolerance withdrawal. Chapter I notes that many patients find their anxiety symptoms gradually increasing over the years despite continuous benzodiazepine use. Professor Ashton wrote that this is probably due to tolerance, so that withdrawal symptoms “emerge even in the continued presence of the drugs.” She noted that tolerance has often led doctors to raise the dose or to add a second benzodiazepine.

The second is interdose withdrawal. A short-acting benzodiazepine is cleared quickly, and its level in the blood rises and falls between doses. Chapter II describes many people who take alprazolam or lorazepam (Ativan) feeling a “mini-withdrawal” between each dose. This is one reason the Manual describes a crossover to diazepam for some patients, because its slow elimination allows a smoother fall in the blood level.

To the person living through either pattern, the medication seems to be causing the very symptoms it was prescribed to treat. That feels like a paradox. It is tolerance, and it is a recognized part of physical dependence.

Why do good days and bad days alternate?

Withdrawal does not move in a straight line. In Chapter III, Professor Ashton wrote that symptoms “characteristically wax and wane, varying in severity and type from day to day, week to week, and even during the course of a day.” She described “Windows” of normality, lasting a few hours or days, that appear after some weeks and gradually become more frequent and last longer. Patients call the hard stretches between them waves.

A wave that arrives after two good weeks can feel like proof that something has gone wrong. Usually, it is the ordinary shape of a nervous system that is readjusting.

What about kindling? Kindling is the name for a pattern in which repeated rounds of stopping suddenly and starting again seem to make each withdrawal harder than the last. The Ashton Manual does not use the word, and the evidence for it with benzodiazepines is limited. Still, it may explain why a person with several abrupt stops in the past reacts strongly to a small reduction.

What should a patient do when symptoms seem to contradict expectations?

The first step is to tell the prescriber, and to bring the timing. Did the symptom begin with a new prescription or a dose increase? Is it worse just before the next dose is due? Did it start in the days after a reduction? Those answers separate a drug effect from withdrawal better than any label does.

During a taper, one response to rising symptoms is a short hold at the current dose and then smaller steps, though everybody is different, and some patients do better continuing at a steady pace than waiting out a long hold, so the change is planned with the prescriber and the medication is never stopped suddenly. Chapter II suggests reductions of up to one tenth of the dose at each step, and it tells the reader, “you must be in control and must proceed at the pace that is comfortable for you.” The Maudsley Deprescribing Guidelines describe hyperbolic tapering, in which the reductions become smaller as the dose gets lower.

Professor Ashton advised staying at the same dose for a few weeks at a difficult point, and trying to avoid going back up. In Dr. Mark Leeds’ practice, a small updose after a cut that proves too large is also a legitimate choice.

What a patient should not do is stop the medication suddenly. The FDA warns that stopping a benzodiazepine abruptly, or reducing the dose too quickly, can cause withdrawal reactions, including seizures, which can be life-threatening. That holds even when the medication itself seems to be the cause, and a suspected paradoxical reaction is a reason to call the prescriber the same day.

Call 911 for a seizure or any other medical emergency, and call or text 988, the Suicide and Crisis Lifeline, if agitation or sleeplessness turns into thoughts of self-harm.

Worse symptoms on less medication do not mean the taper has failed.

Feeling worse while taking less can make a person doubt the whole plan. Fortunately, in most cases it points to something that can be changed, which is the pace. With the right pace for that person, a short hold or smaller steps for some and a steady pace for others, and with time, the nervous system can catch up.

Dr. Leeds is an osteopathic physician and deprescribing specialist in Fort Lauderdale, Florida, and his practice offers medically supervised benzodiazepine and z-drug tapering for patients in Florida. Each taper is gradual, lasts months and sometimes longer, and moves at a pace the patient directs. Contact the office to ask about a medically supervised taper.

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.