Did you know that patients could be experiencing benzodiazepine withdrawal even if they’re not decreasing their dose? This phenomenon is known as “tolerance.” Tolerance may develop, for many, in as little as 2-4 weeks after a person initiates a benzodiazepine, as the body and brain neuro adapt or work to overcome the drug’s effects. The tolerance or “tolerance withdrawal” phenomenon is often how patients initially discover that their benzodiazepine is making them sick. Beyond anxiety, tolerance to the anticonvulsant effects of benzodiazepines makes them generally unsuitable for the long-term control of epilepsy.
Tolerance, As Explained in the Ashton Manual
Tolerance to the various effects of benzodiazepines develops with regular use. The initial dose of the benzodiazepine has progressively less effect, and a higher amount is required to obtain the original effect. In response, prescribers might either increase the dosage or add another benzodiazepine. Some patients even end up being prescribed two benzodiazepines at once.
Tolerance to the various actions of benzodiazepines develops at variable rates and to different degrees. Tolerance to the hypnotic (sleep) effects develops rapidly. While dreams are initially suppressed by benzodiazepines, with deep sleep increased, sleep recordings have shown that sleep patterns, after a few weeks, return to pre-treatment levels. Similarly, daytime users of the drugs for anxiety no longer feel sleepy after a few days. Tolerance to the anxiolytic effects develops more slowly. However, there is little evidence that benzodiazepines retain their effectiveness after a few months.
Long-term benzodiazepine use may even aggravate anxiety disorders. Many patients find that anxiety symptoms gradually increase over the years despite continuous benzodiazepine use, and panic attacks and agoraphobia may appear for the first time after chronic use. Development of or worsening symptoms during long-term benzodiazepine use is probably due to the development of tolerance to the anxiolytic effects. This makes “withdrawal” symptoms emerge even in the continued presence of benzodiazepines.
Tolerance may not be complete and chronic users sometimes report continued efficacy, but this may be partly due to the suppression of withdrawal effects. Many symptoms of increased anxiety gradually disappear after the successful tapering and withdrawal of benzodiazepines. Among the first 50 patients attending Dr. Heather Ashton’s clinic, ten patients became agoraphobic for the first time while taking benzodiazepines. She found that agoraphobic symptoms abated dramatically within a year of withdrawal, even in patients who had been housebound. None were incapacitated by agoraphobia at the time of follow-ups, which occurred between 10 months to 3.5 years after withdrawal.
Tolerance to the anticonvulsant effects of benzodiazepines makes them generally unsuitable for the long-term control of epilepsy. However, complete tolerance to the impact on memory and cognition does not seem to occur. Many studies show that these functions remain impaired in chronic users, recovering slowly, though sometimes incompletely, after withdrawal.
Tolerance is a phenomenon that develops with many chronically used drugs (including alcohol, heroin, morphine, and cannabis). The body responds to the continued presence of the drug with a series of adjustments that tend to overcome the drug’s effects. For benzodiazepines, compensatory changes occur in the GABA and benzodiazepine receptors, making the receptors less responsive. These changes make the inhibitory actions of GABA and benzodiazepines decrease. For unknown reasons, tolerance to different effects of benzodiazepines varies between individuals. The development of tolerance is one of the reasons people become physically dependent on benzodiazepines, and it also sets the scene for withdrawal syndromes.
Why Does Tolerance Occur?
There are a few hypotheses on why tolerance develops. One is receptor down-regulation from repeated and long-term exposure (more than 2-4 weeks) to benzodiazepines. Another is receptor uncoupling, also known as decoupling. Receptor uncoupling is the process of receptor-binding sites or domains becoming separated, moving alignments, and/or becoming internalized, resulting in medication tolerance from prolonged exposure to benzodiazepines. Compensatory changes occur in the GABA and benzodiazepine receptors. As they become less responsive, the inhibitory actions of GABA and benzodiazepines decrease. At the same time, changes in systems controlled by GABA increase the activity of excitatory neurotransmitters.
Tolerance is why many medical prescribers often increase a patient’s prescribed dose over time. Sometimes they even add another benzodiazepine, and some patients are prescribed two (or more) at once. Of course, the body inevitably becomes tolerant to the new dose or second benzodiazepine, and the cycle repeats.
Tolerance to the various actions of benzodiazepines develops at variable rates and to different degrees. Tolerance to the hypnotic (sleep-inducing) effects can develop rapidly, where daytime users of the drugs for anxiety no longer feel sleepy after a few days. As an example of tolerance to the sedative effects: An anesthesiologist reported that in pre-op with an elderly patient, one who had been taking moderate-high doses of prescribed benzodiazepines for over a decade, was given a ‘standard’ dose of pre-surgery benzodiazepine (e.g., Versed) for her age and weight, and he was shocked to see her still sitting up in the bed. She had become so tolerant to benzodiazepines that the pre-surgery dose didn’t have the desired effect, so the patient was administered more.
There is little evidence that benzodiazepines retain their effectiveness after a few months. In fact, because of tolerance, long-term benzodiazepine use may even exacerbate or worsen anxiety disorders while on the drug or during withdrawal.
Many patients find that anxiety symptoms gradually increase over the years despite continuous benzodiazepine use; panic attacks and agoraphobia may appear for the first time. Some long-term benzodiazepine patients report severe, worsening anxiety. Some individuals prescribed a benzodiazepine for a physical condition with no previous clinically significant anxiety develop new severe anxiety during tolerance withdrawal for the first time. Interdose withdrawal (discussed below) may also be a sign that tolerance to benzodiazepines is developing. However, for some patients, tolerance may also be absent or partial, and some chronic users still report some continued efficacy of the drugs. The development of tolerance is one of the reasons people become physically dependent on benzodiazepines, and also may be the precursor for the withdrawal syndrome.
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