Did you know that you could be experiencing the benzodiazepine withdrawal syndrome even if you’re not decreasing your dose? This is the tolerance or “tolerance withdrawal” phenomenon, and it is often how people figure out that their benzodiazepine is making them sick in the first place. Put simply, as soon as a person initiates taking a drug, the body and brain are working to overcome, or work around, the drug’s effects (also known as neuroadaptations). This is how tolerance to a drug develops.

With benzodiazepines (BZs), specifically, when the receptors in the brain become adapted or accustomed to the action of the original dose of BZ, more of the drug is needed in order for the desired therapeutic effect (or the original effect at the original dose) to be achieved. This often develops with regular (long-term, past the 2-4 week recommended guideline for use) use and is known as tolerance.

Receptor down-regulation from the repeated and long-term (past 2-4 weeks) exposure to benzodiazepines is one theory on why tolerance develops. Another is receptor uncoupling, also known as decoupling, which is the process of receptor-binding sites or domains becoming separated, moving alignments and/or becoming internalized resulting in drug tolerance from prolonged exposure to benzodiazepines.

Tolerance is the reason why many medical prescribers often increase a patient’s prescribed dose over time. Sometimes they even add another BZ and some patients have ended up taking two (or more) BZs at once! Of course, then, eventually, the body then becomes tolerant on the new, higher dose and the cycle repeats

Tolerance to the various actions of BZs develops at variable rates and to different degrees. Tolerance to the hypnotic (sleep-inducing) effects develops rapidly, where daytime users of the drugs for anxiety no longer feel sleepy after a few days. An example of tolerance to the sedative effects: An anesthesiologist reported that in pre-op with an elderly patient, who had been taking moderate-high dose prescribed BZs for over a decade, was given a ‘standard’ dose of premedicant BZ (e.g., Versed) for her age and weight, and he was shocked to see her still sitting up in the bed! She was so tolerant the BZs after her long-term, higher-dose use that the premedicant didn’t have the desired and typical effect and the patient had to be administered more.

Tolerance to the anxiolytic effects develops more gradually, but there is little evidence that BZs retain their effectiveness after a few months. In fact, long-term BZ use may even exacerbate anxiety disorders, or worse, create newer, worse ones while on the drug or suffering the withdrawal syndrome of it.

See: Alprazolam-induced Panic Disorder

Many patients find that anxiety symptoms gradually increase over the years despite continuous BZ use, and panic attacks and agoraphobia may appear for the first time. Some long-term BZ patients report more severe anxiety than they’ve ever had, even before taking the BZ. Some individuals never had anxiety prior, as they were prescribed the BZ for a physical condition as opposed to a psychological one, and they develop it during tolerance withdrawal for the first time, after years of chronic BZ prescription. These worsening of symptoms are most likely due to ‘tolerance withdrawal’ because when the original dose of the drug starts to have less effect, individuals can start to experience withdrawal symptoms while still taking their BZ. Interdose withdrawal (discussed below) may also a sign that tolerance to the BZ is developing. However, tolerance may be partial and some chronic users still report some continued efficacy of the drugs.

Tolerance to the anticonvulsant effects of benzodiazepines makes them generally unsuitable for long-term control of epilepsy. Tolerance to the motor effects of benzodiazepines can develop to a remarkable degree so that people on very large doses may be able to ride a bicycle and play ball games.

Tolerance doesn’t only occur with BZs – it’s a phenomenon that develops with many chronically used medications where the body responds to the continued presence of the drug with a series of adjustments that tend to overcome the drug effects. In the case of BZs specifically, what happens is: compensatory changes occur in the GABA and benzodiazepine receptors which become less responsive so that the inhibitory actions of GABA and benzodiazepines are decreased. At the same time, there are changes in the secondary systems controlled by GABA so that the activity of excitatory neurotransmitters tends to be restored. Tolerance to different effects of benzodiazepines may vary between individuals – perhaps as a result of differences in intrinsic neurological and chemical make-up. The development of tolerance is one of the reasons people become dependent on benzodiazepines, and also may be the precursor for the withdrawal syndrome.

The following video is a short (2:19) discussion of benzodiazepine tolerance and interdose withdrawal:

Click on CC for captions in English.

Sources: – Ashton Manual

Medscape: Alprazolam-Induced Panic Disorder


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