Tolerance 

What is Tolerance?

Unlike standard withdrawal, which occurs following a reduction or cessation of a medication, or interdose withdrawal, which can occur between doses as drug levels fall, tolerance can develop while a person is still taking the same dose every day. Tolerance occurs when the body adapts to repeated exposure to a drug and its effects become less pronounced over time. This phenomenon occurs with many drugs and substances, including benzodiazepines.¹

In psychiatric medicine, tolerance is particularly well recognised with benzodiazepines. With continued exposure, the brain makes compensatory changes that can reduce its sensitivity to the drug's effects.

How Tolerance Can Develop

The Benzodiazepine Information Coalition explains that tolerance can develop "in as little as a few days to a few weeks as the body and brain neuro adapt or work to overcome the drug’s effects."² With regular benzodiazepine use, tolerance does not necessarily develop equally to every effect of the drug. For example, tolerance to the sedating and sleep-inducing effects can develop relatively quickly, while tolerance to the anti-anxiety effects may develop more gradually.²

This means that a person may initially experience significant relief from anxiety or insomnia but find that the same dose becomes less effective over time. In response, the dose may be increased or another benzodiazepine added.²

"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."² - BIC

Tolerance can also be incomplete. Some people continue to experience some benefit from a medication even after tolerance has developed. However, BIC notes that some of what feels like continued benefit may actually be the medication suppressing withdrawal symptoms that have emerged as physical dependence has developed.²

Long-term benzodiazepine use may also be associated with worsening anxiety in some patients. BIC describes reports of people developing increasing anxiety, panic attacks or agoraphobia with prolonged use.²

With repeated benzodiazepine exposure, the brain adapts to the drug's presence. BIC describes compensatory changes involving GABA and benzodiazepine receptors, which can make the brain less responsive to the drug's effects. These adaptations are one part of the process underlying tolerance and physical dependence.²

The FDA also distinguishes physical dependence from addiction: physical dependence is an adaptation to repeated drug exposure that can result in withdrawal when the medication is abruptly stopped or substantially reduced. The FDA warns that this can occur even when benzodiazepines are taken as prescribed.³

Signs of Tolerance 

Symptoms of tolerance can include:

Escalating anxiety and panic: intense anxiety, fear or a sense of impending doom that may feel very different from a person's previous anxiety.

Physical symptoms: restlessness, muscle tension, tremors, internal vibrations, burning or unusual sensory sensations and severe sleep disturbance.

Cognitive and emotional changes: problems with concentration or memory, emotional blunting, depersonalisation or derealisation.

Autonomic symptoms: palpitations, sweating, changes in blood pressure, digestive disturbances and difficulty regulating body temperature.

The Dangerous Escalation Cycle

Tolerance can contribute to a cycle where patients find themselves trapped on escalating doses of medication for years. 

When a patient goes to their GP or psychiatrist reporting severe anxiety, tremors, insomnia and physical pain while taking their medication, it can easily be misdiagnosed as a relapse of the original psychiatric. Believing that the patient's original anxiety is worsening, clinicians may increase the dose or add another benzodiazepine to the mix. (Learn more about the dangers of polydrugging)

The result: initially, a dose increase of medication or addition may mask the symptoms because it floods the receptors with more chemical braking power. But very quickly, the brain builds tolerance to that higher dose, plunging the patient right back into tolerance - only now at a higher, more entrenched chemical baseline. 2

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."² - BIC

References

1. National Institute for Health and Care Excellence. (2022). Medicines associated with dependence or withdrawal symptoms: Safe prescribing and withdrawal management for adults (NG215). NICE. NICE NG215. https://www.nice.org.uk/guidance/ng215

2. Benzodiazepine Information Coalition. (n.d.). Tolerance. Benzodiazepine Information Coalition. https://www.benzoinfo.com/

3. U.S. Food and Drug Administration. (2020, September 23). FDA requiring boxed warning updated to improve safe use of benzodiazepine drug class. FDA Drug Safety Communication. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class