Patients using benzodiazepines drugs to induce sleep develop tolerance to the drug much faster compared to patients who use it for as anxiolytic. While those who use it as muscle-relaxant and anticonvulsant take few weeks to develop tolerance.
Tolerance comes about as a result of the GABA receptors desensitization while the excitatory neurotransmitter system (glutamate like the NMDA glutamate receptors) becomes more sensitized. This results from the body’s normal homeostasis process overriding or overcoming the effects of the benzodiazepine drug, it also leads to a reduction in the amount of GABA receptors and in the long run, it leads to gene transcription coding of brain cells.
The variance in the speed at which tolerance is occurring to the effects of the benzodiazepine drugs, is explained by the speed of change that chronic use of benzodiazepine drug is altering the range of the neurotransmitter subsystems. In essence, the neurotransmitters systems and its subsystems could reverse tolerance at difference levels of speed. This explains the extended nature of some certain withdrawal symptoms.
Resulting from physical dependence that comes from being tolerant to the benzo drug, the patient will experience the benzodiazepine withdrawal syndrome which comes about after the patient restrains from using the drug anymore. It has also been observed that patients already taking the benzodiazepine drug show reduced sensitivity when further additional dosage of the benzodiazepine drug is increased.
To demonstrate that a patient has become tolerant to the benzodiazepine drug, they are injected with diazepam and a very blunt reaction will be observed. In contrast to this, a patient who has not been using this drug will show drastic increase in growth hormones should s/he be injected with diazepam.
Studies conducted on lab animals have shown that repeated withdrawals from the benzo drug will make the patient experience more severe withdrawal symptoms in every withdrawal attempt. This is known as kindling, which was established from studies on patients withdrawing from alcohol addiction. Alcohol and benzodiazepine drugs have similar withdrawal and tolerance mechanism, all involving the NMDA, AMPA and the GABAA receptors.
The term cross tolerances refers to the action of one drug alleviating the withdrawal effects of another drug. Benzodiazepines have similar actions with certain sedative compounds that have the same effect of enhancing GABAA receptors. This also means that when a patient develops tolerance for one type of drug, s/he will also develop tolerance to “similarly-acting” drug.
The cross tolerance characteristic of benzodiazepine makes them the best substance to detoxify alcoholic patients, and has proved to be quite reliable even in the most severe and life threatening alcohol withdrawal syndromes like the delirium tremens. However benzodiazepine drug also act as positive reinforce to the alcoholics by increasing their desire to take alcohol.