It’s interesting to have an explanation of what’s happening to us in Benzodiazepine withdrawal and I’ve chosen this one as it's reasonably explicit without over-blinding us with Science. It's quite long but I’m reluctant to leave anything out that may help understanding.
Benzodiazepines primary mode of action is on GABA (gamma-aminobutryic acid), the most common receptor in the nervous system. GABA is a neurotransmitter that is the cornerstone of the inhibitory (calming) system of the body, and controls the action of epinephrine, norepinephrine and dopamine. The main function of GABA is to prevent anxiety and stress-related messages from reaching the motor centers of the brain. They regulate excitability, including the seizure threshold. The brain must balance the excitatory and calming influences. Excessive excitation can lead to seizures, insomnia, anxiety and other clinical conditions; whereas excessive inhibition results in incoordination, sedation and anesthesia.
Benzodiazepines, barbiturates and alcohol all act on GABA, and chronic use down-regulates and modify the GABA receptors, which in turn causes dependence. With continued use of Benzodiazepines, the calming effect of GABA is diminished while the excitatory neurotransmitter Glutamate, is increased. Glutamate is always an excitatory neurotransmitter, and GABA is what counters this action. As GABA is initially enhanced by Benzodiazepines, the brain’s output of excitatory neurotransmitters, including Norepinephrine (noradrenalin), Serotonin, Acetyl Choline and Dopamine are reduced. These neurotransmitters are necessary for alertness, muscle tone, coordination, memory, emotional responses, endocrine gland hormones, heart rate, blood pressure control and other functions. As a result, all these may be impaired by Benzodiazepines.
Additional receptors for Benzodiazepines (non-GABA) are located in the colon, kidney, blood cells and adrenal cortex, and therefore may also be affected by Benzodiazepines. These actions are responsible for the well-known side effects and adverse reactions.
As the primary inhibitory neurotransmitter, GABA filters out irrelevant messages by terminating the excitatory glutamate, epinephrine and norepinephrine. GABA is viewed as the ‘braking system’ among neurotransmitters and it is estimated that about 40% of the synapses in the human brain work with GABA. GABA also enhances alpha wave production to promote relaxation and moderate occasional stress and supports immune health. It has been shown that T-cells (white blood cells critical to the immune system), are inhibited by GABA, and GABA has been shown to inhibit the response to foreign antigens. This suggests that the immune system needs GABA to function properly. This may explain why it is common to have frequent infections and a compromised immune system after long-term use of Benzodiazepines, or in the withdrawal process.
In situations of high stress or excitement, the brain responds with an increase in GABA production. Under normal situations, our levels of GABA are sufficient to maintain control of the excitatory stimuli. GABA’s high concentration in the hypothalamus suggests it plays a critical role in both hypothalamus and pituitary function. The hypothalamus is a region of the brain that is the regulating center for instinctive functions such as sleep cycles, body temperature, and the pituitary gland is the master endocrine gland affecting all hormone functions of the body.
The GABA receptor allows more chloride ions to enter the brain cell, thus working to maintain the electrical charge within the cells. Benzodiazepines work by increasing the effectiveness of GABA in the chloride opening so the chloride ion cells to allow more chloride to enter the nerves. Caffeine does the opposite and inhibits the property of GABA. Therefore Benzodiazepines work as a tranquilizer and caffeine as a stimulant. Benzodiazepines act as a booster to the actions of GABA, and allow more chloride ions to enter the neuron. This in turn makes the nerve more resistant to excitation.
The Calcium-Channel activity is also increased by Benzodiazepines. Calcium-channels are located in the central nervous system, but also are located in excitable cells including in the muscle, nerve cells and in the Glial cells that form myelin to protect the nerve endings, and provide support and protection for the brain’s nerve cells. There is roughly one Glial for every neuron in the gray matter of the brain. Prolonged use of benzodiazepines result in adaptation of the receptors that may increase in number and/or their sensitivity to GABA. A larger dose of the Benzodiazepine may be needed to produce the same calming effect. This phenomenon is known as ‘tolerance’. Additionally, upregulated Calcium Channels are linked to an increase in neuropathy pain. Withdrawal of the drug can result in the receptor becoming hypoactive, producing symptoms worse than what the patient originally sought treatment for. If Benzodiazepines are suddenly stopped or reduced too rapidly, the calcium floods into the cell. This can cause intense withdrawal symptoms and be life-threatening due to the seizure risk.
Additionally, prolonged exposure to Benzodiazepines measurably increase accumulation of intracellular calcium that over-excites the neurons and increases anxiety, muscle tension, insomnia and many other symptoms associated with tolerance and withdrawal.
When the GABA is no longer capable of opening the chloride ion channels, the cells become overly excited. This cellular hyper-excitability is responsible for the insomnia, irritability, tachycardia, hypertension, hallucinations and seizures from the abrupt cessation of long-term alcohol use and also benzodiazepines.
Alcohol has a similar effect to benzodiazepines, increasing the release of chloride back into the neurons. This is the major way in which alcohol affects the brain. Tolerance to alcohol and benzodiazepines is the receptor adapting to the drug by increasing the number of receptors so more of the drug is needed to have the effect. The receptors become hypoactive by the drug being withdrawn, which enhances the symptoms that the drug was intended to treat.
Benzodiazepine withdrawal is far more involved than alcohol, heroin, methamphetamine or even opiates. Yet 112.8 million prescriptions were filled in 2008, with the majority prescribed by primary care physicians. They remain among the most frequently recommended medication.
Benzodiazepines can be extremely habit-forming and long-term use is not recommended (longer than 14 consecutive days).
