A Series of Benzodiazepine Articles
by Liz Wood
1995
Liz Wood is the Midlands Co-ordinator for
VOT (Victims of Tranquillisers) in the UK
· Physiological · Psychological · Benzodiazepine Withdrawal Symptoms · List of Benzodiazepine Withdrawal Symptoms |
Psychology versus Physiology
It is often very difficult to tell how much of addiction is psychological and how much is physiological primarily because these drugs act on the brain and therefore affect the mind. The rule to follow, however, is that the psychological and physiological are interactive processes; they are interconnected.
Many GPs and psychiatrists unconsciously revert to the hypothesis that the mind affects the brain but not vice versa and that these two areas are in some way separate (therefore addiction is all in the mind). It is a school of thought called Cartesian Dualism by the philosopher René Descartes.
Of course, the mind, the way you think, affects the brain and affects your physiological activities. If it did not we wouldn't have freedom of choice and the ability to move about in our own environments successfully. However, there are constraints, physiological constraints. We can all daydream about stepping off the doorstop onto a tropical beach even when we are living in a big city but we know that our mind will not physically transport us there.
The same is true in addiction, no doubt the way that we think and what we are thinking has an effect upon our withdrawal experience positively or negatively to some extent, but it is a nonsense to suggest that some so-called neurotic individual is creating a whole range of physiological withdrawal affects simply by imagining that they are happening. One only has to look at the withdrawal in new born babies to see that this is a nonsense. A new-born baby has a very limited ability to affect itself psychologically but once it is separated from the placenta, the source of the drug, after the birth, it will suffer withdrawal symptoms. Some people will try to argue that it is picking up its mother's experience in the womb, but the fact of the matter is the baby will withdraw once it is separated from the source of the drug regardless of whether the mother was comfortable on a steady dosage and not experiencing withdrawal symptoms or was experiencing withdrawal symptoms during pregnancy and birth.
In the physiological section below I shall explain how benzodiazepines work biologically and why tapering the dosage is a logical method to use. In the psychological section I shall explain the effects of classical conditioning on addiction and withdrawal and its possible limitations.
Physiological
Biological mechanisms of action of benzodiazepines and withdrawal.
A receptor is a sensory nerve ending that changes specific stimuli into nerve impulses. It is an excitable cell that receives information.
All benzodiazepines bind to specific receptors and these receptors mediate an anti-anxiety effect. These receptors are found in the body and the brain with the highest concentration existing in the cerebral cortex.
Benzodiazepines have no direct effects after binding to their receptor sites, but they seem to increase the effect of the neurotransmitter GABA (a chemical by which a nerve cell communicates with another nerve cell) which diminishes the excitability of the cells reducing the excitability of the central nervous system. It is this inhibiting effect of benzodiazepines which is responsible for the reduction of anxiety, sedation and anticonvulsant actions.
Benzodiazepines exhibit the phenomenon of tolerance which depends upon adaptive changes in the receptor complex. The therapeutic effect of the drug or its biological action will decrease with time when the drug is taken on a regular basis and that is why patients will feel the need to either increase the dosage or put up with feeling unwell. These adaptive changes may also explain why in order to achieve a desired therapeutic effect dosage may vary from person to person.
As well as binding to receptors, benzodiazepines also bind to plasma proteins (plasma is a fluid portion of the blood or lymph in which the corpuscles and cells are suspended) and possibly of tissue proteins as well. For a given dose of benzodiazepines the blood plasma levels for different individuals can vary enormously.
The duration of action of benzodiazepines will be determined by its rate of elimination from the body. The rate tends to determine both the rapidity of onset of action and the duration of action. However when certain benzodiazepines are metabolised (broken down) within the system they are broken down into active metabolites like oxazepam or temazepam which are also available as prescription drugs. (A doctor prescribing diazepam is in effect prescribing a cocktail of drugs and this underlines how unscientific it is for some doctors to prescribe both oxazepam and temazepam together or certain other combinations simultaneously.) As far as the elimination rate is concerned, it is the most slowly cleared active metabolite that determines the rate and not the drug itself.
Some researchers claim that there is a significant inverse relationship between plasma benzodiazepine levels and severity of withdrawal symptoms. There are two reasons for this decrease: the amount that you cut down and the elimination half life. If the half life is long as it is in diazepam then the drug will remain within the system longer and withdrawal symptoms will be spread over a longer period of time easing the severity. If the drug is also cut down slowly the withdrawal symptoms may be less painful. However, a clear inverse relationship is not always seen in patients because neuroadaption (where changes occur at the benzodiazepine receptor) seem to play a very significant role. In this case the receptor and neurotransmitters etcetera, do not recover at the rate that the drug is eliminated from the system and withdrawal may go on for much longer than would be otherwise expected. This would explain why someone who has been withdrawing continually over a long period of time has symptoms that become more and more severe as time progresses and may have to pause for a rest period before cutting down any further amounts of the drug. After a period of rest from reduction and on restarting reducing again it may be possible to see a clear pattern of withdrawal emerge for a while. I found when reducing lorazepam an increase of symptoms would occur on the third day and taper away to nothing on the tenth day. However, if I continued to try to reduce a small amount every ten days after a period of time the withdrawals would become more and more prolonged until they were continual and severe and I would have to take a rest from reduction for a while.
Neuroadaption in tranquilliser addiction is primarily a physical occurrence with a physiological input - the tranquilliser in question. However there is also a psychological component in recovery and neuroadaption must be considered within both contexts psychological and physiological.
It will take the body time to recover from a continual input of a particular chemical as it will need to start producing its own natural tranquillisers once again amongst other things. However, regardless of the reasons why a person is given a tranquilliser either for psychological or physiological reasons, the psychological impact of addiction due to physical changes in the brain is enormous. As the physiological changes and symptoms of withdrawal occur, the addictive brain will colour the perception of that person's environment and his everyday experiences producing habits or behaviour patterns that may be difficult to change even once this person is drug free. It is also possible that these experiences cause neuronal changes which are physical as will be dealt with in biological mechanisms of memory. This is why recovery from addiction should be viewed as a five-fold one: physical, mental (intellectual), sociological, emotional and spiritual.
There are four phases of addiction and withdrawal:-
Tolerance withdrawals
As neuroadaption increases and the drug loses its therapeutic effect those withdrawals begin to occur. This can happen within one week of a normal dosage depending on the individual.
Detoxification
Withdrawal occurs as the drug is eliminated from the system until body levels reach a minimum of a few per cent.
Full blown withdrawals
These occur once the drug is at a minimum and the length of withdrawal varies widely from drug to drug and from person to person.
Recovery
No hard and fast rules to the length of withdrawal as neuroadaption has a psychological and physiological component. Again the emphasis is on the interactive process. The reason for prescribing may be physical or psychological. Once the drug is taken physical changes occur in the brain which affect the mind and therefore the psychology of the patient.
The World Health Organisation states that psychological craving must not be considered in isolation and only in the context of physiological changes caused by the drug.
Sometimes when people have withdrawn from benzodiazepines they find that the original problem re-emerges. This is not always the case, however. Often after many years of addiction the original problem for prescribing the drug in the first place has been resolved years before and is no longer of any relevance. This does not mean however that a person will not suffer long term physical and psychological withdrawal after stopping the tablets. These may occur because:
It takes the benzodiazepines receptor complex a long time to recover.
The psychological trauma of addiction has created learned behavioural responses that need to be changed.
Psychological
An important psychological area that affects addicts in withdrawal is called classical conditioning or associative learning. A Russian scientist [Pavlov] was the first to document this phenomenon. He studied salivation which is a reflex response given in the mouth to the presence of food and he decided to see if a dog could make an association between the ringing of a bell and the possibility of food. In order to do this he paired the sound of a bell with receiving food. Eventually the dog associated the sound of the bell with food to such an extent that it would salivate at the sound of a bell alone.
The implication of classical conditioning in addiction is straightforward: once you have associated the little blue or yellow tablet with a bad physical experience due to its chemically addictive properties you will set up an expectation of withdrawal anxiety every time you try to reduce, adding to the misery of the physiological withdrawals. Also, there will have been, initially, an association with the drugs therapeutic effects, regardless of the reasons why you were prescribed them so that you may begin to associate taking the drug with being able to relax rather than using your own innate ability to relax. A possible biological mechanism for this could be due to a form of neuroadaption or biological mechanism of memory.
A synapse is the point at which a nerve impulse is relayed from the terminal portion of an axon (a long extension of a nerve cell that conducts impulses from the cell body) to the dendrites (short extensions of a nerve cell which conducts nerve impulses towards the cell body) of an adjacent neuron (nerve cell).
It may be that the formation of new synaptic connections or improved connections of existing synapses between neurons may be involved in the process of learning and memory.
A psychologist, Donald Hebb, proposed that existing synapses within a neural circuit will change the efficiency of the activated synapses in the circuit so forming a 'memory trace' of information.
This point could be illustrated through classical conditioning:
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Neuron A is involved in salivation. There are two neural pathways (axons) X and Y converging on the neuron A. X is a strong pathway from the olfactory system that responds to the smell of food and always activates the neuron A. Y is a weaker pathway from the auditory system that responds to the sound of a bell but rarely activates neuron A. If X and Y are activated together the activation of A by X sends a retrograde signal to Y which strengthens the synaptic connection between A and Y. The neuron A will have learned to become responsive to Y as well as X and Y will have learned how to activate A more efficiently. So that an association between X and Y and been 'learned' by neuron A and the sound of a bell would produce salivation.
X is the strong pathway that responds to the olfactory system. Y is a weak pathway from the auditory system. A is a neuron involved in salivation.
This is a very simplified model of learning. However, there is some evidence that learning creates structural changes in the nervous system: the synapse contains little vesicles that contain neurotransmitters and massive changes in the number of synaptic vesicles in synapses have been recorded in animal learning experiments. This may all seem very complicated and involved but the point of it is to give some idea of how experience can affect a person physically and how habits can be formed by neural pathways in the brain. We do have some conscious control over these pathways. It may not always seem easy but habits can be broken by using our minds to consciously control the habit and that by doing this we are no longer activating that particular neural pathway or pathways and therefore no longer activating these synapses. We may not be able to erase these pathways completely once they are formed, we may be merely 'holding down' the old pathways with new ones which would explain why old habits can be easily reformed again if we are not vigilant. However by consciously controlling our actions we are able to change our ways to some extent.
Stopping benzodiazepines effectively relieves the physical withdrawals and the conditioning associated with taking the tablets. However, memory often plays an irritating role in reminding us that benzodiazepines once tranquillised us and stopped horrible withdrawal symptoms. Sometimes when we are off tablets memory can trigger off certain problems as we are reminded of what it used to be like when we were on the drugs and we need to have a tremendous amount of conscious control over our feelings. Sometimes recovery from benzodiazepine addiction can take a long time because of learned behavioural responses during physical withdrawals. There are a number of people who develop agoraphobia whilst they are on benzodiazepines and continue to have this very disabling problem for years after coming off them. This may be because of neural damage. On the other hand, it may be that the original phobia that was triggered by withdrawals has become a learned response and a frustrating habit that needs to be broken and would respond to behaviour therapy.
The psychological fear associated with drug withdrawal can be helped by the placebo method. In order to overcome this, the doctor withdraws the patient in hospital from the real drug over a period of a few weeks and then substitutes it for a substance that looks like the real drug but has no pharmacological effect as it does not contain any molecules of the original substance. If this method is used correctly with a sensible reduction of the real drug initially and then a substitution of the real drug with placebo without the patients knowledge it can help with the psychological strain of a physical withdrawal.
However there are limitations to all of this and doctors should not believe that the placebo effect is all that occurs in benzodiazepine withdrawal and that withdrawal is all in the mind and therefore that the placebo-controlled method is all that is studied (Pecknold et al, 1991). There were three groups of people involved in this trial. The first group A were given short term treatment with diazepam. The second group B were given a short term treatment with a non-addictive tranquilliser Buspirone and the third group C were given placebo. The results of this trial showed that after group A discontinued diazepam their symptoms increased whereas both groups B and C had no increase of symptoms.
The moral of the tale is that benzodiazepine withdrawal symptoms are not all in the mind.
My own experience in hospital also illustrates that associative learning can have a limited effect in drug withdrawal. When I was taking lorazepam on a daily basis I was in a strict regime of taking it by the clock as I believe it gave me control of my reduction programme. If I took the tablet about 20 minutes out of the appointed time I would suffer from withdrawals unless I cleverly adjusted the time to compensate. When I went into hospital I was told that this clock watching was purely a conditioned response: a l earned habit of associating the time with the need for a tablet. I was told that if I could break these habits by substituting lorazepam with diazepam by taking the diazepam at differing times to which I was taking lorazepam I would be over the worst part of the withdrawal. As it happened this substitution and so-called breaking of clock watching was by far the easiest part of the withdrawal. In fact I quite enjoyed disappearing into a nebulous cloud of long-acting drug induced relaxation after years of struggling with the short-acting lorazepam. This experience would suggest that the effects of the metabolic half life of the tablets is over and above the possible conditioning effects of clock watching to take tablets. Almost from day one of the withdrawal programme the irritating habit of taking the tablet by an alarm became like a long forgotten dream.
In conclusion, doctors like all of us to tend to compartmentalise, as it is very difficult to work within a framework of many possible variables rather than just one. When a withdrawal programme is introduced it is best to take an interactive approach rather than trying to quantify which bits of withdrawal are psychological and which bits are physiological.
The possibility of withdrawal falling into the expected pharmacokinetic patterns is small if a short acting drug is substituted with a long acting one, or the withdrawal programme is started when the patient hasn't cut down tablets for many months and whose tolerance is high, or a further therapy like five point ear acupuncture is introduced. If all these variables occur together the possibility of a clear pattern emerging is even smaller.
Therefore, if the pattern does not emerge as expected, it does not mean that the patient is not experiencing physical or pharmacological withdrawals. It does not mean that the anxiety or the original problem is returning.
If you are a researcher, of course, you are aware of these variables and ensure that the trials are properly controlled. If you are a doctor, merely treating a patient, it is best not to jump to conclusions unless you are involved in a proper double blind placebo-controlled trial situation.
Benzodiazepine Withdrawal Symptoms
