Posted 19 April 2011 - 05:37 PM
In the 2011 Ashton Manual Supplement Prof. Ashton attempts to answer these frequently asked questions about benzodiazepine withdrawal, quoted in part below:
Permanent brain damage?
...Many long-term benzodiazepine users who have stopped taking the drugs complain of a variety of seemingly irreversible psychological and/or physical symptoms which they attribute to permanent brain damage caused by the drugs. However, the question of whether benzodiazepines cause brain damage is still unsolved. ....CAT scan studies in 1987, 1993, and 2000 failed to find any consistent abnormalities in long-term benzodiazepine users, and concluded that benzodiazepines do not cause structural brain damage, e.g death of neurones, brain shrinkage or atrophy etc. A later more accurate development in brain scanning, MRI (magnetic resonance imaging), does not appear to have been systematically studied in benzodiazepine users. However MRI, like CAT, only shows structural changes and it is unlikely that the use of this technique would clarify the picture; many still symptomatic long-term ex-benzodiazepine users have had normal MRIs.
....It is more likely that any long-term brain changes caused by benzodiazepines are functional rather than structural. In order to show such changes it would be necessary to examine abnormalities of brain activity in long-term benzodiazepine users....Cognitive performance could indicate impairments in certain brain areas, but no studies have extended for more than six months. Finally post-mortem studies could show abnormalities in brain receptors, and animal studies could show changes in neuronal gene expression. None of these studies has been undertaken. Nor have there been any studies examining abnormalities in other tissues or organs in long-term benzodiazepine users.
A controlled study of long-term benzodiazepine users using brain function techniques would have to be carefully designed....Such a study would be expensive and funding would be difficult to obtain. Drug companies would be unlikely to offer support, and to date 'independent' bodies such as the Medical Research Council, the Wellcome Foundation and the Department of Health have shown little interest. Thus the question of whether benzodiazepines cause brain or other organ damage remains unanswered.
Long-term effects of benzodiazepines
One mechanism which might be involved in long-term (and possibly permanent) effects of benzodiazepines is an alteration in the activity of benzodiazepine receptors in brain GABA neurones. These receptors down-regulate (become fewer) as tolerance to benzodiazepines develop with chronic use. Such down-regulation is a homeostatic response of the body to the constant presence of the drugs. Since benzodiazepines themselves enhance the actions of GABA, extra benzodiazepine receptors are no longer needed, so many are, in effect, discarded. These down-regulated receptors are absorbed into neurones where, over time, they undergo various changes including alterations in gene expression. When these receptors are slowly reinstated after drug withdrawal, they may return in a slightly altered form. They may not be quite so efficient as before in increasing the actions of GABA, the natural 'calming' neurotransmitter. As a result, the brain may be generally less sensitive to GABA and the individual is left with heightened central nervous system excitability and increased sensitivity to stress. Molecular biologists point out that changes in gene expression can be very slow, or even unable, to reverse. (The action of benzodiazepines at GABA receptors is explained more fully in the Manual).
Some people appear to be naturally more prone to anxiety than others.....Perhaps these individuals with genetically fewer GABA/benzodiazepine receptors are those more likely to experience long-term effects of benzodiazepines, protracted symptoms after withdrawal, and apparent recurrence of withdrawal symptoms.
Symptoms of a chronic hyperactive nervous system persisting after withdrawal are listed in the Manual Chapter 3, Table 3.
Benzodiazepine receptors: is there a natural benzodiazepine?
....A search for the elusive natural benzodiazepine has been going on for about twenty years. Natural benzodiazepines have been found in plants, including potatoes, wheat, corn, rice, valerian and poppy and have also been demonstrated in animal tissues. Diazepam and its metabolite nordiazepam have been found in human blood and brain but these could have been derived from dietary sources. However, some substances which are not chemically related to benzodiazepine drugs but combine with GABA/benzodiazepine receptors have been found in the brain and other tissues of a variety of animals including rats, cattle, frogs, fish and humans and in isolated rat brain slices. These agents, which are small polypeptides, have been termed endozepines and are thought to be the body's natural benzodiazepines. They have a number of actions, among which is the ability to react specifically with the benzodiazepine site of the GABA-A receptor and to modulate GABA neurotransmission in the brain. Endozepines probably interact also with other types of GABA receptors which are distributed all over the body and have many functions.
There is still much to discover about endozepines. Some inhibit diazepam binding and may therefore be anxiogenic while others appear to act like diazepam and enhance GABA activity (as explained in the Manual, Chapter 1). It seems likely that the balance between different endozepines acting at the GABA-A receptor may determine an individual's susceptibility to anxiety and response to benzodiazepine drugs by acting as 'fine-tuners' of GABA-A function.
The role of endozepines is still controversial but in my opinion natural benzodiazepines certainly exist, and they may already have been tracked down. Their presence adds to the complexity and sophistication of the brain. We know so little about what goes on in the brain, which makes it difficult to give advice on individual benzodiazepine problems.
Recurrence of symptoms after successful withdrawal
It is not unusual to experience recurrence of apparent benzodiazepine withdrawal symptoms years after a successful withdrawal and a return to normal health. The particular pattern of symptoms is unique to the individual, depending on his physical and psychological makeup, and no doubt on the innate density of his/her benzodiazepine receptors and the balance of his endozepines (see above). The experience of benzodiazepine withdrawal is deeply etched into the mind and memory of those who have been through it, and is actually physically present in the strength and connections of their neural synapses, as all memories are. These recurrent symptoms are all signs of GABA underactivity with its accompanying increased output of excitatory neurotransmitters, resulting in a hyperactive, hypersensitive central nervous system. The mechanism is exactly the same as that of benzodiazepine withdrawal, which is why the symptoms are the same.
In nearly every case of apparent recurrence, the precipitating cause for the return of symptoms turns out, on close inspection, to be an increase in environmental stress. The trigger may be a new stress or worry which may be unrecognised so that the return of symptoms seems to occur out of the blue. Contributing factors can be an infection, surgery, dental problems, work problems, fatigue, bereavement, family problems, loss of sleep, adverse reaction to a drug, change of environment - almost anything. It may also be that with increasing age and long-term worries, the brain simply gets less efficient at coping with stress. In addition, there may still be some lingering old disturbing worries/thoughts/memories that have been buried in the unconscious mind but are resurfacing now because the brain has not been able to deal with them adequately in the past. For those who have experienced a traumatic benzodiazepine withdrawal, an element of post-traumatic-stress disorder (PTSD) may be involved. This is a recurrent condition that can be triggered by small reminders of the past trauma. It is as if any new stress pushes the individual over the limits of his stress-coping abilities. As discussed above, some people who have been on long-term benzodiazepine treatment have a lowered tolerance to stress, even after they have stopped taking the drug, and are therefore more vulnerable to new or recurrent stresses.
It is not clear why many people report experiencing adverse effects from new drugs or drugs they have tolerated before taking benzodiazepines. The drugs involved are so disparate - from skin ointments to eye drops to local anaesthetics to antidepressants, steroids and many others - that it is difficult to attribute these reactions to metabolic effects, allergies or other known effects. Presumably the general hypersensitivity of the nervous system magnifies the reaction to any foreign substances, but no clear explanation has yet emerged. An exception is quinolone antibiotics which displace benzodiazepines from their binding sites and should not be taken by patients on, or recently on, benzodiazepines.
A dilemma faced by some people in the process of benzodiazepine withdrawal, or after withdrawal, is what to do if they have intolerable symptoms which do not lessen after many weeks. If they are still taking benzodiazepines, should they increase the dose? If they have already withdrawn, should they reinstate benzodiazepines and start the withdrawal process again? This is a difficult situation which, like all benzodiazepine problems, depends to some degree on the circumstances and the individual, and there are no hard and fast rules.
Reinstatement after withdrawal? Many benzodiazepine users who find themselves in this position have withdrawn too quickly; some have undergone 'cold turkey'. They think that if they go back on benzodiazepines and start over again on a slower schedule they will be more successful. Unfortunately, things are not so simple. For reasons that are not clear, (but perhaps because the original experience of withdrawal has already sensitised the nervous system and heightened the level of anxiety) the original benzodiazepine dose often does not work the second time round. Some may find that only a higher dose partially alleviates their symptoms, and then they still have to go through a long withdrawal process again, which again may not be symptom-free.
Updosing during withdrawal? Some people hit a "sticky patch" during the course of benzodiazepine withdrawal. In many cases, staying on the same dose for a longer period (not more than a few weeks) before resuming the withdrawal schedule allows them to overcome this obstacle. However, increasing the dose until a longed-for plateau of 'stability' arrives is not a good strategy. The truth is that one never 'stabilises' on a given dose of benzodiazepine. The dose may be stable but withdrawal symptoms are not. It is better to grit one's teeth and continue the withdrawal. True recovery cannot really start until the drug is out of the system.
Pharmacologically, neither reinstating nor updosing is really rational. If withdrawal symptoms are still present, it means that the GABA/benzodiazepine receptors have not fully recovered (see above). Further benzodiazepines cause further down-regulation, strengthen the dependence, prolong withdrawal, delay recovery and may lead to protracted symptoms. In general, the longer the person remains on benzodiazepines the more difficult it is to withdraw. On the whole, anyone who remained benzodiazepine-free, or has remained on the same dose, for a number of weeks or months would be ill-advised to start again or to increase dosage. It would be better to devote the brain to solving individual symptoms and to finding sources of advice and support. Advice about how to deal with individual symptoms is given in the Manual (Chapter 3)....
This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.
"It has become appallingly obvious that our technology has surpassed our humanity." -- Albert Einstein
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