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Last part of Good Info on Benzos and other drugs in common use AND ABUSE 

Patients at Special Risk from Benzodiazepines

Individual differences apply more to the third reason why benzodiazepines are prescribed inappropriately, which is when they are given in the wrong dose to the wrong people.

Vulnerable Patients

Slide 12
The elderly are especially susceptible to the sedative effects of benzodiazepines which may cause mental confusion, cognitive impairment suggesting dementia and ataxia leading to falls and fractures. This is partly because of reduced metabolism, especially oxidation and partly because of increased central nervous system vulnerability. Benzodiazepine dosage for elderly patients should always be half of the adult dose, and benzodiazepines which are not oxidised but conjugated, such as oxazepam and temazepam are preferred. Patients with chronic respiratory or liver disease are at increased risk of respiratory depression, which can be fatal, and oversedation and benzodiazepines are relatively contraindicated in these cases. Benzodiazepines should be avoided in patients with depression which they may aggravate and increase the risk of suicide. Additive effects may occur with patients taking other depressant drugs such as alcohol or sedative antidepressants. In pregnancy there is a risk of adverse effects on the fetus, neonatal depression (floppy baby syndrome) and neonatal withdrawal effects. Patients with a history of alcohol or drug abuse or those with personality disorder may be more likely to become dependent. There are also genetic differences in drug metabolism. Slow metabolism of benzodiazepines, and also of alcohol, is common in Orientals, and the recommended dose of benzodiazepines in Hong Kong, for example, is half that recommended in Europe and North America. On the other hand, some drugs such as barbiturates and nicotine in smoking induce liver enzymes, increasing the rate of metabolism. Benzodiazepines are not enzyme inducers but the rate of metabolism may be affected by other drugs which induce or inhibit liver enzymes (ketoconazole). Finally tolerance to previous benzodiazepine use, alcohol or barbiturates may reduce sensitivity to benzodiazepines.

With all these caveats for benzodiazepines, what about the more recently introduced “Z drugs”—zopiclone, zolpidem, zaleplon and now the introduction of eszopiclone (Lunesta)?

The Z Drugs

Half-Lives and Equivalent Potencies of Z-Drugs
Slide 13
These are not chemically benzodiazepines but they bind to GABA receptor complexes which are close to or actually coupled with benzodiazepine receptors. They are said to be more selective, binding mainly to the a1 GABA receptor subtype which mediates the hypnotic effects of benzodiazepines. In practice they are not all that selective and have much the same actions as benzodiazepines. In the UK, the National Institute for Clinical Excellence (NICE), which advises the Health Service on optimum drug use, recommended that Z drugs should be used for short-term treatment only (2–4 weeks) and then only as second line treatments after benzodiazepines. They concluded that the Z drugs produced the same therapeutic and adverse effects as benzodiazepine hypnotics, including tolerance, dependence and abuse, and were also more expensive.

As a clinical example, a psychiatrist recently asked my advice about the nursing sister he was helping to withdraw from lorazepam (Ativan). She developed quite severe withdrawal symptoms as the dosage was lowered and had trouble sleeping. To help her, the psychiatrist prescribed zopiclone (Zimovane) to take at night. She found that this drug completely relieved her withdrawal symptoms. In fact, it was so successful that she started taking zopiclone in the daytime as well. She ended up taking zopiclone six times a day as well as at night, ending up with a total dose of over 40mg/day (the recommended dose is 7.5mg at night). The psychiatrist was chagrined to find that he had merely replaced one form of addiction with another.  :P

There are a number of cases in the literature of such escalation of dosage with zopiclone, followed by dependence and withdrawal symptoms on stopping. There are also an increasing number of cases reported of misuse and abuse of high doses of zolpidem (Ambien). This can result in hallucinations and psychosis and is reminiscent of the adverse effects of triazolam (Halcion), the short-acting benzodiazepine hypnotic now banned in the UK.

Now eszopiclone is being promoted for long-term use and the manufacturers report trials lasting two weeks to six months of its hypnotic effects. They report little tolerance or loss of efficacy over these periods and a low incidence of rebound insomnia or anxiety (3.7%) on stopping. Euphoria was noted in high doses, suggesting an abuse potential. I remain sceptical of these results which involved relatively small numbers of subjects with various types of insomnia. I am not convinced that eszopiclone is all that different from zopiclone, apart from its potency, and I think it would be prudent to limit it to short-term use until proved otherwise.

There is a basic pharmacological principle that any drug which acts on intrinsic body receptors will cause adaptive changes in these receptors if used chronically. This is because the body is programmed to restore homeostasis if its internal environment is disturbed. For every drug action in the body there is an equal (as far as possible) reaction which tends to restore the status quo. This mechanism underlies the development of drug tolerance and dependence and also of withdrawal reactions if the drug is stopped. It applies not only to benzodiazepines but also to non-psychotropic drugs like B blockers. For example, B blockers such as propranolol are used to slow the heart and lower the blood pressure. If these are suddenly stopped there is a rebound of increased heart rate and raised blood pressure. We accept that tolerance and withdrawal reactions occur with benzodiazepines, barbiturates and all the hypnotic and sedative drugs that have gone before. We even understand much about the molecular mechanisms involved — which I won't go into here. There seems no reason to believe that these reactions will not apply to Z-drugs.

I suspect that the Z-drugs will undergo the fate of many newly introduced drugs — a fate that is becoming all too familiar.  :(

Historical Evolution of New Drugs
Slide 14
Management of benzodiazepine withdrawal

So how should we withdraw benzodiazepines in people who have become dependent through long-term use? I have already described this is some detail elsewhere. I make no claims that this is the last word in benzodiazepine withdrawal, but the methods are based on experience in my withdrawal clinic and on many other patients I have been in contact with since then.

Benzodiazepine Withdrawal

Slide 15
The basic principles for people withdrawing from therapeutic doses of benzodiazepines are simple: gradual dosage reduction and anxiety management if needed. It is generally agreed that dosage should be tapered gradually. Abrupt withdrawal, especially from high doses, can precipitate convulsions, acute psychotic or confusional states and panic reactions. The rate of tapering should be tailored to the patient's individual needs, taking into account lifestyle, personality, environmental stresses, reasons for taking benzodiazepines, amount of support available and other personal factors. Various authors suggest optimal times of 6-8 weeks to a few months for the duration of withdrawal, but some patients may take a year or more. The best results are achieved if the patient himself (not the doctor) is in control of the rate of withdrawal and proceeds at whatever rate he or she finds tolerable. The doctor and patient together can devise a mutually agreed withdrawal schedule, but this may require readjustments from time to time according to progress. If problems arise, either in the form of increased symptoms or extra environmental stresses, it may be necessary to stabilise the dosage for a few weeks or to reduce the rate of withdrawal. But it is important always to go forwards, avoiding a backward step of increasing the dosage again.

The size of each dosage reduction depends on the starting dose. Patients on higher doses can usually tolerate larger dose decrements than those on lower doses. For patients taking less than 20mg diazepam or equivalent, reductions of 1mg every 1-2 weeks are generally tolerated. When dosage is down to 4–5mg diazepam or equivalent, decrements of 0.5mg may be preferred. On the other hand, initial dosage reductions of 2mg every 1–2 weeks may be appropriate for patients starting on 40mg diazepam or equivalent.

Stopping the last few milligrams is often seen by patients as particularly difficult, because of fears of how they will cope without any drug at all. However, the final parting is often surprisingly easy, especially as confidence increases during withdrawal, and patients are encouraged by their new sense of drug-free freedom.

For most patients on therapeutic doses of benzodiazepines withdrawal is best carried out as an outpatient. Rapid withdrawal in detoxification clinics, even with phenobarbitone substitution, is inappropriate because the patient has no time to build up alternative living skills, which may take many months. Detoxification in drug and alcohol clinics is utterly inappropriate and traumatic for people involuntarily addicted to benzodiazepines by doctors' prescriptions.

The general aim of the dosage tapering strategy is to achieve a smooth, slow, steady fall in blood concentration of benzodiazepine, allowing time for the body to adjust to the change. This slow, smooth decline is not possible with rapidly eliminated benzodiazepines like lorazepam, (Ativan) or alprazolam (Xanax) with which blood concentrations fluctuate with peaks and troughs between each dose. It is therefore often advisable for those taking these drugs to switch to diazepam. When doing so, it is important to keep in mind the equivalent potencies that I have mentioned, and also to make the changeover gradually in a stepwise fashion, replacing each dose, or even half dose, one at a time over perhaps weekly intervals. Withdrawal can then proceed as for diazepam with small decrements of 0.5–1mg at a time, decrements that are not easily achievable with other benzodiazepines. The same technique can be used for Klonopin. I know that some patients report that they find this difficult, but I suspect it is because the changeover is not carried out carefully enough, with due regard to potencies and individual differences.

I should add that some benzodiazepines are available in liquid form and it is possible to withdraw from these directly, reducing dosage millilitre by millilitre or drop by drop.

What about adjuvant drugs? Are there any drugs that help to cushion the withdrawal process? The short answer is no: any drug that substitutes for benzodiazepines is benzodiazepine-like itself. However, several drugs have been tried, though none have proved generally useful.

Adjuvant Drugs In Benzodiazepine Withdrawal

Slide 16
Antidepressant drugs may be indicated if depression is severe, and anyone already on an antidepressant should continue it until after the benzodiazepine has been withdrawn. Antidepressants, including SSRIs, have been shown to have anxiolytic effects and may be indicated as longer-term treatment for chronic anxiety disorders. Small doses of sedative antidepressants can be helpful for insomnia. But all antidepressants, as I mentioned yesterday, also produce withdrawal effects when stopped.

B blockers may help tremor and palpitations as a temporary measure. Carbamazepine and other anticonvulsants prevent fits during withdrawal from high doses of benzodiazepines. Sedative antihistamines such as Phenergan may help with sleep but should not be used long-term.

Bispirone, clonidine, and nifedipine have all been shown to be unhelpful. Gabapentin has been claimed to be beneficial but there are no controlled trials. The benzodiazepine receptor antagonist flumazenil (Romazicon) was effective in some trials but has to be given intravenously and repeatedly and it can actually precipitate reactions.

None of these drugs (except possibly antidepressants) should be necessary for people on therapeutic doses withdrawing slowly enough.

SLIDE 15 Again
Slide 15
What about psychological support? Many people require little more than simple and repeated encouragement and proper information. Self-support groups can be a great help for many. Some may need more formal psychological therapies including anxiety management, stress-coping strategies and cognitive behavioural therapy. Support when needed should be available both during and after withdrawal. Some patients may remain vulnerable to stress for some months.

In general practice settings, even minimal information can be effective. In one general practice study of elderly patients on long-term hypnotics, a single letter advising them to try reducing by half a tablet every few weeks resulted in significant dose reduction or complete withdrawal within six months, with improvement in mental and physical health and no withdrawal symptoms or sleep problems. Another general practice study of withdrawal in elderly hypnotic users using placebo tablets found that 80% had withdrawn in six months with no sleep or withdrawal problems and significant improvement in cognitive performance.

Of course patients have to be motivated to withdraw—it is no use forcing withdrawal on reluctant patients. But a single medical consultation explaining the risks of long-term benzodiazepine use, or even media publicity can help to motivate people.

Finally, what can we do to halt overprescription of benzodiazepines in the future and to prevent yet more people getting caught in the so-called tranquilliser trap?
Slide 17
Steps Needed to Reduce Benzodiazepine Overprescribing

Some Steps Needed to Reduce Benzodiazepine Overprescribing
Slide 18

Prof. Ashton's speaking notes did not include Slide 18 but the PowerPoint® presentation did. So we have included the slide here, as it obviously flows from Slide 17.

Copyright © Prof. C. Heather Ashton, DM, FRCP, Emeritus Professor of Clinical Psycho-Pharmacology at the University of Newcastle upon Tyne, England.

 Updated October 31, 2012
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