BENZODIAZEPINES
Quotations & Abstracts
Twenty-one patients with significant long-term therapeutic benzodiazepine (BZ) use, who remained abstinent at 6 months follow-up after successfully completing a standardized inpatient BZ withdrawal regime, and 21 normal controls matched for age and IQ but not for anxiety, were repeatedly tested on a simple battery of routine psychometric tests of cognitive function, pre- and post- withdrawal and at 6 months follow-up. The results demonstrated significant impairment in patients in verbal learning and memory, psychomotor, visuo-motor and visuo-conceptual abilities, compared with controls, at all three time points. Despite practice effects, no evidence of immediate recovery of cognitive function following BZ withdrawal was found. Modest recovery of certain deficits emerged at 6 months follow-up in the BZ group, but this remained significantly below the equivalent control performance. The implications of persisting cognitive deficits after withdrawal from long-term BZ use are discussed. [SUMMARY p. 203]
"The main cognitive functions assessed in this study include working memory, verbal learning and memory, visuo-motor and visuo-conceptual skills. The lack of evidence for clinically significant cognitive recovery raises concern about the severity and reversibility of any underlying BZ-induced organic impairment." [p. 211]
"The adverse effects of acute diazepam administration on memory and arousal in man are well known (Lister & File, 1984; Lister, 1985), and have been linked to the high density of BZ receptors in the hippocampus and reticular formation (Wolkowitz et al. 1987), although the neurochemical basis of chronic post-withdrawal deficits has yet to be demonstrated." [p. 212]
"Persisting neuropsychological deficits affecting psychomotor function and new verbal learning have occupational implications. Driving and safety at work with machinery may both be impaired (Skegg et al. 1979, Roy-Byrne & Cowley, 1990).Patients' impairment, following withdrawal from long-term BDZ use, is likely to be less than that due to acute drug ingestion or the early withdrawal phase. Yet, one must be cautious in predicting either rapid or comprehensive cognitive recovery for those patients contemplating or undergoing a withdrawal regime, or in estimating the cognitive effects of mood dysfunction, which require further investigation." [p. 211] Lack of Cognitive Recovery Following Withdrawal from Long-Term Benzodiazepine Use. Tata PR, Rollings J, Collins M, Pickering A, Jacobson RR, Psychological Medicine 1994; 24: 203-213.
"...the use of benzodiazepines in patients with chronic pain would theoretically be ill-advised because they reduce the turnover of serotonin, thus interfering with natural sleep and lowering the tolerance to chronic pain. However, the most significant problem that benzodiazepines create seems to be cognitive impairment with associated EEG changes (--). Acute, single dose administration of diazepam does seem to produce impairment in learning, memory, and psychomotor functioning." [p. 828]
"...the evaluating psychiatrist noted that a great deal of cognitive impairment seemed to occur more often in patients using benzodiazepines than in patients using only narcotics." [p. 828]
"...one could conclusively state that benzodiazepines were far more likely to produce cognitive impairment, with concomitant EEG changes, than were narcotics."[p. 830] " While neither narcotics nor benzodiazepines should be used on a long-term basis, cognitive impairment was far more apparent with the latter class of drugs. The question of the reversibility of the benzodiazepine effect is the subject of current research, but at this time one may only underscore a recent suggestion by the Food and Drug Administration that benzodiazepines be limited to short-term use." [p. 830] Comparison of Cognitive Impairment Due to Benzodiazepines and to Narcotics. American Journal of Psychiatry 1980; 137: 828-830.
"The committee further noted that there was little convincing evidence that benzodiazepines were efficacious in the treatment of anxiety after four months' continuous treatment. It considered that an appropriate warning regarding long-term efficacy be included in the recommendations, particularly in view of the high proportion of patients receiving repeated prescriptions for extended periods of time ... It further suggested that patients receiving benzodiazepine therapy be carefully selected and monitored and that prescriptions be limited to short-term use" Committee on Review of Medicines, Systematic Review of the Benzodiazepines, Brit Med J, 29 March 1980, 910-912.
"Benzodiazepine dependence would be of minor clinical significance if it occurred only in those few individuals taking high doses of drugs; but it would be very important indeed if it supervened even to a minor degree in patients on usual clinical doses. Our clinical impression is that many patients experience symptoms on reduction or withdrawal of their benzodiazepine medication, and that whilst these symptoms somewhat resemble those of anxiety they differ qualitatively and are often more severe than those for which the medication was originally given" C. Hallström, M. Lader, Benzodiazepine withdrawal phenomena, Int. Pharmacopsychiat, 1981, 16, 235-244.
"Dependence on the benzodiazepines does occur. Patients taking these drugs, even at therapeutic doses, for two or more months, may develop a physical withdrawal syndrome. The cardinal feature of the syndrome is anxiety, which may be mistakenly interpreted as a recrudescence of the original anxiety for which the drug was prescribed" N. Hockings, B.R. Ballinger, Hypnotics and anxiolytics, in New Drugs, [London: British Medical Association, 1983, 149-155.
"The medical profession took nearly 20 years from the introduction of benzodiazepines to recognise officially that these minor tranquillisers and hypnotics were potentially addictive. The 'happiness pills', which had been propping up a fair proportion of the adult population since the early 1960s, were found to have an unexpectedly bitter aftertaste: doctors and patients alike were unprepared for the problems of dependence and withdrawal that are now known to be common even with normal therapeutic doses" Editorial (Anon), The benzodiazepine bind, The Lancet, 22 September 1984, 706.
"The extent of pharmacological dependence with regular as opposed to intermittent dosage of benzodiazepines was not fully appreciated until recently. This was probably because prominent features of drug dependence, such as tolerance and escalation of dosage, are uncommon among patients starting on normal doses. The chief manifestation is a withdrawal syndrome on stopping the drug" Anon (A. Herxheimer, ed.), Some problems with benzodiazepines, Drug & Ther Bull, March 25 1985, 23 (6), 21-23.
"In the UK, 11.2% of all adults take an anti-anxiety drug at some time during any one year. But over a quarter of these people (3.1% of all adults) are chronic users, taking such medication every day. Even at a conservative estimate, 20% of these will develop symptoms when they attempt to withdraw. That means a quarter of a million people in the UK. The sooner the medical profession faces up to its responsibilities towards these iatrogenic addicts, the sooner it will regain the confidence of the anxious members of our community" M.H. Lader, A.C. Higgitt, Management of benzodiazepine dependence - Update 1986, Brit J Addiction, 1986, 81, 7-10.
"There is now little doubt that regular use of benzodiazepines can lead to drug dependence in patients who are not drug abusers. Such patients come to rely on the drugs for psychological comfort and suffer withdrawal symptoms if the drug is stopped or the dosage reduced. It is estimated that one-third of patients taking benzodiazepines for six months become dependent... Present estimates suggest that perhaps 500,000 people in the UK... are now dependent on benzodiazepines" H. Ashton, Dangers and medico-legal aspects of benzodiazepines, J. Med Defence Union, Summer 1987, 6-8.
"It seems likely that many popular beliefs about benzodiazepine 'addiction' are related to the clear cut and increasingly documented phenomenon of withdrawal reactions following the use of these drugs and to the resulting difficulty anxious patients sometimes have stopping drug treatment because of such reactions. This phenomenon (ie inability to discontinue the drug because of withdrawal symptoms) is termed 'dependence' and by itself is enough to qualify patients for the new DSM-III-R. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised) diagnosis of 'psychoactive substance dependence" (P.R. Roy-Byrne, D. Homer, Benzodiazepine withdrawal: overview and implications for the treatment of anxiety, Am J Med, June 1988, 84, 1041 - 1052.
"It has been estimated that one in three patients prescribed benzodiazepines in normal therapeutic doses for six weeks would experience withdrawal symptoms if treatment were withdrawn abruptly. Even with gradual withdrawal, patients would request further prescriptions. Thus, there is a considerable risk of dependence even in comparatively short-term use" M.A. Cormack, R.G. Owens, M.E. Dewey, The effect of minimal interventions by general practitioners on long-term benzodiazepines use, J Roy Coll Gen Practitioners, October 1989, 39, 408-411.
"The presence of a predictable abstinence syndrome following abrupt discontinuance of benzodiazepines is evidence of the development of physiological dependence... "Historically, long-term, high-dose, physiological dependence has been called addiction, a term that implies recreational use. In recent years, however, it has become apparent that physiological adaptation develops and discontinuance symptoms can appear after regular daily therapeutic dose administration ... in some cases after a few days or weeks of administration. Since therapeutic prescribing is clearly not recreational abuse, the term dependence is preferred to addiction, and the abstinence syndrome is called a discontinuance syndrome" American Psychiatric Association Task Force on Benzodiazepine Dependency. Benzodiazepine Dependence, Toxicity, and Abuse. Washington DC: APA, 1990.
"I don't think anyone really knows what long-term effects the benzodiazepines are likely to have on the brain tissue ... [they] may damage your brain cells and produce real physical damage to your thinking processes and there is also the risk that the benzodiazepines will cause psychological damage." Dr Vernon Coleman, Life Without Tranquillisers, 1985, p55.
Drug companies making these products constantly warn doctors not to allow patients to take them for more than a week or two. They advise doctors not to make these drugs available on 'repeat prescription'. Evidence showing that these drugs are addictive and potentially dangerous has been accumulating rapidly since the early 1970s. Numerous research papers have been published showing that products in this group can cause problems such as memory loss as well as anxiety, depression and sleeplessness.
Ironically, these are the three symptoms for which they are most commonly prescribed. The Committee on Safety of Medicines has received reports showing that these drugs are well known to cause well over 100 different side effects. Earlier this month the DHSS and the Home Office publicly admitted that the size of Britain's tranquilliser addiction problem is worrying them by bringing these drugs under the Misuse of Drugs Act 1971 - the same legislation that controls drugs such as heroin. And yet thousands of doctors don't seem to take any notice. It may be true that many still don't know what else to do for patients who are suffering from anxiety or stress-related diseases. The only conclusion I can draw is that several thousand British doctors do not read articles in the medical journals nor do they study literature which is published by the drug companies.
These painfully ignorant doctors have between them created the biggest drug addiction problem this country has ever known. It's their addiction to prescribing these terrible drugs that has given us a nation of junkies. The nightmare pills: How millions are caught in the tranquilliser trap, Today, 07 May, 1986, Dr Vernon Coleman.
"Anxiolytic treatment should be limited to short periods... because of the danger of insidious development of dependence and subsequent difficulty in withdrawing the drug... Withdrawal of the drug following either high dosage or long-term administration should be gradual as abrupt withdrawal may produce confusion, toxic psychosis, convulsions or a condition resembling delirium tremens. In milder cases symptoms may be similar to the original complaint and encourage further prescribing." 1981 British National Formulary.
Anxiolytic treatment should be limited to the lowest possible dose for the shortest possible time... Prescribing of these drugs is widespread but dependence (both physical and psychological) and tolerance occurs. This may lead to difficulty in withdrawing the drug after the patient has been taking it regularly for more than a few weeks. Hypnotics and anxiolytics should therefore be reserved for short courses to alleviate acute conditions. British National Formulary, March 1998 edition.
Benzodiazepines are indicated for the short-term relief (two to four weeks only) of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness. The use of benzodiazepines to treat short-term 'mild' anxiety is inappropriate and unsuitable. Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or subjecting the individual to extreme distress. The Committee on Safety of Medicines, January 1988.
"Prolonged or excessive use of benzodiazepines may occasionally result in the development of psychological dependence with withdrawal symptoms on sudden discontinuation. This is more likely in patients with a history of alcoholism, drug abuse or patients with marked personality disorders. Treatment in all patients should be withdrawn gradually. Careful monitoring of all patients is essential." 1983 John Wyeth Data Sheet.
"It is more difficult to withdraw people from BDZs than it is heroin, it just seems that the dependency is so ingrained and the withdrawal symptoms you get are so intolerable that people have a great deal of problem coming off. The other aspect is that with heroin, usually the withdrawal is over within a week or so, with BDZs, a proportion of patients go on to long term withdrawal & they have very unpleasant symptoms for month after month, & I get letters from people saying you can go on for two years or more. Some of the tranquilliser groups can document people who still have symptoms ten years after stopping." Professor Malcolm H Lader, Royal Maudesley Hospital, "You & Yours" - BBC Radio 4, 1999.
The benzodiazepines are still extensively used in psychiatry, neurology and medicine in general. Anxiety disorder and severe insomnia are important syndromal indications, but these drugs are widely prescribed at the symptomatic level, resulting in potential overuse. The official data sheets recommend short durations of usage and conservative dosage. Although short-term efficacy is established, long-term efficacy remains controversial, as relevant data are scanty and relapse, rebound and dependence on withdrawal not clearly distinguished. The risks of the benzodiazepines are well-documented and comprise psychological and physical effects. Among the former are subjective sedation, paradoxical release of anxiety and/or hostility, psychomotor impairment, memory disruption, and risks of accidents. Physical effects include vertigo, dysarthria, ataxia with falls, especially in the elderly. Dependence can supervene on long-term use, occasionally with dose escalation. The benzodiazepines are now recognised as major drugs of abuse and addiction. Other drug and non-drug therapies are available and have a superior risk benefit ratio in long-term use. It is concluded that benzodiazepines should be reserved for short-term use - up to 4 weeks - and in conservative dosage. Professor Malcolm H Lader, Institute of Psychiatry, University of London, UK. Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified? In: Eur Neuropsychopharmacol 1999 Dec;9 Suppl 6:S399-405.
The concepts of dependence, addiction and abuse comprise overlapping clinical phenomena. The earlier anxiolytic drugs, in particular the barbiturates, were prone to abuse, i.e., non-medical use, and to high-dose misuse. Their modern counterparts, the benzodiazepines, are abused in a patchy way and are sometimes taken in regularly high doses. However, the main problem is physical dependence as manifested by a withdrawal syndrome on discontinuation of the drug. The withdrawal syndrome has been carefully described and comprises physical and psychological features. In particular, perceptual symptoms such as photophobia, hyperacusis and feelings of unsteadiness may predominate. The syndrome may come on during dosage reduction but generally starts 2-10 days after cessation of the benzodiazepine, depending on its elimination half-life. About a third of long-term users suffer a recognisable syndrome even after a tapered withdrawal, its duration usually being only a few weeks. A few patients go on to a prolonged withdrawal syndrome, often characterised by muscular spasm. The treatment of the withdrawal syndrome is supportive and non-specific. A few patients started on benzodiazepine therapy escalate the dose. They tend to show the characteristic 'passive-dependent' personality features and may previously have misused other CNS depressants such as the barbiturates and alcohol. Abuse of benzodiazepines occurs in a rather varied way from country to country. Worldwide, flunitrazepam has caused concern but, in the UK, the main problem has been the intravenous use of temazepam. The molecular pharmacology of the benzodiazepine receptor has been extensively studied and is undoubtedly complex. Professor Malcolm H Lader, Department of Clinical Psychopharmacology, Institute of Psychiatry, London, UK. Anxiolytic drugs: dependence, addiction and abuse. Eur Neuropsychopharmacol 1994 Jun;4(2):85-91.
Withdrawal of benzodiazepines is currently advised for long-term benzodiazepine users because of doubts about continued efficacy, risks of adverse effects, including dependence and neuropsychological impairment and socio-economic costs. About half a million people in the UK may need advice on withdrawal. Successful withdrawal strategies should combine gradual dosage reduction and psychological support. The benzodiazepine dosage should be tapered at an individually titrated rate which should usually be under the patient's control. The whole process may take weeks or months. Withdrawal from diazepam is convenient because of available dosage strengths, but can be carried out directly from other benzodiazepine. Adjuvant medication may occasionally be required (antidepressants, propranolol) but no drugs have been proved to be of general utility in alleviating withdrawal-related symptoms. Psychological support should be available both during dosage reduction and for some months after cessation of drug use. Such support should include the provision of information about benzodiazepines, general encouragement, and measures to reduce anxiety and promote the learning of non-pharmacological ways of coping with stress. For many patients the degree of support required is minimal; a minority may need counselling or formal psychological therapy. Unwilling patients should not be forced to withdraw. With these methods, success rates of withdrawal are high and are unaffected by duration of usage, dosage or type of benzodiazepine, rate of withdrawal, symptom severity, psychiatric history or personality disorder. Longer-term outcome is less clear; a considerable proportion of patients may temporarily take benzodiazepines again and some need other psychotropic medication. However, the outcome may be improved by careful pharmacological and psychological handling of withdrawal and post-withdrawal phases. Ashton CH, Department of Pharmacological Sciences, University of Newcastle upon Tyne, UK. The treatment of benzodiazepine dependence, Addiction 1994 Nov;89(11):1535-41.
This paper presents the results of a survey carried out to investigate the benzodiazepine (BZD) prescribing patterns of the general practitioners (GP) in the catchment area of a Drug Dependence Unit located in a general hospital in Mataro (Barcelona, Spain). The aims of the survey were: (i) to obtain descriptive information on the knowledge of the GPs about BZD and its potential for dependence; (ii) to study the frequency of their prescribing; and (iii) to examine different factors linked to their prescribing. The study was carried out using a combination of a personal interview and a self-administered questionnaire. A total of 68 doctors (88.3%) completed the questionnaire. The results show that the GPs have, in general, correct knowledge about the therapeutic indications for BZD prescribing, but are far less aware of their potential to induce dependence and how to manage withdrawal. The rate of prescribing seems to be high. Furthermore, the results of the external check of validity point out that doctors tend to underestimate the number of prescriptions. The majority of GPs express the need for alternative resources to BZD prescribing. No significant associations have been found between doctor's characteristics, such as postgraduate training and type of practice, and their knowledge about BZD and frequency of their prescribing. In our view, a more accurate knowledge about BZD and alternatives to its use, both factors closely linked to training, together with the availability of non-pharmacological resources, are likely to improve the quality of doctors prescribing habits, thus preventing risks such as dependence of BZD. Benzodiazepines in primary health care: a survey of general practitioners prescribing patterns, Boixet M, Batlle E, Bolibar I, Unitat Assistencial de Drogodependencias, Servei de Psiquiatria, Barcelona, Spain.
Benzodiazepines are medications that are addicting - both in combination with other drugs and alone. The scope of the problem is thought to be wide, but it has not been well documented for unclear reasons. Pharmacologic dependence has been documented in virtually all long-term users. Adverse effects occur secondary to their use and these effects are often subtle, but significant. Various benzodiazepines present differences in reinforcement, withdrawal, and adverse effects. Diagnostic issues, withdrawal, and treatment issues are discussed. Benzodiazepines and addiction. Psychiatr Clin North Am 1993 Mar;16(1):75-86. Juergens SM Virginia Mason Outpatient Chemical Dependency Program, Virginia Mason Clinic.
Some Highlights from The Beat the Benzos Conference, Croydon, November 2000:
Dr Nicholas Seivewright
Dr Seivewright is a psychiatrist working in the area of drug misusers. At the end of his talk he mentioned that he felt that his profession had no problem with reclassifying benzodiazepines (BDZs). He said that this would solve the immediate problem of street abuse of the drugs, although there may be problems with other aspects of reclassification.
Dr James Robertson
Paediatrician at Arrowe Park Hospital, The Wirral. Dr Robertson said he categorised BDZs as more dangerous than opiates or methadone to the newborn and that "babies affected can go on suffering for months and months" and "that the parenting 'benzo babies' receive will be poor, not through any fault of the parent, but the fault of the drug plus the parent".
Professor Stefan Borg
Head of Addiction Medicine, Karolinska Institute, Sweden. Professor Borg has been researching the biochemical changes induced by long term BDZ use. He said extensive research in this area showed that cognitive / psycho-neurological impairment was measurable during long term BDZ use, increased during acute withdrawal and very slowly reverses over months or years after cessation of the drugs. A most significant finding was that flumazenil, a BDZ antagonist ("antidote") when given to people, who had been off the drugs for some time but continued with unpleasant symptoms, improved or were completely relieved of these symptoms. Flumazenil is a Roche product licensed for use in reversing the action of BDZs after anaesthesia and overdose.
