BENZODIAZEPINES; RISKS AND BENEFITS. A RECONSIDERATIONBaldwin, Aitchison, Bateson, Curran, Davies, Leonard, Nutt, Stephens and Wilson.
J Psychopharmacol 2013, 27 (11) 967-71

A REVIEW BY PROFESSOR C HEATHER ASHTON, DM, FRCPNOVEMBER 2013This paper consists of recommendations for clinical practice about prescribing
benzodiazepines and managing prescribed benzodiazepine users. It has been compiled
by representatives from the Royal College of Psychiatrists and the British Association forPsychopharmacology. Considering that one of the authors and the editor of this journal,Professor David Nutt, has received the 2013 John Maddox Prize for Standing up forScience, it is surprising and disappointing that there is virtually no science in the article.
P 967, col 1 Introduction** “ The group contends that benzodiazepine prescribing, like other aspects of clinicalpractice, should be based on thoughtful consideration of the likely risks and benefits ofbenzodiazepines,….
and of alternative interventions.”“The balance of risks andbenefits…. is ultimately a matter of clinical judgment.”
This statement is trite and unnecessary since it applies, as stated, to all drugprescriptions and all interventions. It is presumptuous and insulting to doctors to remindthem of this ethic which forms the very basis of the medical profession. It is patronising
if it is meant to apply especially to benzodiazepine prescriptions. Prescribedbenzodiazepine users, the patients themselves, were the first – before the doctors- torecognise that benzodiazepines could be addictive if used long term.
Doctors should be more scientific in their clinical judgments. I have written elsewhere:“How the dependence potential of benzodiazepines was overlooked when it was clearthat they could replace barbiturates and similarly acting drugs is a matter foramazement and casts shame on the medical profession which claims to be scientifically
based. Cross-tolerance between different drugs, for instance between barbiturates andalcohol, was well understood at the time and clearly implied that if one drug could
replace another it must have common characteristics and usually a common mode ofaction. This similarity between benzodiazepines and barbiturates was ignored anddoctors were urged in a campaign by the UK medical profession in the 1970s toprescribe benzodiazepines instead of barbiturates. They complied with such zeal that
benzodiazepines, believed to be harmless, were prescribed long term, often for many
years, for anxiety, depression, insomnia and ordinary life stresses.” (Ashton, 2004)
Thus doctors, acting thoughtlessly and unscientifically, and still today prescribing
benzodiazepines long term, are responsible for causing benzodiazepine dependence andall its attendant suffering in millions of people. The victims have received no apology.
P 970, col 1 Dependence**“Withdrawal reactions are generally short-lived, typically lasting less than one month…”

This statement is not scientific; where is the evidence? On how many patients has thewithdrawal reaction been measured including, age, drug dose, duration of use, indication
for prescription, type of benzodiazepine, length of follow-up, etc.? What is the withdrawal
reaction measured from? Is it from the start or the end of dosage tapering? Is it after
rapid, sudden or gradual cessation of use? Is it the time after the last molecule ofbenzodiazepine including active metabolite has left the body? What about patients whoalready have withdrawal symptoms while still taking the benzodiazepine, because of thedevelopment of tolerance? (New symptoms of apparent ‘withdrawal’ while continuing totake the drugs is common in long term users, and may lead to dosage escalation).
**“There is controversy whether symptoms persisting for many months…..arewithdrawal symptoms or simply the features of an underlying disorder, or worsening ofthat condition triggered by treatment withdrawal.”This statement ignores the large number of patients who have no underlying disorderbut who have been prescribed benzodiazepines for sports injuries, after accidents
requiring splints (commonly prescribed by orthopaedic surgeons for muscle relaxation
after surgery requiring splinting) and those who have been wrongly prescribedbenzodiazepines for unrelated conditions such as influenza, menorrhagia, dentaltreatment, bereavement or other personal tragedies, and many other reasons. Thesepatients may also have persistent withdrawal symptoms after long- term benzodiazepine
treatment. The authors have not considered the possibility that benzodiazepines
themselves cause the symptoms they suggest as an “underlying disorder”. Where is thescience in that?
(See also Tolerance, p969, below)
P 969, col 2 ToleranceThis section is extremely short. It does not mention the mechanism of tolerance orexplain the immense clinical importance of this phenomenon in long term
benzodiazepine use and dependence, and its essential contribution towithdrawal effects. I am surprised that Dr Bateson, who reviewed thesubject in 2002 (and possibly more recently), let this omission pass, as an
author of this paper.
Tolerance to benzodiazepines, probably results as a homeostatic response involving‘down-regulation’ of benzodiazepine receptors on GABA-A receptor
subunit), which become internalised within neurones during chronic use.
Changes in gene transcription (gene expression) occur in the internalised
receptors, resulting in a long-term alteration of function. This pathway
could operate on different time scales, depending on the receptor subtype
and brain region involved, and thus give rise to differing rates ofdevelopment of tolerance to various benzodiazepine actions. Suchtolerance occurs in long-benzodiazepine use in ‘therapeutic’ dosage,
whether taken as anxiolytics or as hypnotics (the latter demonstrated in astudy of long-term benzodiazepine hypnotic users by Professor Curran(Curran, 2003).
Once tolerance has developed, withdrawal of benzodiazepines exposes the recipient to
the drug-induced alterations in benzodiazepine receptors, resulting inunder-activity in the many domains of function normally modulated by

GABA-ergic mechanisms, accounting for the multiple and diverse nature ofbenzodiazepine withdrawal reactions. The various changes in GABA
/benzodiazepine receptors induced by tolerance, including changes in gene
expression, may be slow to reverse after drug withdrawal and may do so
at different rates, possibly accounting for the variable time of emergenceand duration of individual withdrawal symptoms and the prolonged, andsometimes protracted, nature of the benzodiazepine withdrawal reaction.
(See dependence, p970 above).
It is a pity that this whole aspect of benzodiazepine effects, one of the few areas ofbenzodiazepine actions that has been studied scientifically, is neglected inthis article. Where is the science here?
Long-term benzodiazepine use
P 968, col 1**“ …. usually in acute treatment for the reduction of anxiety symptoms, butsometimes in longer-term treatment, designed to prevent a relapse…”

P 968, col 2** “…. Longer term treatment….might be considered desirable…… in conditions such as
chronic treatment-resistant anxiety disorders or in patients who haveestablished dependence and have not been able to stop treatment
successfully”.
P 969, col 1** “. …there is little evidence that longer term use [of benzodiazepine hypnotics] is morehazardous than short term use.”
There is plenty of evidence that long term use is hazardous, especially in the elderly,
because of cognitive impairment (Curran), night wandering, falls and fractures andmuch else reported in the clinical literature including controlled trials.
P 970, col 1** “ In some patients pharmacological and psychological interventions will be only oflimited benefit, so certain individuals will be unable to stopbenzodiazepines.”

This advice about long-term benzodiazepine use is negative and dangerous. It will tend
to perpetuate, prolong and possibly increase long-term benzodiazepine
prescribing. It is not a scientific way to solve the problem.
The emphasis on the difficulty of withdrawal in some patients will deter some doctors
from even trying. Yet, given information and time, experience has shownthat most people can withdraw successfully from their iatrogenic addiction.
At present effective withdrawal is mostly carried out by voluntary support
groups, largely financed by charities. Some of these have excellent results(e.g. Bristol and District Tranquilliser project).
informed of available support groups.

Patients should beSuccessful withdrawal may require more time and help than GPs are able to give toindividual patients, but doctors should campaign for more support fromtheir grant-giving bodies for practice nurses , counsellors, pharmacists andothers who could work within their practice and give advice on withdrawal
schedules. In very many cases, patients have been able to withdraw by
their own efforts, given information and very little intervention, and haveregained better physical and psychological health than patients whoremained on long-term benzodiazepines (Heather et al, 2004).
Long-term benzodiazepine treatment, prescribed for whatever reason, inevitably
condemns the patient both to dependence and to cognitive impairment
and psychomotor slowing, to which complete tolerance does not develop,
as many studies of long-term users have shown. Because of theimpairment, patients are not always able to recognise their dependence or
to make rational decisions about continuance or withdrawal
The effects on the brain of long-term benzodiazepine use have never been adequately
researched despite the reports of many patients of enduring, perhaps
irreversible, adverse effects. Some preliminary CAT studies of long termusers by Professor Malcolm Lader were suggestive of brain damage but
have never been followed up with modern techniques such as MRI andfMRI. An influential multi-authored paper of this kind should surely make aplea for further research in this area.
One does not solve problems or advance science by trying to make the best of the statusquo - which is what the advice in the present superficial and unscientific paper does. The
medical profession deserves better than that of nine distinguished authors.
P 969, col 2 Risks
Use of benzodiazepines in pregnancy. Mention should be made that benzodiazepines
cross the placenta and affect the foetus. Risks to the neonate (benzodiazepinedependence; floppy infant syndrome) are well known and should be mentioned. There
are also as potential risks to the developing foetal brain. Animal studies have shownthat maternally administered psychotropic drugs can adversely affect the foetal
development of transmitter systems. This is another area which requires research - forexample, recording the use of benzodiazepines during pregnancy in mothers of children
with ADHD and other pervasive developmental disorders.
P 969, col 1 Z-drugs** “However, the Z-drugs may have some limited advantages… in terms of dependence
and withdrawal, and should be considered as an alternative, particularly if there seems
to be a potential need for longer-term treatment or in patients presumed to be atincreased risk of dependence.”
Superiority of Z-drugs over benzodiazepines in terms of risks of dependence or misuse
has never been adequately shown. Z-drugs are addictive in animal studies and there aremany reports of misuse/abuse in humans. There are not infrequent cases of therelatively short- acting zopiclone or zolpidem being taken is excessive doses, and/or up
to seven times or more a day, though initially prescribed as a single nightly hypnotic
dose. They also have anxiolytic properties and can substitute for benzodiazepines. They
have not been shown to be suitable for long-term use.
P 970, col 2 and 971, col 1 Withdrawing benzodiazepines; Recommendations
The guidance and recommendations are extremely vague and of no help to doctors
inexperienced in prescription or withdrawal of benzodiazepines. These sections should be
more detailed, explicit and comprehensive or should give reference(s) to approved
sources of advice (e.g. NICE, BNF, Clinical Knowledge Summaries).
The
recommendations given here may be well-meaning but are unhelpful. They are highly
unlikely to lead to any improvement in benzodiazepine prescribing or withdrawal, andare not scientific.
Unfortunately, the paper illustrates how little clinical medicine is influenced by scientificobservations. Sixty years after the introduction of benzodiazepines there has been little
improvement in clinical benzodiazepine problems. This contribution is certainly not ashining example of ‘Standing up for Science’.
References
Ashton H (2004 ) Benzodiazepine Dependence in Adverse Syndromes and PsychiatricDrugs eds P.M.Haddad, Serdar Dursun and Bill Deakin , Oxford university Press 2004,
pp 239-259.
Bateson AN (2002) Basic pharmacological mechanisms involved in benzodiazepine
tolerance and withdrawal Curr Pharm Design 8, 5-21
Curran HV (2003) Older adults and withdrawal from benzodiazepine hypnotics in generalpractice Psychological Medicine 33 1233-1237.
Heather N, Bowie A, Ashton H, et al. (2004) Randomised controlled trial of two brief
interventions against long-term benzodiazepine use: outcome of intervention Addiction
research and Theory 12 (2) 141-154.