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Benzodiazepines – the big picture Dr Malcolm Bruce Consultant Psychiatrist in Addiction NHS Lothian History. Greeks / Egyptians up to 17 th & 18 th Century – “without opium there would be no medicine” 1830 - Chloral Hydrate 1860 - Bromides

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Benzodiazepines – the big pictureDr Malcolm BruceConsultant Psychiatrist in Addiction NHS


  • Greeks / Egyptians up to 17th & 18th Century – “without opium there would be no medicine”

  • 1830 - Chloral Hydrate

  • 1860 - Bromides

  • 1930 – Barbiturates

  • 1960 – Ro5-0690 (Librium)

  • 1963 – Valium

  • 1965 – Mogadon

  • 1985 – Roche patent ends on Valium, 4th highest drug sales in USA $354 million in 1984

    ($690 million at 2006 prices)

    In UK 3% pop use daily, 11% use each year


  • Most men & women lead lives at the worst so painful, at the best so monotonous, poor & limited that the the urge to escape, the longing to transcend themselves if only for a few moments, is and always has been one of the principle appetites of the soul

    The Doors of Perception 1954 A Huxley

  • Benzodiazepines

    "the opium of the masses"

    1978 Malcolm Lader

Plusça change……

  • "It is more difficult to withdraw people from benzodiazepines than it is from heroin.”

    1999 Professor Lader

Don’t start from here….

  • Heroin addiction

    • MM doesn’t work

    • I/V abuse Temgesic

    • HepC plus epidemic

    • Shortage of needles

    • Police witnesses

    • Ah! Thank God for benzodiazepines

    • Px 100mg DZ, 60mg TZ

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Neuro-physiologicalTolerance / Homeostasis / Withdrawal

  • Changes in protein expression of endogenous GABA precursors

  • Reduced sensitivity of GABA receptors

  • Down-regulation of GABA sites in inhibitory receptors system

  • Morphological changes in the GABA dendrites

  • Up-regulation of reciprocal excitatory receptor systems

Typical BDZ/Hypnotic Guidelines

  • Use lowest BDZ/hypnotic dose for briefest time

    • 2-4 weeks for hypnotics, up to 4 weeks for anxiolytics

  • Use only one BDZ (give long-acting one at night if need both a hypnotic and an anxiolytic effect)

  • Dose used should be in therapeutic range (i.e. within BNF limits)

  • Reduce gradually after both short term (> 2 weeks) and long term use

  • Only use in acute self-limiting situations/conditions

  • Only use for severe symptoms (never mild symptoms)

  • Do not use in those with a history of addiction

Current BDZ Guidelines:


BDZ treatable clinical problem Addiction

Not Tx resistant Tx resistant

(Tx > 4 wks)

Brief Definite

Situational Identifiable

Stress Endpoint Currently Currently

(Tx < 1 wk) (Tx < 4 wks)excluded from excluded from

treatment treatment

guidelines guidelines

Key to evidence statements and grades of recommendations

Levels of evidence (SIGN)

  • 1++High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias

  • 1+Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias

  • 1Meta-analyses, systematic reviews, or RCTs with a high risk of bias

  • 2++High quality systematic reviews of case control or cohort or studies. High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal

  • 2+Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal

  • 2Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal

  • 3Non-analytic studies, e.g. case reports, case series

  • 4Expert opinion

Level 2 evidence – Psychiatr Serv, 2003 Oct;549(10):1395-401

BZ in SEMI and comorbid SMU

  • Cohort study, N=203, prospective, 6 years

  • Outcomes:Px, Illicit, I/P, QLife, GHQ

  • Results: 43% Px BZ - associated with High GHQ, Low QLife and Illicit BZ use

  • Conclusion: Do not Px BZ in this group

  • Opinion: significant risk that the relationship is not causal

Level 3 evidence – Addiction. 2003 Feb;98(2):191-7

  • Case reports - retrospective analysis of coroners' records in opiate-related poisoning, 1997- 2000

  • Measure: Toxicological findings

  • Outcome: 61% - Concomitant BZ

  • Conclusion: BZ, at least in lower quantities appear to be a feature rather than a risk factor per se in such fatalities.

Level 4 evidence – BDZ Guidelines By August Bodies

  • Committee on Review of Medicines (1980)

  • Quality Assurance Project (1985)

  • Committee on Safety of Medicines (1988)

  • American Psychiatric Association (1990)

  • Consensus conference on GAD (1992)

  • Royal Society of Medicine (1992)

  • Mental Health Foundation (1993)

  • National Medical Advisory Committee (1994)

  • World Health Organisation (1996)

  • Royal College of Psychiatrists (1997)

  • Academy of Sleep Medicine (1999)

  • Many others: BNF, Maudsley, DOH, DVLA, Salzman & Watsky (1993), Ashton (1994) etc etc.

What is the problem, why so many BDZ Guidelines?

  • Audits reveal an enormous divergence between BDZ guidelines and prescribing practice

  • BDZ guidelines for psychiatrists (e.g. WHO 1996, RCPsych 1997) specify a number of principles similar to other guidelines & then provide so many exceptions to them, they seriously undermine themselves

  • Guidelines should be evidence based: Current guidelines have more to do with policy than evidence

Factors Increasing Risk of BDZ Withdrawal Reactions

  • Related to physiological withdrawal:

    • Longer term (e.g. > 4 months)

    • Higher than therapeutic dose use

    • High potency short/intermediate half-life BDZ (e.g. alprazolam, lorazepam)

  • Related to diagnoses:

    • Chronic psychiatric problems: Chronic dysthymia or dysphoria  BPD or dependent PD, panic disorder, chronic psychosis, neuroleptic side-effects

    • Chronic physical problems: Esp. elderly, esp if in pain or chronic sleep difficulties

  • Related to personality factors / addiction proneness:

    • FH or current/past alcohol or other sedative-hypnotic dependence

Risk of Long Term BDZ Prescribing

  • Increased risk of withdrawal reactions and BDZ dependence syndrome

  • The BDZ becomes the problem: Underlying issues avoided & BDZ seen as the solution. Anxiety may reduce if BDZ stopped (Rickels et al 90, 91, Schweizer et al 90)

  • Subtle but definite cognitive deficits:

    • Anterograde amnesia (Episodic memory) (impaired delayed recall) occurs for a few hours after drug taken, can become chronic. Specific defects in visuospatial ability and sustained attention with chronic use.

    • Emotional suppression leading to a cumulative effect on emotional coping and a learning deficit

The Hippocratic Oath: I will prescribe regimens for the good of my patients according to my ability and my judgment and never do harm.

  • Is it defensible to expose patients to the risk of developing dependency by long term or indefinite use of BDZ when:

    • Alternative Tx’s have failed (i.e. Tx resistance)?

    • Benefits of Tx outweigh risks (i.e. alternatives worse or benefits better)?

    • Decision taken in conjunction with patient?

    • Tx is strictly individualised?

    • Need for Tx reviewed periodically (to ensure efficacy is maintained)?

  • All of the above

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