Benzodiazepines – Benzodiazepines – the big picturethe big picture

Dr Malcolm BruceDr Malcolm Bruce

Consultant Psychiatrist in Addiction Consultant Psychiatrist in Addiction NHS Lothian NHS Lothian

malcolm.bruce@lpct.scot.nhs.ukmalcolm.bruce@lpct.scot.nhs.uk

HistoryHistoryGreeks / Egyptians up to 17Greeks / Egyptians up to 17thth & 18 & 18thth Century – “without opium there Century – “without opium there would be no medicine”would be no medicine”1830 - Chloral Hydrate1830 - Chloral Hydrate1860 - Bromides1860 - Bromides1930 – Barbiturates1930 – Barbiturates1960 – Ro5-0690 (Librium)1960 – Ro5-0690 (Librium)1963 – Valium1963 – Valium1965 – Mogadon1965 – Mogadon1985 – Roche patent ends on 1985 – Roche patent ends on Valium, 4Valium, 4thth highest drug sales in highest drug sales in USA $354 million in 1984 USA $354 million in 1984 ($690 million at 2006 prices) ($690 million at 2006 prices) In UK 3% pop use daily, 11% use In UK 3% pop use daily, 11% use each yeareach year

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

The Doors of Perception 1954 A HuxleyThe Doors of Perception 1954 A Huxley

BenzodiazepinesBenzodiazepines"the opium of the masses""the opium of the masses"

1978 Malcolm Lader1978 Malcolm Lader

PlusPlus ça change……ça change……

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

1999 Professor Lader 1999 Professor Lader

Don’t start from here….Don’t start from here….Heroin addictionHeroin addiction– MM doesn’t workMM doesn’t work– I/V abuse TemgesicI/V abuse Temgesic– HepC plus epidemicHepC plus epidemic– Shortage of needlesShortage of needles– Police witnessesPolice witnesses

– Ah! Thank God for Ah! Thank God for benzodiazepinesbenzodiazepines

– Px 100mg DZ, Px 100mg DZ, 60mg TZ60mg TZ

Don’t have this too….Don’t have this too….

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Neuro-physiologicalNeuro-physiological Tolerance / Homeostasis / WithdrawalTolerance / Homeostasis / Withdrawal

Changes in protein expression of Changes in protein expression of endogenous GABA precursors endogenous GABA precursors

Reduced sensitivity of GABA receptorsReduced sensitivity of GABA receptors

Down-regulation of GABA sites in inhibitory Down-regulation of GABA sites in inhibitory receptors systemreceptors system

Morphological changes in the GABA Morphological changes in the GABA dendrites dendrites

Up-regulation of reciprocal excitatory Up-regulation of reciprocal excitatory receptor systemsreceptor systems

Typical BDZ/Hypnotic GuidelinesTypical BDZ/Hypnotic GuidelinesUse lowest BDZ/hypnotic dose for briefest timeUse lowest BDZ/hypnotic dose for briefest time– 2-4 weeks for hypnotics, up to 4 weeks for 2-4 weeks for hypnotics, up to 4 weeks for

anxiolyticsanxiolyticsUse only one BDZ (give long-acting one at night if Use only one BDZ (give long-acting one at night if need both a hypnotic and an anxiolytic effect)need both a hypnotic and an anxiolytic effect)Dose used should be in therapeutic range (i.e. Dose used should be in therapeutic range (i.e. within BNF limits)within BNF limits)Reduce gradually after both short term (> 2 Reduce gradually after both short term (> 2 weeks) and long term useweeks) and long term useOnly use in acute self-limiting Only use in acute self-limiting situations/conditionssituations/conditionsOnly use for severe symptoms (never mild Only use for severe symptoms (never mild symptoms)symptoms)Do not use in those with a history of addictionDo not use in those with a history of addiction

Current BDZ Guidelines:Current BDZ Guidelines: Assessment

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 Key to evidence statements and grades of recommendationsgrades of recommendations

Levels of evidence (SIGN)Levels of evidence (SIGN)1++1++ High quality meta-analyses, systematic reviews of RCTs, or High quality meta-analyses, systematic reviews of RCTs, or

RCTs with a very low risk of biasRCTs with a very low risk of bias1+1+ Well-conducted meta-analyses, systematic reviews, or RCTs Well-conducted meta-analyses, systematic reviews, or RCTs

with a low risk of biaswith a low risk of bias11 Meta-analyses, systematic reviews, or RCTs with a high risk Meta-analyses, systematic reviews, or RCTs with a high risk

of biasof bias2++2++ High quality systematic reviews of case control or cohort or High quality systematic reviews of case control or cohort or

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

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

22 Case control or cohort studies with a high risk of Case control or cohort studies with a high risk of confounding confounding or bias and a significant risk that the relationship is or bias and a significant risk that the relationship is not not causalcausal33 Non-analytic studies, e.g. case reports, case seriesNon-analytic studies, e.g. case reports, case series44 Expert opinionExpert opinion

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

BZ in SEMI and comorbid SMUBZ in SEMI and comorbid SMU

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

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

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

Conclusion: Do not Px BZ in this groupConclusion: Do not Px BZ in this group

Opinion: significant risk that the Opinion: significant risk that the relationship is not causalrelationship is not causal

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

Case reports - retrospective analysis Case reports - retrospective analysis of coroners' records in opiate-related of coroners' records in opiate-related poisoning, 1997- 2000poisoning, 1997- 2000Measure: Toxicological findingsMeasure: Toxicological findingsOutcome: 61% - Concomitant BZOutcome: 61% - Concomitant BZConclusion: BZ, at least in lower Conclusion: BZ, at least in lower quantities appear to be a feature quantities appear to be a feature rather than a risk factor per se in rather than a risk factor per se in such fatalities. such fatalities.

Level 4 evidence – Level 4 evidence – BDZ Guidelines By August BodiesBDZ Guidelines By August Bodies

Committee on Review of Medicines (1980)Committee on Review of Medicines (1980)

Quality Assurance Project (1985)Quality Assurance Project (1985)

Committee on Safety of Medicines (1988)Committee on Safety of Medicines (1988)

American Psychiatric Association (1990)American Psychiatric Association (1990)

Consensus conference on GAD (1992) Consensus conference on GAD (1992)

Royal Society of Medicine (1992) Royal Society of Medicine (1992)

Mental Health Foundation (1993)Mental Health Foundation (1993)

National Medical Advisory Committee (1994)National Medical Advisory Committee (1994)

World Health Organisation (1996)World Health Organisation (1996)

Royal College of Psychiatrists (1997)Royal College of Psychiatrists (1997)

Academy of Sleep Medicine (1999)Academy of Sleep Medicine (1999)

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

What is the problem, why so What is the problem, why so many BDZ Guidelines?many BDZ Guidelines?

Audits reveal an enormous divergence Audits reveal an enormous divergence between BDZ guidelines and prescribing between BDZ guidelines and prescribing practice practice BDZ guidelines for psychiatrists (e.g. WHO BDZ guidelines for psychiatrists (e.g. WHO 1996, RCPsych 1997) specify a number of 1996, RCPsych 1997) specify a number of principles similar to other guidelines & then principles similar to other guidelines & then provide so many exceptions to them, they provide so many exceptions to them, they seriously undermine themselves seriously undermine themselves Guidelines should be evidence based: Guidelines should be evidence based: Current guidelines have more to do with Current guidelines have more to do with policy than evidence policy than evidence

Factors Increasing Risk of Factors Increasing Risk of BDZ Withdrawal ReactionsBDZ Withdrawal Reactions

Related to physiological withdrawal:Related to physiological withdrawal:– Longer term (e.g. > 4 months)Longer term (e.g. > 4 months)– Higher than therapeutic dose useHigher than therapeutic dose use– High potency short/intermediate half-life BDZ (e.g. alprazolam, High potency short/intermediate half-life BDZ (e.g. alprazolam,

lorazepam)lorazepam)

Related to diagnoses:Related to diagnoses:– Chronic psychiatric problems: Chronic dysthymia or dysphoria Chronic psychiatric problems: Chronic dysthymia or dysphoria

BPD or dependent PD, panic disorder, chronic psychosis, BPD or dependent PD, panic disorder, chronic psychosis, neuroleptic side-effectsneuroleptic side-effects

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

Related to personality factors / addiction proneness:Related to personality factors / addiction proneness:– FH or current/past alcohol or other sedative-hypnotic FH or current/past alcohol or other sedative-hypnotic

dependence dependence

Risk of Long Term BDZ PrescribingRisk of Long Term BDZ PrescribingIncreased risk of withdrawal reactions and BDZ Increased risk of withdrawal reactions and BDZ dependence syndromedependence syndromeThe BDZ becomes the problem: Underlying issues The BDZ becomes the problem: Underlying issues avoided & BDZ seen as the solution. Anxiety may avoided & BDZ seen as the solution. Anxiety may reduce if BDZ stopped (Rickels et al 90, 91, Schweizer reduce if BDZ stopped (Rickels et al 90, 91, Schweizer et al 90)et al 90)

Subtle but definite cognitive deficits:Subtle but definite cognitive deficits:– Anterograde amnesia (Episodic memory) Anterograde amnesia (Episodic memory)

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

– Emotional suppression leading to a cumulative Emotional suppression leading to a cumulative effect on emotional coping and a learning effect on emotional coping and a learning deficitdeficit

The Hippocratic Oath: The Hippocratic Oath: I will I will prescribeprescribe regimens for the good of my patients according to my regimens for the good of my patients according to my

ability and my judgment and ability and my judgment and never do harm.never do harm.

Is it defensible to expose patients to the risk of Is it defensible to expose patients to the risk of developing dependency by long term or indefinite developing dependency by long term or indefinite use of BDZ when:use of BDZ when:– Alternative Tx’s have failed (i.e. Tx resistance)?Alternative Tx’s have failed (i.e. Tx resistance)?

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

– Decision taken in conjunction with patient?Decision taken in conjunction with patient?

– Tx is strictly individualised?Tx is strictly individualised?

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

All of the aboveAll of the above

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