Benzodiazepines – the big picture

Dr Malcolm Bruce

Consultant Psychiatrist in Addiction NHS Lothian [email protected]

History

Greeks / Egyptians up to 17 18 th there would be no medicine” 1830 - Chloral Hydrate 1860 - Bromides 1930 – Barbiturates 1960 – Ro5-0690 (Librium) 1963 – Valium 1965 – Mogadon Valium, 4 USA $354 million in 1984 each year th th 1985 – Roche patent ends on ($690 million at 2006 prices) & Century – “without opium highest drug sales in In UK 3% pop use daily, 11% use

Why….

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

Plus ça 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

Don’t have this too….

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Neuro-physiological Tolerance / 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:

Assessment BDZ treatable clinical problem Addiction Not Tx resistant Tx resistant (Tx > 4 wks) Brief Definite Situational Identifiable Stress Endpoint (Tx < 1 wk) (Tx < 4 wks) Currently excluded from treatment guidelines Currently excluded from treatment 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 1 Meta-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 2 3 4 Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal Non-analytic studies, e.g. case reports, case series Expert 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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