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History

Benzodiazepines – the big picture Dr Malcolm Bruce Consultant Psychiatrist in Addiction NHS Lothian malcolm.bruce@lpct.scot.nhs.uk. 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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History

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  1. Benzodiazepines – the big pictureDr Malcolm BruceConsultant Psychiatrist in Addiction NHS Lothianmalcolm.bruce@lpct.scot.nhs.uk

  2. History • 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

  3. 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

  4. Plusça change…… • "It is more difficult to withdraw people from benzodiazepines than it is from heroin.” 1999 Professor Lader

  5. 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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  7. 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

  8. 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

  9. 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

  10. 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 Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal • 3 Non-analytic studies, e.g. case reports, case series • 4 Expert opinion

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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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