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Benzodiazepines

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Title: Benzodiazepines


1
Benzodiazepines
  • Dr Alison Battersby

2
The Problem of Instant Gratification
3
Mothers little helpers
  • Identified 1957, calming effect on test animals
  • Chlordiazepoxide 1960, diazepam 1962
  • Replacement for barbiturates
  • Initially thought to only cause dependence in
    high dose

4
Kids are different today/I hear every Mother
say/Mother needs something to calm her down/And
though shes not really ill/Theres a little
yellow pill/She goes running for the shelter/of a
mothers little helper/and it helps her on her
way/gets her through her busy day.
5
Receptor 101
  • Glutamate activates the brain resulting in
    learning and memory, in excess anxiety and
    seizures
  • NMDA glutamate receptor

6
Receptor 102
  • GABA calms the brain causes sedation, calming,
    relaxation, unsteadiness etc
  • Benzodiazepines have a selective action on GABAA
    receptors
  • Open GABA-activated in the presence of GABA
  • Bind specifically to regulatory site of the
    receptor not the GABA-binding site
  • Allosteric action (increases affinity of GABA for
    the receptor

7
GABAA receptor structure
  • Pentameric structure of subunits
  • ?, ß, ? subunits
  • ?1 subunit sedative, amnesic and anticonvulsant
    effects
  • ?2 subunit anxiolytic and muscle relaxant effects

8
Diazepam Pharmacokinetics
  • Bioavailability almost complete orally
  • Peak concentration 30-90 minutes
  • Protein-binding 90-95
  • Renal excretion negligible for unchanged drug
  • Metabolism phase 1 to active metabolite
    desmethyldiazepam, phase 2 for inactivation of
    metabolites
  • Elimination half life 20 hours, more in elderly
  • Desmethyldiazepam 30-90 hours

9
Diazepam Pharmacokinetics
  • Absorption following im erratic
  • Highly lipid soluble diffuses into CNS rapidly,
    found in breast milk, crosses placenta
  • Newborn infants metabolise BDZ slowly, can
    accumulate to cause respiratory depression
  • Reports of cleft lip and palate

10
CSM 1988 advised limiting length of treatment to
2-4 weeks only
  • COMMITTEE ON SAFETY OF MEDICINES
  • UK Government Bulletin to Prescribing
    DoctorsJanuary 1988
  • CURRENT PROBLEMS1988 Number 21 1-2
  • BENZODIAZEPINES, DEPENDENCE ANDWITHDRAWAL
    SYMPTOMS

11
DH in 2004 reiterated CSM advice
  • BENZODIAZEPINES WARNING
  • A communication to all doctors from the Chief
    Medical Officer CMO's Update 37 January 2004
  • PATIENT SAFETY
  • Doctors are being reminded that benzodiazepines
    should only be prescribed for short-term
    treatment, in light of continued reports about
    problems with long-term use.

12
Adverse effects from BDZ over 2-4 weeks very
limited
  • Sig adverse effects rare at BNF doses-unless
    elderly or hepatic/renal compromise
  • Cognitive and motor effects (initially)
  • Rebound insomnia and anxiety on stopping
  • Physical withdrawal after short-term use rare
  • Memory problems with every dose
  • Hangover and daytime sleepiness

13
Memory problems associated with therapeutic BDZ
use
  • Memory problems routinely occur in people who
    take BDZ
  • Incomplete tolerance occurs to memory effects
    even after long term use
  • Difficulty acquiring new information at
    therapeutic doses of BDZ
  • Occurs with every dose taken
  • A specific effect in remembering recent events
  • Also interferes with concentration and attention

14
Transient global amnesia with high dose BDZ use
  • Loss of memory for previous days events,
    although behaving normally at the time
  • Feel floaty, warm and comfortable with no worries
  • Feel invincible and invisible
  • Flunitrazepam (rohypnol) date rape
  • Similarly with high dose zopiclone (30mg )
  • Utilised for premed and anaesthesia

15
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16
How addictive are BDZs?
  • Normal populations Risk low, moderate drinkers gt
    minimal drinkers
  • Psychiatric populations Intermediate risk
  • Addict population risk considerably higher,
    strong links with alcohol problems ?GABA subunit
    change, opiate use and dependent PD

17
The Benzo Trap
  • Start BDZ script short term use for a clear
    indication
  • Slippage occurs prescriber extends a script
    ?pressure from pt, indication becomes less clear
    eg to help with poor coping or chronic stress.
    Pt put on hold
  • BDZ script becomes difficult to stop pt
    motivated to continue BDZ, may be denied by pt,
    pt reports continuing efficacy, may be partial,
    underlying problems not resolved

18
Prescribing to illicit BDZ usersDH Orange
Guidelines 2007
  • Many drug users misuse BDZs but the majority do
    not require long-term replacement prescribing or
    high doses
  • Clinicians may be faced with a request to
    continue a prescription for maintenance BDZs. To
    help prevent symptoms of BDZ withdrawal, the
    clinician should continue the prescription but
    the dose should be gradually reduced to zero.
    Only very rarely should doses of more than 30mg
    diazepam equivalent per day be prescribed

19
Prescribing for illicit users
  • At least 2 BDZ positive urine screens
  • No BDZ negative urine screens in last 4 mths
  • Evidence from history and symptoms that pt is
    physically dependent on BDZ
  • You believe benefits of Tx will outweigh the
    adverse effects and risks eg diversion
  • You are happy to take clinical responsibility

20
Take into account
  • Short term use memory and hangover effects, BDZ
    symptomativ Tx only, risk of long term use
  • Longer term use adverse effects and associated
    risk including emotional suppression and
    difficulty coping, use in higher risk groups,
    avoid for poor coping or general stress

21
Prevention of fits and BDZ withdrawal symptoms
when stopping high doses (if stopping several
hundred mg diazepam or equivalent)
  • No need to give equivalent replacement doses to
    prevent withdrawal in high dose illicit user
    (Harrison et al 1984, Williams et al 1996)
  • Seizures may occur if high doses stopped
    abruptly, only if physically dependent
  • Long half life prevents most withdrawal, up to
    30mg daily to prevent withdrawal fits
  • Client complaining of withdrawal usually
    complaining of lack of high, anxiolytic or
    sedative effect
  • Look for objective evidence of BDZ withdrawal eg
    signs of anxiety and tachycardia,
    hypersensitivity to light

22
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23
3 subjective reasons to abuse BDZs
  • Fun/pleasure/buzz/high/rush/sedation
  • Numb the mind seek oblivion, escape so dont
    feel part of the world
  • Self-medication psychiatric issues (anxiety,
    depression, reduce voices, medication side
    effects)
  • Psychological issues (sleep, relax, improve
    confidence and low mood, worries and any other
    distress)
  • Drug use (withdrawal, come down and substitution)

24
4 stages of addiction treatment
  • Assessment
  • Induction, engagement and stabilisation
    (including drug stabilisation and psychosocial
    stabilisation)
  • Detoxification
  • Maintenance of abstinence (aftercare)

25
The Addiction Process
  • Rapid onset of drugs positive effects
  • Good effects occur quickly after consumption
  • More conditioning/psychological reinforcement
    every time BDZ taken
  • Psychological aspect of addiction strengthened
  • Psychological addiction (dependence syndrome)
    with predisposition/desire to use more and more

26
Illicit Mexican Diazepam
27
  • The most guaranteed way to battle anxiety.
  • In our modern world a man faces plenty of
    stressful situations that result in the symptoms
    of anxiety like nervous tension, insomnia, panic
    or muscle spasms. In such cases to buy Diazepam
    with no prescription needed is the best way out
    because this medication treats a wide range of
    conditions.

28
Cost of Illicit Diazepam
  • 1 for a 10mg blue tablet
  • Over the web from India 8-13 pence for a 10mg
    tablet (may be white, uncertain if another benzo
    rather than diazepam)

29
Actively pursue best practice when initiating a
BDZ prescription
  • Specify to the patient at the outset maximum
    length of time you are prepared to prescribe BDZ
    for their condition, an agreed time frame for a
    review, explain the risks of BDZ use, explain why
    long term use is not justified
  • Issue short term prescriptions only use the
    lowest effective dose, building up if necessary,
    prescribe for the briefest possible time

30
Benzodiazepine withdrawal
  • After Hallstrom 1990
  • Stop BDZ when pt is emotionally ready to do so
    the need for taking them has passed, pt has
    recovered (returned to premorbid level of
    functioning), pt is no longer preoccupied with
    their symptoms, pt and doctor feel time is right,
    pt learnt about problems and advantages of
    stopping
  • Encourage self-help, alternative coping skills eg
    anxiety management, cognitive control (CBT not
    effect during detoxification)

31
Dealing with BDZ detox problems
  • Continuing anxiety/depression treat psychiatric
    problems more effectively
  • Difficulty coping with stress increase
    psychosocial support
  • Difficulty sleeping reassure and sleep hygiene
  • Difficulty coping with BDZ withdrawal symptoms
    use longer half-life BDZ eg diazepam, clonazepam
  • Liking benzo too much to reduce it, use slow
    onset BDZ eg oxazepam
  • Using different amounts each day or binging etc,
    daily pick ups, supervision

32
Self-help for tranquiliser withdrawal
  • Ashton self-help manual for benzodiazepine
    withdrawal www.benzo.org.uk/manual
  • The Council for Information on Tranquilisers and
    Antidepressants www.citawithdrawal.org.uk
  • Battle Against Tranquilisers (BAT) www.bataid.org

33
How fast to withdraw BDZ?
  • Can be very fast if short term use, non
    dependent, low dose use
  • Reductions slower if dependency syndrome and
    psychological work required (or fits)
  • 10mg every 2-4 weeks if gt60mg diazepam, 5mg every
    2-4 weeks if 20-60mg, 2.5mg every 2-4 weeks less
    than 20mg
  • Or as tolerated

34
Prolonged withdrawal reaction
  • Higgitt et al 1988, 1990, Ashton 1991
  • Criteria suggested by Higgett et al (1988)
  • 3 new complaints on BDZ withdrawal
  • 2 persist for more than 4 weeks after the last
    dose
  • 1 severe enough to interfere with functioning

35
  • Symptoms from Higgitt, decreased concentration,
    memory, energy, insomnia, metallic taste, blurred
    vision, eye soreness, light/touch/noise
    sensitivity, derealisation, cramps, pins and
    needles. Severe pains
  • Many other sx may occur eg tinnitus,
    paraesthesias, other neurological symptoms and
    may last for years

36
Clinical opinion varies!
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