Benzodiazepines

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Benzodiazepines

• Dr Alison Battersby

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The Problem of Instant Gratification
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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

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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.
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Receptor 101

• Glutamate activates the brain resulting in
  learning and memory, in excess anxiety and
  seizures
• NMDA glutamate receptor

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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

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GABAA receptor structure

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

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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4 stages of addiction treatment

• Assessment
• Induction, engagement and stabilisation
  (including drug stabilisation and psychosocial
  stabilisation)
• Detoxification
• Maintenance of abstinence (aftercare)

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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

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Illicit Mexican Diazepam
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• 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.

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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)

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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

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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)

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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

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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

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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

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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

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• 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

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Clinical opinion varies!