Benzodiazepines
Dr Alison Battersby
The Problem of Instant Gratification
Mother’s 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
Kids are different today/I hear every Mother say/Mother
needs something to calm her down/And though she’s not
really ill/There’s a little yellow pill/She goes running for the
shelter/of a mother’s little helper/and it helps her on her
way/gets her through her busy day.
Receptor 101
• Glutamate activates the brain resulting in
learning and memory, in excess anxiety
and seizures
• NMDA glutamate receptor
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
GABAA receptor structure
• Pentameric structure of subunits
• Α, β, γ subunits
• Α1 subunit sedative, amnesic and
anticonvulsant effects
• Α2 subunit anxiolytic and muscle relaxant
effects
Diazepam Pharmacokinetics
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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
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
CSM 1988 advised limiting length
of treatment to 2-4 weeks only
• COMMITTEE ON SAFETY OF MEDICINES
• UK Government Bulletin to Prescribing Doctors
January 1988
• CURRENT PROBLEMS
1988; Number 21: 1-2
• BENZODIAZEPINES, DEPENDENCE AND
WITHDRAWAL SYMPTOMS
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.
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
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
Transient global amnesia with high
dose BDZ use
• Loss of memory for previous day’s 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
How addictive are BDZ’s?
• Normal populations: Risk low, moderate
drinkers > minimal drinkers
• Psychiatric populations: Intermediate risk
• Addict population: risk considerably higher,
strong links with alcohol problems ?GABA
subunit change, opiate use and dependent
PD
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
Prescribing to illicit BDZ users
DH 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
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
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
Prevention of fits and BDZ withdrawal
symptoms when stopping high doses (if
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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
3 subjective reasons to abuse
BDZs
• Fun/pleasure/buzz/high/rush/sedation
• Numb the mind: seek oblivion, escape so don’t 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)
4 stages of addiction treatment
• Assessment
• Induction, engagement and stabilisation
(including drug stabilisation and
psychosocial stabilisation)
• Detoxification
• Maintenance of abstinence (aftercare)
The Addiction Process
• Rapid onset of drug’s 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
Illicit Mexican Diazepam
• 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.
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)
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
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)
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
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
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 >60mg diazepam, 5mg
every 2-4 weeks if 20-60mg, 2.5mg every 2-4
weeks less than 20mg
• Or as tolerated
Prolonged withdrawal reaction
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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
• 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
Clinical opinion varies!