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

• 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 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

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 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

• 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!