GP Liaison Issues in General Practice

Managing the Prescribing of Benzodiazepines in Primary

Care Dr Francis KeaneyConsultant Addiction Psychiatrist

The Beresford Project

Greenwich Drug And Alcohol Service: The Beresford Project

Primary Care Patient

• 50 year old women

• Lives alone• 2 Adult children

• Benign abdominal cyst

• Anxious all the time• Had been alcohol dependent• History of trauma

• Prescribed diazepam, zopiclone and codeine

Benzodiazepines & “Z ” drugs

AnxiolyticsDiazepam (Anxiety)Chlordiazepoxide (Anxiety)Lorazepam (Anxiety)Oxazepam (Anxiety)HypnoticsNitrazepam (Insomnia)Temazepam(Insomnia)Loprazolam (Insomnia)Lormetazepam (Insomnia)Zopiclone (Insomnia)Zolpidem (Insomnia)Zaleplon (Insomnia)

Prevalence BDZ

• UK 2% adult population have used prescribed BDZ regularly for 5 – 10 years plus

• 30 – 50% long-term users have difficulty stopping because of withdrawal symptoms

• 0.5 – 1.5 million people are addicted to BDZ in the UK most on prescribed medication

• Estimated 200,000 illicit BDZ users

Indications for BDZ

• Anxiolytic

• Hypnotic

• Anticonvulsant

• Muscle relaxant

• Pre-amnesia

• Alcohol withdrawal

Iolytics are not licensed for long term use

GABAA receptors with different alpha subunits are not evenly distributed in the brain. The alpha1 subtype which mediates the sedative action of diazepam (Valium®) is abundant in cerebral cortex, cerebellar cortex, thalamus and pallidum, whereas the alpha2 subtype is localized to striatum, hippocampus, amygdala and hypothalamus. The alpha3 subtype is typical for the monoaminergic and serotonergic neurons of the brain stem and the cholinergic neurons of the basal forebrain. The alpha5 subtype is found predominantly in the hippocampus.

Source: Prof. Jean-Marc Fritschy, Institute of Pharmacology and Toxicology, University of Zurich

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

Sleep – Wake Function Regulation Neurotransmitters

• Arousing (noradrenaline,serotonin,acetylcholine,dopamine & histamine)

• Sleep-inducing (gamma-aminobutyric acid (GABA) & adenosine)

• BDZ target & bind to GABAa receptors

• Increases GABA activity, reduces neuron firing

• Results in sedating & sleep- inducing effects

Munro et al. TiPS (2009) 30: 453-459

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 2 – 4 weeks), in light of continued reports about problems with long-term use.

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

Problems associated with long-term use

of BDZ (may also occur with short-term

use)Adverse effects:

Drowsiness & fallsImpairment in judgement & dexterityIncreased risk of RTAForgetfulness,confusion,irritability, aggression &Paradoxical disinhibition

Complications:

DepressionReduction in coping skillsTolerance & dependence

Presentations of Dependence

• Patients gradually “need” BDZ to carry out normal day –to-day activities

• Patients continue to take BDZ although the original indication for the prescription is no longer relevant

• Patients have difficulty in stopping in stopping treatment or reducing the dosage due to withdrawal symptoms

• Short-acting BDZ may cause patients to develop anxiety symptoms between doses

• Patients contact their doctor regularly to obtain repeat prescriptions

• Patients become anxious if the next prescription is not readily available

• Patients may increase the dosage stated in the original prescription

• Despite BDZ therapy, patients may present with recurring anxiety symptoms, panic, agoraphobia, insomnia, depression and an increase in physical symptoms of anxiety

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

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

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

Prescriber Approach

• Positive Drug Screen

• BDZ converted to equivalent doses Diazepam

• Lowest possible dose prescribed 10 – 30mgs

• Upper limit 30mgs Diazepam

• Blue FP10 MDA dispense daily

Prescriptions ‘Acute’ rather than ‘Repeat’

Benzodiazepine withdrawal

Perceptual disturbances

Cognitive changes

Autonomic overactivty (usually much less than in alcohol withdrawal)

Seizures (uncommon, but EEG abnormalities common)

Plus a myriad of non-specific symptoms including anxiety and insomnia

Benzodiazepine withdrawalOnset and severity depend on:half-life of the drugduration of treatmentpersonality of the patient

Benzodiazepine Prescribing Review

in Greenwich

Background

GP practiced with high rates of BDZ prescribing closed

Large number of patients registered with a nearby practice

The GPs requested support in managing clients prescribed BDZ & Z drugs

Pilot organised through the Medicines Management Department

Supportive Interventions

BDZ & Z drugs PowerPoint presentation to all practice staffGPs to list top 15 patients1:1 consultations with each GP on patients prior to been

seenAn one hour assessment offered to each patient Information leaflets to clients, protocols to prescribersSupport in referring to IAPT or Adult Mental Health

PsychologyWritten reports to GPs1:1 consultations with each GP after assessments

Individual Assessments

Urine testing

Quantity, Frequency and History of BDZ & Z drug patterns of use

Psychological Issues (Past Psychiatric History)

Medications

Past Medical history

Impression (MSE & Formulation)

Recommendations

Results of Pilot

15 Patients Referred

8 Assessed at practice

3 Assessed at the Beresford Project

1 deregistered

3 DNAs

BDZ & Z Drugs

• Diazepam 16mgs od & Zopiclone 7.5mgs od (Switch to 18mgs Diazepam, reduce over 3 months)

• Zopiclone 7.5mgs (Leave alone)

• Temazepam 20mgs (Switch to Diazepam 10mgs reduce by 2mgs every 2 weeks)

• Temazepam 10mgs 2 nocte (Leave alone)

• Diazepam 2 mgs BD & Nitrazepam 5mgs 2 nocte (switch to 5mgs at night as a trial)

Observations on 11/15

All patients prescribed within licensed indications but all outside licensed duration

8 patients current but mainly former drug and alcohol dependent (mainly alcohol) (Stable but substitute substance)

3 patients had complex psychological issues, trauma, GAD, Depression, Panic Attacks referred to Time to Talk

(No direct referral route to Adult Psychology)

Two thirds agreed to modification and reduction

2 patients have stopped

Observations on The Process

Involvement of Practice Manager, Admin & Reception Staff Crucial

Culture changes important, urine testing, daily dispensing

How to manage patient behaviour (their anxieties and acting out)

Consultant Addiction Psychiatrist to now work in other practices for the duration of the pilot