1. Consultant Addiction Psychiatrist
Greenwich Drug And Alcohol Service: The Beresford Project
GP Liaison Issues in General Practice Managing the Prescribing of Benzodiazepines in Primary Care
Dr Francis Keaney
Consultant Addiction Psychiatrist
The Beresford Project

2. 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

3. Benzodiazepines & “Z” drugs
Anxiolytics Diazepam (Anxiety) Chlordiazepoxide (Anxiety) Lorazepam (Anxiety) Oxazepam (Anxiety) Hypnotics Nitrazepam (Insomnia) Temazepam(Insomnia) Loprazolam (Insomnia) Lormetazepam (Insomnia) Zopiclone (Insomnia) Zolpidem (Insomnia) Zaleplon (Insomnia)

4. 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

5. Indications for BDZ Anxiolytic Hypnotic Anticonvulsant Muscle relaxant
Pre-amnesia
Alcohol withdrawal

6. 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

7. 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

8. 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

9. Munro et al. TiPS (2009) 30:

10. 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.

11. Diazepam Pharmacokinetics
Bioavailability: almost complete orally
Peak concentration: 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 hours

12. Problems associated with long-term use of BDZ (may also occur with short-term use)
Adverse effects: Drowsiness & falls Impairment in judgement & dexterity Increased risk of RTA Forgetfulness,confusion,irritability, aggression & Paradoxical disinhibition Complications: Depression Reduction in coping skills Tolerance & dependence

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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’

21. 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 21

22. Benzodiazepine withdrawal
Onset and severity depend on:
half-life of the drug
duration of treatment
personality of the patient 22

23. Benzodiazepine Prescribing Review in Greenwich

25. 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

26. Supportive Interventions
BDZ & Z drugs PowerPoint presentation to all practice staff GPs to list top 15 patients 1:1 consultations with each GP on patients prior to been seen An one hour assessment offered to each patient Information leaflets to clients, protocols to prescribers Support in referring to IAPT or Adult Mental Health Psychology Written reports to GPs 1:1 consultations with each GP after assessments

27. 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

28. Results of Pilot
15 Patients Referred 8 Assessed at practice 3 Assessed at the Beresford Project 1 deregistered 3 DNAs

29. 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)

30. 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

31. 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