Detoxification from Detoxification from Benzodiazepines.Benzodiazepines.

Why, when and how…Why, when and how…Lucy CockayneLucy Cockayne

Lead ClinicianLead Clinician

Key pointsKey points

• It is possible

• It is worth doing

• It needs the right time, the right support and the right regimen

• Relapse happens but should not be a reason not to try and keep trying!

Not every one needs a detox…Not every one needs a detox…

• Even with long term use mot everyone develops dependency.

• More likely when• Longer durations of treatment• Higher doses• More potent benzodiazepines• Shorter-acting drugs• A history of anxiety problems

• (Kan et al 2004)

ADDICTION IS A ADDICTION IS A BRAIN DISEASEBRAIN DISEASE

AND IT MATTERS !!

Drug addiction is a chronic, Drug addiction is a chronic, relapsing brain diseaserelapsing brain disease

Why detoxifyWhy detoxify

• Long term use:– Affects thinking and memory– Reduces emotional responsiveness– Increased depression and anxiety

• Most actually feel better after coming off the drugs “the net curtain lifted …”

• Even short term consequences can be dire!! (look away if you are squeamish))

BENZODIAZEPINES !!BENZODIAZEPINES !!

temazepam injecting & necrotizing fasciitis

““If the only tool you own is a If the only tool you own is a hammer, everything starts tohammer, everything starts to

look like a nail”look like a nail”

Is it possibleIs it possible

• Evidence for brief interventions

• Evidence for various graded withdrawal regimens – but no robust comparison (Sweetmen, Lingord-/hughes)

• Slow seems better (Ashton 1987) – but cohort study

Withdrawals depend on speed of Withdrawals depend on speed of reductionreduction

• Most people only experience mild withdrawal symptoms when withdrawal is slow and tapered to their needs [Ashton, 2002d].

• Severe withdrawal symptoms are associated with the following [Kan et al, 2004]:– Rapid withdrawal– Prolonged use of benzodiazepines– High-dose use– Short-acting, potent benzodiazepines– People with a history of anxiety problems

• Withdrawal symptoms characteristically vary in severity and type from day to day and from week to week. As some symptoms resolve, others may take their place. These symptoms gradually become less severe and less frequent with time [Ashton, 2002d].

What has been tried?What has been tried?

• NO EVIDENCE for:-– Anticonvulsants– Antipsychotics – makes it worse!!– Antidepressants– Beta blockers– Buspirone

• SOME evidence for propranolol

Lingford- Hughes et al 2004

Hard facts!Hard facts!

• Most people will become dependent after > 6 weeks continuous use

• Only 30% of benzodiazepine dependent people ever get off them completely

• Methadone patients at high risk of benzodiazepine abuse (25 - 65%)

Why is it so hard to come off?Why is it so hard to come off?

• Reducing causes increased excitation throughout the brain which causes the symptoms of withdrawal, including agitation, anxiety, and insomnia.

• The number of GABA receptors is slowly restored in response to benzodiazepine cessation or dose reduction.. The rate of withdrawal of treatment needs to allow time for GABA receptors to regenerate if withdrawal symptoms are to be minimized.

Common problems when detoxing.Common problems when detoxing.

• Symptoms of depression

• Symtopms of anxiety

• Insomnia

• Worsening of pre-existing mental health problems– OCD– Panickattacks– Psychotic symptoms

Anxiety symptomsAnxiety symptoms

Common to all anxiety• Agitation• panic attacks• agoraphobia• Insomnia• nightmares• Depression• Poor memory,• loss of concentration

Specific to withdrawal• Perceptual distortions,

depersonalization• Hallucinations (visual and

auditory)• Tingling and loss of

sensation, formication (a feeling of ants crawling over the skin)

• Sensory hypersensitivity• Muscle twitches and

fasciculations– Psychotic symptoms,

confusion, convulsions (rare)

How long do symptoms last?How long do symptoms last?

• Up to 15% of people develop protracted withdrawal symptoms (months or years)

Anxiety:- Gradually diminishes over 1 yearInsomnia:- Gradually diminishes over 6–2 monthsDepression:- May last a few months

responds to antidepressantsCognitive impairment:- Gradually improves, but may last for >1 year

Perceptual symptoms (e.g.tinnitus, paraesthesia, pain (usually in limbs)Gradually recedes, but may last for at least 1 year and occasionally persist indefinitely

Motor symptoms (e.g.muscle pain, weakness, tension, painful tremor, jerks)Usually gradually recede, but may last for >1 year

Gastrointestinal symptoms:-Gradually recede, but may last for at least 1 year and occassionally persist indefinitely

GABA BRAIN CIRCUITRYGABA BRAIN CIRCUITRY

60 - 75% OF ALL BRAIN SYNAPSES ARE GABAERGIC – “natural tranquilliser”

Some people don’t need benzos!Some people don’t need benzos!

Different detoxes for different types Different detoxes for different types of addiction?of addiction?

• Therapeutic dose dependence. • Prescribed high dose dependence

• More flexibility in reduction

• Recreational use of benzodiazepines – to increase the "kick" obtained from illicit

drugs – alleviate the withdrawal symptoms of other

drugs of abuse • Tend to be fixed withdrawal – why?

Suggested principles.Suggested principles.

• Where possible change to a long acting drug – usually diazepam

• Avoid extra medication

• Antidepressants only useful for clinical depression or panic attacks

• SUPPORT.. SUPPORT.. SUPPORT!• Family, friends, helplines, addiction or GP staff

Why use diazepam?Why use diazepam?

• Withdrawal is most easily managed from diazepam because:

• Diazepam and its metabolites (desmethyldiazepam and nordiazepam) have long half-lives (between 20 hours and 200 hours), which ensures a gradual fall in blood concentrations. The blood level of its longest active metabolite for each dose falls by a half in about 8 days [Micromedex, 2006

When to detox?When to detox?

• Sometimes required to “get on a script”• Usually only short term success

• Well prepared:– Good physicaland psychological health– Stable on other drugs – e.g. methadone or

anti depressants– Stable personal circumstances

Detox regimensDetox regimens

• Be flexible in following the schedule• For people taking 40 mg per day of diazepam or less, a typical

withdrawal schedule that is tolerated by most people would be to:– Reduce by 2 mg to 4 mg every 1–2 weeks to 20 mg per day– Reduce by 1 mg to 2 mg every 1–2 weeks to 10 mg per day– Reduce by 1 mg every 1–2 weeks to 5 mg per day– Reduce by 0.5 mg to 1 mg every 1–2 weeks until completely stopped.

• Total withdrawal time from diazepam 40 mg per day might be 30–60 weeks; withdrawal from diazepam 20 mg per day might take 20–40 weeks.

• Stopping the last few milligrams is often seen by patients as being particularly difficult but this is usually an unfounded fear derived from long-term psychological dependence on benzodiazepines.

RCGP new guidelinesRCGP new guidelines

• Highlight benefits of stopping

• Recommend FLEXIBLE, GRADUAL reduction, “tailored to individual”

• “consider the need for psychological support”

• “When symptoms arise…– Explain– Slow or suspend withdrawal

New developmentsNew developments

FLUMAZENILFLUMAZENIL• benzodiazepine receptor “antagonist” (high

affinity, low agonist action)

• attenuates withdrawal and reduces withdrawal symptoms & signs

• normalizes and upregulates BZD receptors

• restores GABA receptor allosteric structure and inhibits BZD induced uncoupling

• reverses tolerance

• reduces craving

Intravenous flumazenil versus Intravenous flumazenil versus oxazepam in the treatment of oxazepam in the treatment of benzodiazepinewithdrawal: a benzodiazepinewithdrawal: a

randomized, placebo-randomized, placebo-controlled study controlled study

Gerra G et alGerra G et al

Addiction Biology; 7:385 -395, 2002Addiction Biology; 7:385 -395, 2002

Single-blind, randomized, placebo- Single-blind, randomized, placebo- controlled trialcontrolled trial

• (n = 20) IV flumazenil 1mg in 500ml normal saline over 4hrs x twice daily (0900 - 1300; 1430 - 1830) for 8 days + (oxazepam 30mg,15mg, 7.5mg nocte x 3 days)

• (n = 20) tapering oxazepam 105mg - 7.5mg over 8 days

• (n = 10) placebo tablets and saline infusion

Intravenous flumazenil in the Intravenous flumazenil in the treatment of benzodiazepine treatment of benzodiazepine

dependencedependence

• reduced withdrawal symptoms & signsreduced withdrawal symptoms & signs

• reduced cravingreduced craving

• reduced post detoxification relapse reduced post detoxification relapse ratesrates

Intravenous flumazenil in the Intravenous flumazenil in the treatment of benzodiazepine treatment of benzodiazepine

dependencedependence

•reduced post detoxification relapse reduced post detoxification relapse ratesrates•DAY 30DAY 30

– FLUMAZENIL: 40%

– OXAZEPAM: 70%

Westmead protocolWestmead protocol

• IV flumazenil 1mg in 500mg normal saline per 6 hours continuous infusion for 4 - 5 days

• No benzodiazepine supplementation

• 24 hours post infusion observation

BENZODIAZEPINE ABSTINENCE AT LONG TERM BENZODIAZEPINE ABSTINENCE AT LONG TERM FOLLOW-UPFOLLOW-UP

• I MONTH

– Abstinent = 75%

– Known Relapse = 11%

– Relapse + lost to follow up = 25%

• 3 MONTHS

– Abstinent = 54%

– Known Relapse = 34%

– Relapse + lost to follow up = 46%

ReferencesReferences• Ashton, C.H. (1987) Benzodiazepine withdrawal: outcome in 50 patients. British Journal of

Addiction 82(6), 665-671.• Ashton, C.H. (2002a) Benzodiazepines: how they work and how to withdraw. The Ashton

Manual. University of Newcastle. www.benzo.org.uk [Accessed: 16/03/2006]. [Free Full-text]• Ashton, C.H. (2002b) How to withdraw from benzodiazepines after long-term use. The Ashton

Manual. University of Newcastle. www.benzo.org.uk [Accessed: 31/03/2006]. [Free Full-text]• Ashton, C.H. (2002c) Slow withdrawal schedules. The Ashton Manual. University of

Newcastle. www.benzo.org.uk [Accessed: 31/03/2006]. [Free Full-text]• Ashton, C.H. (2002d) Benzodiazepine withdrawal symptoms, acute and protracted. The

Ashton Manual. University of Newcastle. www.benzo.org.uk [Accessed: 31/03/2006]. [Free Full-text]

• Ashton, C.H. (2004a) Protracted withdrawal symptoms from benzodiazepines. Comprehensive handbook of drug & addiction. University of Newcastle. www.benzo.org.uk [Accessed: 10/04/2006]. [Free Full-text]

• Ashton, H. (2004b) Benzodiazepine dependence. In: Haddad, P., Dursun, S. and Deakin, B. (Eds.) Adverse syndromes and psychiatric drugs. Oxford: Oxford University Press. 239-260.

• Ashton, H. (2005) The diagnosis and management of benzodiazepine dependence. Current Opinion in Psychiatry 18(3), 249-255.

• Bashir, K., King, M. and Ashworth, M. (1994) Controlled evaluation of brief intervention by general practitioners to reduce chronic use of benzodiazepines. British Journal of General Practice 44(386), 408-412. [Free Full-text]

• Bateson, A.N. (2002) Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal. Current Pharmaceutical Design 8(1), 5-21. [NHS Athens Full-text]

References (cont)References (cont)• BNF 51 (2006) British National Formulary. 51st edn. London: British Medical Association and

Royal Pharmaceutical Society of Great Britain.• Bowie, A., McAvoy, B., Spencer, I. et al. (2006) Randomised controlled trial of two brief

interventions against long-term benzodiazepine use: outcome of intervention. Addiction Research and Theory 12(2), 141-154.

• Cormack, M.A., Owens, R.G. and Dewey, M.E. (1989) The effect of minimal interventions by general practitioners on long-term benzodiazepine use. Journal of the Royal College of General Practitioners 39(327), 408-411.

• CSM (1988) Benzodiazepines, dependence and withdrawal symptoms. Current Problems in Pharmacovigilance 21(Jan), 1-2. [Free Full-text]

• Curran, H.V., Collins, R., Fletcher, S. et al. (2003) Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychological Medicine 33(7), 1223-1237.

• DTB (2004) What's wrong with prescribing hypnotics? Drug & Therapeutics Bulletin 42(12), 89-93.

• Kan, C.C., Hilberink, S.R. and Breteler, M.H. (2004) Determination of the main risk factors for benzodiazepine dependence using a multivariate and multidimensional approach. Comprehensive Psychiatry 45(2), 88-94.

• Kaplan, E.M. and DuPont, R.L. (2005) Benzodiazepines and anxiety disorders: a review for the practicing physician. Current Medical Research and Opinion 21(6), 941-950. [NHS Athens Full-text]

References (cont)References (cont)

• Lingford-Hughes, A.R., Welch, S. and Nutt, D.J. (2004) Evidence-based guidelines for the pharmacological management of substance misuse, addiction and comorbidity: recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology 18(3), 293-335.

• Longo, L.P and Johnson, B. (2000) Addiction: part I. Benzodiazepines - side effects, abuse risk and alternatives. American Family Physician 61(7), 2121-2128. [Free Full-text]

• MeReC (2005) Benzodiazepines and newer hypnotics. MeReC Bulletin 15(5), 17-20. [Free Full-text]

• Micromedex (2006) MICROMEDEX [CD-ROM]. (vol 127, 1st quarter 2006). Thomson Healthcare.

• Montgomery, P. and Dennis, J. (2003) Cognitive behavioural interventions for sleep problems in adults aged 60+ (Cochrane Review). The Cochrane Library. Issue 1. Chichester, UK: John Wiley & Sons, Ltd. www.thecochranelibrary.com [Accessed: 08/03/2007]. [Free Full-text]