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Transcript
Detoxification from
Benzodiazepines.
Why, when and how…
Lucy Cockayne
Lead Clinician
Key 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…
• 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
BRAIN DISEASE
AND IT MATTERS !!
Drug addiction is a chronic,
relapsing brain disease
Why 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 !!
temazepam injecting & necrotizing fasciitis
“If the only tool you own is a
hammer, everything starts to
look like a nail”
Is 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
reduction
• 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?
• NO EVIDENCE for:– Anticonvulsants
– Antipsychotics – makes it worse!!
– Antidepressants
– Beta blockers
– Buspirone
• SOME evidence for propranolol
Lingford- Hughes et al 2004
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?
• 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.
•
•
•
•
Symptoms of depression
Symtopms of anxiety
Insomnia
Worsening of pre-existing mental health
problems
– OCD
– Panickattacks
– Psychotic symptoms
Anxiety 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?
•
Up to 15% of people develop protracted withdrawal symptoms (months
or years)
Anxiety:Gradually diminishes over 1 year
Insomnia:Gradually diminishes over 6–2 months
Depression:May last a few months
responds to antidepressants
Cognitive 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 CIRCUITRY
60 - 75% OF
ALL BRAIN
SYNAPSES
ARE
GABAERGIC
– “natural
tranquilliser”
Some people don’t need benzos!
Different detoxes for different types
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.
• 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?
• 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?
• 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 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 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 developments
FLUMAZENIL
• 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
oxazepam in the treatment of
benzodiazepinewithdrawal: a
randomized, placebocontrolled study
Gerra G et al
Addiction Biology; 7:385 -395, 2002
Single-blind, randomized, placebocontrolled 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
Intravenous flumazenil in the
treatment of benzodiazepine
dependence
• reduced withdrawal symptoms & signs
• reduced craving
• reduced post detoxification relapse
rates
Intravenous flumazenil in the
treatment of benzodiazepine
dependence
•reduced post detoxification relapse
rates
•DAY 30
– FLUMAZENIL: 40%
– OXAZEPAM: 70%
Westmead 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
FOLLOW-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%
References
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•
•
•
•
•
•
•
•
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)
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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 Fulltext]
References (cont)
• Lingford-Hughes, A.R., Welch, S. and Nutt, D.J. (2004) Evidencebased 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]