Detoxification from Benzodiazepines. Why, when and how

1. Detoxification from Benzodiazepines.Why, when and how… Lucy Cockayne Lead Clinician

2. 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!

3. 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)

4. ADDICTION IS A BRAIN DISEASE Not allowing people into treatment has consequenses!Not allowing people into treatment has consequenses!

5. Addiction work needs to be evidence base and delivered with compassion. Evidence can guide guidelines – but must be adapted to the individual sitting in front of you.Addiction work needs to be evidence base and delivered with compassion. Evidence can guide guidelines – but must be adapted to the individual sitting in front of you.

6. 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)) It was as though a net curtain or veil had been lifted from their eyes: slowly, sometimes suddenly, colours became brighter, grass greener, mind clearer, fears vanished, mood lifted, and physical vigour returned.It was as though a net curtain or veil had been lifted from their eyes: slowly, sometimes suddenly, colours became brighter, grass greener, mind clearer, fears vanished, mood lifted, and physical vigour returned.

8. “If the only tool you own is a hammer, everything starts tolook like a nail”

9. 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

10. 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].

11. 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

12. 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%)

13. 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.

14. Common problems when detoxing. Symptoms of depression Symtopms of anxiety Insomnia Worsening of pre-existing mental health problems OCD Panickattacks Psychotic symptoms

15. 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)

16. 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

17. GABA BRAIN CIRCUITRY

18. Some people don’t need benzos!

20. 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?

21. 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

22. 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

23. 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

24. 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.

25. 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

26. New developments

28. 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

29. Intravenous flumazenil versus oxazepam in the treatment of benzodiazepinewithdrawal: a randomized, placebo-controlled study Gerra G et al Addiction Biology; 7:385 -395, 2002

30. Single-blind, randomized, placebo- controlled 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

31. Intravenous flumazenil in the treatment of benzodiazepine dependence reduced withdrawal symptoms & signs reduced craving reduced post detoxification relapse rates

32. Intravenous flumazenil in the treatment of benzodiazepine dependence reduced post detoxification relapse rates DAY 30 FLUMAZENIL: 40% OXAZEPAM: 70%

33. 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

34. 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%

36. References 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]

37. 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]

38. 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]