Stapleford-Athens 2011 International Addiction Conference Further Experience with Ambulatory Benzodiazepine detox Dr George O’Neil Fresh Start Recovery Programme Perth, Western Australia

History of Flumazenil treatment for benzodiazepine addiction 1961: Hollister, L.E., Motzenbecker, F.P. & Degan, R.O. (1961) Withdrawal reactions from chlordiazepoxide ('Librium'). Psychopharmacologia, 2, : McNicholas, L.F. & Martin (1982) The effect of a benzodiazepine antagonist, R , in diazepam dependent rats. Life Science. Vol 31, (8); : Savic, I., Widen, L, & Stone-Elander, S. (1991) Feasibility of reversing benzodiazepine tolerance with flumazenil. Lancet 337: : Lader, M.H. & Morton S.V. (1992) A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. Journal of Psycopharmacology 6(3);

History - continued 1996: Gerra, G. et al (1996) Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal. International Clinical Psychopharmacology, Jun;11(2):81-8 –IV flumazenil following prolonged exposure to lormetazepam 2002: Gerra, G. Zaimovic, A., Giusti, F., Moi, G. & Brewer, C (2002) Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controled study. Addiction Biology, 7(4): patients 20 flumazenil. 20 oxazepam taper; 10 placebo -Demonstrated flumazenil efficiency at reversing benzo effects and withdrawal symptoms. 2004: Pericic, D. et al (2004) Chronic exposure of cells expressing recombinant GABB A receptors to benzodiazepine antagonist flumazenil enhances the maximum number of benzodiazepine binding sites. Life Science, Vol 76 (3): –Prolonged occupancy of benzo receptors by benzos leads to uncoupling of the allosteric linkages to the GABBA receptor. –Result - Tolerance/ craving for benzos, Flumazenil – recouples receptor function –Resets tone. Tolerance & cravings decrease.

Background Gerra et al (2002) demonstrated that flumazenil was efficient at reversing the effects of benzodiazepine and withdrawal symptoms. In 2006, we reported IV flumazenil infusions in 29 benzodiazepine dependent patients

Experience with flumazenil infusions Melbourne – IV only – (SC only) –4 day (In Patient only) Perth – IV only (usually 4 days) – SC only (4-30 days) –out patient with carer after first 2 days.

Flumazenil 12mg/30ml filtered infusion system

Jon Currie, Melbourne Blood Levels

Perth Flumazenil Work Continuous infusion of µg/hr causes some detox symptoms in the first 6hrs with relief of anxiety and aggression during the infusion. Subcutaneous infusion have proven more reliable in more than 100 patients compared to 100 managed by IV infusion Patients were noted to have a return of anxiety when the infusion stoped and so the infusion is now continued up to 30 days

Flumazenil reducing cravings for Benzodiazepines Hood, S., O’Neil, G & Hulse, G. (2009) The role of flumazenil in the treatment of benzodiazepine dependence: physiological and psychological profiles. Journal of Psychopharmacology, 23(4);

Perth Flumazenil Work cont. Perth is the first city to allow the patients home providing a carer remains with them after the first 1-2 days of infusion. Research work is continuing; –Flumazenil implants –Flumazenil injections 7-28 days –Flumazenil patches

Prolonged infusions Detox symptoms in first 6 hours usually. Detox symptoms usually settle but in high benzo users can continue for days. Anxiety may return when infusion stops but the return of anxiety is decreased with long infusions. Anxiety control, cognitive depression and depression symptoms all improve with length of the infusion.

In Vitro Release of FLU/PLA/PLGA tablets

Perth Flumazenil Infusions Aug IV infusions balloon driven –Patients became irritable whenever the infusion was stop by a blocked IV site –On one occasion a patient fitted 100+ Subcutaneous infusions –No obstructions to flow occurred and outpatient management became practical

Drug use Before & After Naltrexone & Flumazenil (Hood, 2009)

Flumazenil Reducing Anxiety (Hood, 2009)

Flumazenil infusions the future Subcutaneous has replaced IV Nasal may be useful for symptom control. Transdermal experiments are continuing. Implant delivery; trial protocols are developed. Use in benzo addiction is well demonstrated. Use in alcohol, amphetamine and other addictions is less well established.

Karolinska Institute 2010 In aggressive patients flumazenil decreases the existing aggression In the control group, flumazenil increases aggression and alertness The dose delivery method of large bolus intermittent doses may have caused aggression in the controls where it is my belief that a continuous low dose infusion might have increased alertness without increasing aggression. Saxon, L., Borg, S. & Hiltunen, A.J. (2010) Reduction of aggression during benzodiazepine withdrawal: Effects of flumazenil. Pharmacology, Biochemistry and Behaviour, 96,

Croatia 2008, Molecular & Neuropharmacology They confirm up-regulation of GABA A receptors may be from; –Growth of new receptors via synthesis of receptor proteins confirmed with their experiments during prolonged flumazenil exposure or –Via flumazenil causing the correction of uncoupling of non sensitive GABA A receptors so that they return to full sensitivity (uncoupling of receptors follows exposure to benzodiazepines) Jazvinscak, M. et al (2008) The role of transcriptional and translational mechanisms in flumazenil-induced up-regulation of recombinant GABA A receptors. Neuroscience Research, 61;

GABA A Receptor

Case Study – Female Aged 30 Childhood terror PTSD diagnosed at 15 Anxiety led to 20 years benzo and 10 years opiate addiction Total of 35 admissions for benzo overdoses requiring ventilation occurred

Case Study – Female Aged 30 cont. Presenting medications: –200 x 2mg/day Xanax (alprazolam) –50 x 5mg/day Valium (diazepam) –50 x 5mg/day Mogadon (nitrazepam) –1600 mg/day Seroquel (quetiapine: atypical antipsychotic) –80/day Panadeine Forte (co-codamol: each tablet paracetamol 500 mg + codeine phosphate 30 mg) Naltrexone implants to control the opiate disorder Flumazenil infusions to control the GABA A system anxiety disorder

Heart rate patterns following Valium at midday and flumazenil at 6.15pm Heart rate (bpm) Valium (agonist)Flumazenil (antagonist)

Case Study – female aged 50 PTSD following presence at 9/11 Stilnox addiction (agonist at benzo receptor) followed sleep disturbance Culminating in 20 tab/day Stilnox (zolpidem) Treated with flumazenil infusions to upregulate (re-sensitise) the benzo receptors damaged by chronic stress from PTSD and Stilnox

Contact Information Dr George O’Neil Phone –Perth (GMT+8) 6-8am or 7-11pm –London (GMT) 10-12pm or 11am-3pm –New York (GMT-5) 5-7pm or 6-10am –Los Angeles (GMT-8) 2-4pm