George O`Neill 1

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, 63-68.
• 1982: McNicholas, L.F. & Martin (1982) The effect of a
benzodiazepine antagonist, R015-1788, in diazepam dependent rats.
Life Science. Vol 31, (8); 731-737.
• 1991: Savic, I., Widen, L, & Stone-Elander, S. (1991) Feasibility of
reversing benzodiazepine tolerance with flumazenil. Lancet 337: 133137
• 1992: 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);357-363.3
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):385-95
- 50 patients 20 flumazenil. 20 oxazepam taper; 10 placebo
- Demonstrated flumazenil efficiency at reversing benzo effects and withdrawal
• 2004: Pericic, D. et al (2004) Chronic exposure of cells expressing
recombinant GABBA receptors to benzodiazepine antagonist flumazenil
enhances the maximum number of benzodiazepine binding sites. Life
Science, Vol 76 (3):303-317
– 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.
• Gerra et al (2002) demonstrated that
flumazenil was efficient at reversing the
effects of benzodiazepine and withdrawal
• In 2006, we reported IV flumazenil
infusions in 29 benzodiazepine dependent
Experience with flumazenil infusions
• Melbourne
– 2005-2008 IV only
– 2009-2011 (SC only)
– 4 day (In Patient only)
• Perth
– 2005-2008 IV only (usually 4 days)
– 2009-2011 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 100-400µg/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);401-409
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 2010
• 100+ 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
• 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, 148-151
Croatia 2008, Molecular & Neuropharmacology
• They confirm up-regulation of GABAA receptors may be from;
– Growth of new receptors via synthesis of receptor
proteins confirmed with their experiments during
prolonged flumazenil exposure
– Via flumazenil causing the correction of uncoupling of
non sensitive GABAA receptors so that they return to full
(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 GABAA receptors. Neuroscience
Research, 61;234-241
GABAA 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 GABAA system
anxiety disorder
Heart rate patterns following Valium at
midday and flumazenil at 6.15pm
Valium (agonist)
Flumazenil (antagonist)
Heart rate (bpm)
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
Contact Information
• Dr George O’Neil
• Email:
• Phone +61 893881991
– 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