1. Peter Coleman MD The Coleman Institute Richmond Va. USA

2. Background Traditional methods of detoxification for patients dependent on Benzodiazepine usually involve substitution and slow taper These methods have low patient acceptance and low success rates

3. Rapid Benzodiazepine Detoxification using Flumazenil Early work by Gerra Further experience by O’Neil and Currie RBD program begun in Richmond Va. in 2007

4. History of RBD at TCI First 10 patients detoxified in hospital Subsequently moved to outpatient procedure with home infusion pump Flumazenil infusion begun at 1mg IV over 24 hours, and advanced as tolerated. Most patients seemed to do very well, but some had an increase in withdrawal symptoms

5. Current Study Questions 1. What is the successful completion rate for a Flumazenil assisted detoxification? 2. How severe are the withdrawal symptoms during the detoxification? 3. How severe are the withdrawal symptoms following the detoxification? 4. Are there indicators that will predict which patients will do well? 5. Are there medications that are helpful for withdrawal symptoms during and after the detoxification?

6. Current Study - Overview Observational study All patients from February 2010 until December 2010

7. Current Study – Participants 12 patients who were scheduled to receive a RBD Pre-procedure telephone screening using : Beck Anxiety Beck Depression Benzo Withdrawal Scale Usual treatment No exclusions because of the study

8. Benzodiazepine Withdrawal Scale 1. Confused or disoriented01234 2. Tense01234 3. Dizzy or lightheaded01234 4. Weaker than usual01234 5. Heart pounding01234 6. Difficulty concentrating0123 7. Mentally less active than usual01234 8. Hands or fingers feel trembly01234 9. Clumsy or uncoordinated01234 10. Nervous or anxious01234 11. A feeling of unreality01234 12. Numb, tingling in the extremities01234 13. Irritable or grumpy01234 14. Noises and sounds seem louder01234 15. Perspired01234 16. As if I were moving01234 17. Shaky or jittery01234 18. Detached or withdrawn01234 19. Heaviness in limbs01234 Total Possible Score = 76

9. RBD Procedure – Day 1 Routine History and physical Routine Lab work and EKG Pre-treatment with Lyrica (Pregabalin) 50-75mg Infusion of Flumazenil at 1mg over 24 hours Observation in clinic for 3-4 hours PRN meds – Clonidine, Propranolol, Zyprexa, and Phenobarbital

10. RBD procedures – Subsequent Days Daily visits Flumazenil advanced each day by 1 mg over 24 hours, unless there was withdrawal discomfort Monitored in clinic for 3-4 hours if Flumazenil increased PRN meds – Clonidine, Propranolol, Zyprexa, and Phenobarbital

11. RBD - Completion Completion of Detoxification defined as a negative Drug screen

12. RBD Aftercare Patients encouraged to use Lyrica for at least 7 days post completion Continue PRN meds Follow up with their local Physician and Therapist Follow up phone calls with TCI at: 2 weeks 4 weeks 2 months 3 months

13. Results – Completion of Detoxification Completion of Detoxification83% (10/12) One patient stopped after 12 hours One patient stopped after 3 days

14. Results – Detoxification Discomfort We defined the detoxification as “comfortable” when there was no more than a 10% increase in symptoms on the withdrawal scale Overall 58% - (7/12) - had a comfortable detoxification

15. Benzo Withdrawal Scale results during detoxification – Comfortable patients

16. Benzo Withdrawal Scale results during detoxification – Uncomfortable patients

17. Predictors of a Comfortable and Successful Detoxification We considered the following: 1. Type of Benzodiazepine 2. Level of Benzodiazepine use 3. History of previous Substance Abuse 4. Pre-treatment Beck Anxiety Score 5. Pre-treatment Beck Depression Score 6. Pre-treatment Benzodiazepine Withdrawal Scale

18. Results – Possible Predictors of Detoxification success PatientsSpecific Benzo Benzo Dose High/Low Substance Abuse Hx Beck AnxietyBeck Depression Initial Benzo Withdrawal Scale Completed Detox Increase in W/d Sx MPXHY27NA21YN THEKHY71713YN MHKHY273324YY EHXHN121733YN GJKLN513770YN JRAHN31257YY ABKLN361325NY RBAHN211733NY ZMALY241718YN LGXLN9916YN LMVLN333246YN KDXLN472957YY

19. Predictors - 1 Type of Benzodiazepine No obvious difference - numbers were small Benzodiazepine Dose – High Dose defined as daily use of over: 6mg of Xanax, Klonopin or Ativan, 60mg of Valium No obvious difference - numbers were small

20. Predictors - 2 Substance abuse History If a previous SA Hx75% comfortable detox If no previous SA Hx50% comfortable detox Pre-treatment Beck Anxiety Scale Score less than 20100% comfortable detox Score over 20 44% comfortable detox Score over 30 40% comfortable detox

21. Predictors - 3 Pre-treatment Benzodiazepine Withdrawal Scale Less than 30 67% comfortable detox Over 30 60% comfortable detox Over 40 67% comfortable detox Pre-treatment Beck Depression Scale Less than 20 67% comfortable detox Over 30 67% comfortable detox

22. Summary – predictors of success or withdrawal discomfort None of the instruments we used were completely reliable to predict outcomes There was a large variation on the scales used Beck Anxiety Scale was the most predictive Substance abuse history was somewhat predictive Beck Depression scale was not predictive The initial Benzodiazepine Withdrawal Scale was not helpful

23. Results – Discomfort after the Detoxification - PAWS Detoxification discomfort defined as more than a 10% increase in symptoms from the pre-treatment withdrawal scale 67% - (8/12) – had no increase in withdrawal symptoms after the detoxification Some had dramatic and rapid resolution, while some took up to 3 months Very incomplete data

24. Withdrawal Scores after Detoxification – Comfortable patients

25. Withdrawal Scores after Detoxification – Uncomfortable patients

26. Results - Adverse events No seizures or other major adverse events One patient continued to have severe anxiety and had suicidal thoughts. About 4 weeks after the detoxification he was hospitalized by his local psychiatrist. He was put back on benzodiazepines for a time but took himself off them and following this he had an unsuccessful suicide attempt.

27. Results – Medications to help We used prn: Clonidine 0.1 mg Propranolol 20mg Zyprexa 2.5 mg Phenobarbital 30mg We have tried: Depakote Buspar Lamotrigine Trileptal

28. Further research This was a small pilot study Larger study More detailed psychiatric evaluation tools More narrowly focused with exclusions for other drug use More rigorous follow up

29. Conflicts of interest None