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Dr George O’Neil email@drgeorgeoneil Fresh Start Recovery Programme Perth, Western Australia

Stapleford-Athens 2011 International Addiction Conference A 11 Year History of Research and Clinical use of Naltrexone Implants . Dr George O’Neil email@drgeorgeoneil.com Fresh Start Recovery Programme Perth, Western Australia. Follow up- PHREE program. P hysiology – changing physiology

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Dr George O’Neil email@drgeorgeoneil Fresh Start Recovery Programme Perth, Western Australia

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  1. Stapleford-Athens 2011International Addiction ConferenceA 11 Year History of Research and Clinical use of Naltrexone Implants Dr George O’Neil email@drgeorgeoneil.com Fresh Start Recovery Programme Perth, Western Australia

  2. Follow up- PHREE program • Physiology – changing physiology • Housing “where you know you belong” – The essence of a home is love, joy, peace, patience, gentleness, kindness and self control • Relationships – self, God, family, community • Empowerment • Education, Employment, Exit from rehab, Entry to Society – occupational therapy, short term employment, career, university/training email@drgeorgeoneil.com

  3. Accelerated Detox & Emergency Dept. • 93% outpatient only, 7% required hospital admission following detox • Main Presentations • GI symptoms – fluid replacement • CNS symptoms – agitation, excessive sedation requiring ventilation • 74% of all admission occurred within 48 hours Armstrong, J., Little, M., Murray, L. (2003) Emergency Department Presentations of Naltrexone-accelerated Detoxification. Journal of Academic Emergency Medicine, Vol. 10, No. 8, pp 860 - 866 email@drgeorgeoneil.com

  4. 11 Year Detox Summary • Deaths occur whilst patients are waiting to detox at a rate of approx. 4 per year in booked patients with a 2 day waiting period • No deaths from detox in over 10,000 accelerated detox’s • Methadone and very high dose opiate patients transferred to Buprenorphine for up to 2 weeks prior to implant • 4mg Buprenorphine pre treatment PRN email@drgeorgeoneil.com

  5. 2010-11 Estimate of Regular Use email@drgeorgeoneil.com

  6. Worst Complications • Patient MW– Admitted to SCG Hospital • Developed Cardiac Failure/Myocadiopathy with a heavy detox • Good recovery within 48h with ventilation and intensive care • Usual complications – Fluid replacement • Rare complications - Ventilation email@drgeorgeoneil.com

  7. Common Complications • With approx. 6-800 detox’s per year, the number requiring ventilation is approx. 4 per year or less than 1 in 200 • Fresh Start Detox (moving and yelling permitted/sedation stops if you cannot stand up or name the Prime Minister) • Nursing on the floor • Oral sedation (only if the patient can stand) • No Sedation after disorientation email@drgeorgeoneil.com

  8. Common Complications cont. • Hospital detox (Moving &Yelling not permitted) • Patients are managed on trolleys • Patients are tied to the trolleys when they move their arms and legs • Patients who have a 6h illness with extreme agitation between hour 2-4 are given IV Medazolam until they require ventilation • Each of the 4 patients ventilated each year related to hospital methods of sedation email@drgeorgeoneil.com

  9. RCT comparing accelerated detox from traditional detox • 80 patients randomized to accelerated detox or conventional detox • Accelerated detox – 89% success • Conventional detox – 30% success Arnold-Reed, D.E & Hulse, G.K (2005) A comparison of rapid (opioid) detoxification with conidine-assisted detoxification for heroin-dependent persons. Journal of Opioid Management, Vol1, No. 1, p17-23 email@drgeorgeoneil.com

  10. Changes to our practice • Suboxone/norspan detox's for methadone • 4mg Suboxone for high opiate loads • Medical House for 24 hour care • Contract – hospital if vomiting • GIT medication email@drgeorgeoneil.com

  11. Balance the risks of immediate vs. delayed detox • Detox delays cause some deaths • Reduce opiate load (e.g. high dose methadone) • Partial antagonists reduce withdrawal illness email@drgeorgeoneil.com

  12. Implant vs. Injection (Vivitrol) Estimated duration of therapeutic effect Assuming 4ng/ml, Go Medical = 100 days, Vivitrol 17days Assuming 3ng/ml, Go Medical = 140 days, Vivitrol 21days Assuming 2ng/ml, Go Medical = 200 days, Vivitrol 28days Assuming 1ng/ml, Go Medical = 272 days, Vivitrol 31days email@drgeorgeoneil.com

  13. Relative Risk of All Deaths • Reduced 33% in a population exposed to implant naltrexone treatment • 8787 Patient Years (Implant Ntx) • 15056 Patient Years (Oral Ntx) • Implant Ntx Deaths; 6.94/1000 pt yrs • Oral Ntx Deaths; 10.50/1000 pt yrs • Observation period 13 years email@drgeorgeoneil.com

  14. Mental Health& Morbidity email@drgeorgeoneil.com

  15. Comparison of mental health admissions in a cohort of heroin users prior to and after rapid opiate detoxification and oral naltrexone maintenance D. E. Arnold-Reed; P. O'Neil; C. D. J. Holman; M. K. Bulsara; C. Rodiguez; G. Gawthorne; R. J. Tait; G. K. Hulse 2007, Vol. 33, No. 5, 655 - 664 email@drgeorgeoneil.com

  16. Mental Health Post Detox • 1184 patients • 338 had 685 MH admissions • Study 36 months before and 36 months after treatment • Peak in MH related admission 3 months prior to treatment • Significant decline in admission in the 36 months following treatment email@drgeorgeoneil.com

  17. Mental Health Post Implant • 359 implant patients • Ave follow up 1.78 years before and after Rx via WA data linkage system • Post Rx MH admissions decreased for overall cohort, rather than an expected increase Ngo, H.T.T, Tait, R.J., Arnold-Reed, D.E. & Hulse, G.K. (2003) Mental health outcomes following naltrexone implant treatment for heroin-dependence. Journal of Neuro-Psychopharmacology & Biological Psychiatry, Vol. 31, pp 605 – 612 email@drgeorgeoneil.com

  18. Hospital Morbidity Pre & Post Implant • 3.5 Years post implant • 522 Methadone patients • 314 Naltrexone implant patient • WA Data Linkage Ngo, H.T.T., Tait, R.J. & Hulse, G.K. (2008) Comparing drug-related hospital morbidity following heroin dependence treatment with methadone maintenance or naltrexone implantation. Archives of General Psychiatry, Vol. 65, No. 4, 457 - 465 email@drgeorgeoneil.com

  19. Hospital Morbidity 3.5 Years Pre & Post Implant * Significant at alpha = 0.05 email@drgeorgeoneil.com

  20. Implant Treatment – RCT’s email@drgeorgeoneil.com

  21. RCT of Oral vs. Implant Naltrexone • Patients: • 35 Naltrexone implant + placebo oral • 35 placebo implant + oral Naltrexone • Return to regular heroin use • Rates of regular heroin use were higher in the oral Naltrexone patients then the Naltrexone implant patients (p<0.001) Hulse, G.K., Morris, N., Arnold-Reed, D. & Tait, R.J. (2009) Improving clinical outcomes in treating heroin dependence. Archive of General Psychiatry, Vol. 66, No. 10, 1108 – 1115. email@drgeorgeoneil.com

  22. email@drgeorgeoneil.com

  23. Norway RCT Implant vs. Standard Treatment • 56 abstinence orientated patients • Implant (29 randomised, 26 Rx) • Standard Rx (27 randomised) • Observed : 180 days • Implant: 60 days less opiate use, blood Naltrexone above 1ng/ml for 6 months • Two patients died neither received an implant Nikolaj Kunøe, N et al (2009) Naltrexone implants after in-patient treatment for opioid dependence: randomised controlled trial. The British Journal of Psychiatry Vol. 194, 541 – 5446 email@drgeorgeoneil.com

  24. Cravings with Oral and Implant Naltrexone • Craving levels are a sensitive indicator of relapse next month • Effective Rx of 1-3 ng/ml Hulse, G.K., Ngo H.T.T. & Tait, R.J. (2010) Risk Factors for Craving and Relapse in Heroin Users Treated with Oral or Implant Naltrexone. Journal of Biological Psychiatry. Vol. 68, pp 296 – 302 email@drgeorgeoneil.com

  25. Cravings with Oral and Implant Naltrexone email@drgeorgeoneil.com

  26. Pregnancy email@drgeorgeoneil.com

  27. Publications Hulse, G.K. & O'Neil, G. (2002) A possible role for the implantable naltrexone in the management of the high-risk pregnant heroin user. Australian and New Zealand Journal of Obstetrics and Gynaecology. 42(1):93 - 4. Hulse, G.K. & O'Neil, G. (2002) Using naltrexone implants in the management of the pregnant heroin user. Australian and New Zealand Journal of Obstetrics and Gynaecology. 42(5):102 - 6. Hulse, G.K., Arnold-Reed, D.E., O'Neil, G. & Hanssen, R.C. (2003) Naltrexone implant and blood naltrexone levels over pregnancy. Australian and New Zealand Journal of Obstetrics and Gynaecology. 43:386 - 8. Hulse, G.K., O'Neil, G. & Arnold-Reed, D.E. (2004) Methadone maintenance vs. implantable naltrexone treatment in the pregnant heroin user. International Journal of Gynecology and Obstetrics. 85:170 – 1. email@drgeorgeoneil.com

  28. Publications Hulse, G.K., O'Neil, G., Pereira, C. & Brewer, C. (2001) Obstetric and neonatal outcomes associated with maternal naltrexone exposure. Australian and New Zealand Journal of Obstetrics and Gynaecology. 41(4):424 - 8. Minozzi, S., Amato, L., Vecchi, S. & Davoli, M. (2009) Maintenance agonist treatments for opiate dependent pregnant women (review). The Cochrane Collaboration: John Wiley & Sons, Ltd. Rayburn, W.F. & Bogenschultz, M.P. (2004) Pharmacotherapy for pregnant women with addiction. American Journal of Obstetrics & Gynecology. 191(6):1885 - 97. email@drgeorgeoneil.com

  29. Pregnancy and Pharmacotherapy • All treatments have risks, as does no treatment • Methadone: Category C drug • Well established • Decreased growth • Neonatal withdrawal syndrome • Buprenorphine: Category C drug. Less established, less growth retardation and less neonatal withdrawal than methadone • No Pharmacotherapy: 13 x overdose risk email@drgeorgeoneil.com

  30. Pregnancy and Pharmacotherapy • Reproductive age group 15 – 45 years • All treatments in pregnancy have risks • Naltrexone is a category B3 drug • Not associated with growth retardation • Not associated with congenital abnormalities • 4800 people in reproductive age group exposed in Perth • 100+ pregnancies • WISC IV study of 13 children 3/12 to 10 years email@drgeorgeoneil.com

  31. Opioid Overdose and Implants • Identified via WA Hospital Linked Data & ECHO Project EDIA data • 361 patients • 21 patient overdoses in the 6 months before treatment • 0 opiate overdoses in the 6 months after treatment Hulse, G.K., Tait, R.J., Comer, S.D., Sullivan, M.A., Jacobs, I.G. & Arnold-Reed, D. (2005) Reducing hospital presentations for opioid overdose in patents treated with sustained release naltrexone implants. Journal of Drug and Alcohol Dependence, Vol. 79, 351 - 357 email@drgeorgeoneil.com

  32. Implants in Adolescent Poly Drug Users • Hulse, G.K. and R.J. Tait, A pilot study to assess the impact of naltrexone implant on accidental opiate overdose in 'high-risk' adolescent heroin users. Addiction Biology, 2003. 8: p. 337 - 342. • Tait, R.J. and G.K. Hulse, Reduction in emergency presentations by adolescent poly-drug users: A case-series. Journal of Child and Adolescent Substance Abuse, 2005. 14(4): p. 41 – 52. email@drgeorgeoneil.com

  33. Overdose in 3 adolescents • 91 weeks before implants, 14 overdose events • 91 weeks post implants, no overdose events • Conclusion: Jo Kimber’s BMJ paper (2010) confirms methadone increases the duration of injection x 4 (5 yrs - 20) • In contrast, implants eliminate injecting Kimber, J., et al (2010) Survival and cessation in injecting drug users: prospective observational study of outcomes and effect of opiate substitute treatment. British Medical Journal, 341:c3172. email@drgeorgeoneil.com

  34. A B C Implants in Poly Drug Use email@drgeorgeoneil.com

  35. Reducing Overdose by Reducing Injecting using Naltrexone Implant Service for 10 Years

  36. Reducing Overdose by Reducing Injecting with a single implant

  37. Implants in Amphetamines email@drgeorgeoneil.com

  38. Methadone vs. Naltrexone email@drgeorgeoneil.com

  39. Mortality Rates • Methadone – 533 patients (2.7%), 2571 pt yrs • Naltrexone – 341 patients (1.8%), 1594 pt yrs • MMT: • 0 to 14 days = 94.4/1000 pt yrs • Stable Rx = 0.0/1000 pt yrs • Overall = 5.8/1000 pt yrs • NIT: • 0 to 180 days = 0.0/1000 pt yrs • >180 days = 4.2/1000 pt yrs • Overall = 3.8/1000 pt yrs • Relative risk NIT:MMT 0.645 (95% CI 0.123 – 1.17) Tait, R. Hgo, H. & Hulse, G. (2008) Mortality in heroin users 3 years after naltrexone implant or methadone maintenance treatment. Journal of substance Abuse Treatment, Vol. 35, pp 116 - 124 email@drgeorgeoneil.com

  40. Naltrexone Implants in Medical Practitioners Hulse, G.K., et al (2003) Use of oral and implantable naltrexone in the management of the opioid impaired physician. Anaesthesia and Intensive Care, 31(2): p. 196 – 201 Hulse, G.K., A.G. O'Neil, and D.E. Arnold-Reed (2004) Management of an opioid-impaired anaesthetist by implantable naltrexone.Journal of Substance Use. 9(2): p. 86 – 90. email@drgeorgeoneil.com

  41. Findings • These articles describe the value of measuring serum naltrexone to confirm control of the disease • Oral naltrexone: monitoring daily naltrexone use and detecting early relapse is difficult • Implant naltrexone: assured compliance, virtually guaranteed abstinence for ~5 months email@drgeorgeoneil.com

  42. Blood Naltrexone Levels email@drgeorgeoneil.com

  43. Published Results • Ngo, H.T.T., et al. (2008) Blood naltrexone levels over time following naltrexone implant.Progress in Neuro-Psychopharmacology and Biological Psychiatry. 32(1): p. 23-28 • Hulse, G.K., et al (2004) Achieving long term continuous blood naltrexone and 6-beta-naltreol coverage following sequential naltrexone implants. Addiction Biology. 9: p. 65 – 70 • Brewer, C., (2002) Serum naltrexone and 6-beta-naltrexol levels from naltrexone implants can block very large amounts of heroin: A report of two cases.Addiction Biology. 7: p. 321 – 323 email@drgeorgeoneil.com

  44. email@drgeorgeoneil.com

  45. PK Challenge Study • University of Bristol • Dr Jan Melichar (Honorary Senior Lecturer and Consultant Psychiatrist) • Prof. David Nutt (Professor of Psychopharmacology • Pharmacokinetics • 50 and 250 mg heroin challenge • To commence shortly email@drgeorgeoneil.com

  46. Hep C Treatment with Implants • 50 patients • 62% sustained viral response at 6 months • Comparable to non intravenous drug using patients • Side effects and compliance also similar Jeffery, G., MacQuillan, G., Chue, F., Galhenage, S., Bull, J., Young, E., Hulse, G & O’Neil, G. (2007) Hepatitis C Virus Eradication in Intravenous Drug Users Maintained with Subcutaneous Naltrexone Implants.Journal of Hepatology, Vol. 45, No. 1, pp 111 - 117 email@drgeorgeoneil.com

  47. Biocompatibility email@drgeorgeoneil.com

  48. Biodegradation & Biocompatibility • Hulse, G.K., et al (2005)Histological changes over time around the site of sustained release naltrexone-poly(DL-lactide) implants in humans. Journal of Controlled Release. 108: p. 43 - 55. • Hulse, G.K., et al (2007) Biodegradability of naltrexone-poly(DL) lactide implants in vivo assessed under ultrasound in humans. Addiction Biology. 13: p. 364-372. email@drgeorgeoneil.com

  49. Findings • Low level tissue reaction that settled by 25 months • Most implants adequately absorbed by 2 years • In Western Australia patients requiring implants for 5 to 10 years in a row have good absorption when requiring 3 to 4 implants in a 2 to 3 year period email@drgeorgeoneil.com

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