Ross Colquhoun D H Sc, M App Sc, B Sc Hons Addiction Treatment and Psychology Services

1. 10th Stapleford International Addiction Conference Long Acting Chinese NTX Implant Trial Ross Colquhoun D H Sc, M App Sc, B Sc Hons Addiction Treatment and Psychology Services 67 Macarthur St, Ultimo NSW 2007 Phone Number: (612) 9280 2070 Email: ross@addictiontreatment.com.au www.addictiontreatment.com.au

2. Introduction • Since early 2000, naltrexone implants have been manufactured or imported and used in Australia. • Naltrexone (NTX) implants, especially long-acting ones, seem to offer a solution to the problem of compliance with oral NTX and may appear to improve long-term outcomes. • Most available implants are still unregistered and unlicensed and concerns have been raised about their pharmacokinetics, safety and effectiveness.

3. Introduction • The present trial was designed to test the serum blood levels of naltrexone (NTX) and 6-β-naltrexol (NTL) over the 6 mths of the claimed effectiveness of the “Chinese” naltrexone implant manufactured by Shenzhen Civil Life Scientific of Shenzhen, China • Serum blood levels were compared to other outcomes of interest including drug use, changes in liver function and social functioning

4. Naltrexone Treatment and Implants- Context • Naltrexone is non-toxic, non-addictive and with few and no serious side-effects • Naltrexone has never caused anyone to die • Naltrexone does not cause depression • Naltrexone was never a ‘miracle cure’. • Good outcomes can be achieved using Naltrexone Implants combined with counselling • It is a valuable adjunct to treatment. Addicts know this; so do experts

5. Naltrexone Treatment and Implants- Context • Three stage treatment program for Methadone and Heroin Treatment 1. Assessment and Pre-detox Counselling and Preparation – family involvement 2. Detoxification - Rapid One-day, Accelerated and Home Detoxification 3. Aftercare Counselling and Structured Rehabilitation, Naltrexone Implant • Psychological and Medical Assessment • Inclusion of Families • Pre-detox Counselling and Preparation • Treatment Planning

6. Naltrexone Treatment and Implants- Context • The form of detoxification does notpredict long-term outcomes (Colquhoun, 1999; Currie, 1999) only the number who complete the process and therefore, the number who are able to commence the after-care program. • After-care protocol of implant naltrexone, 6 months out-patient counselling and family support is recommended • Far superior results to traditional after-care programs, including in-patient rehabs.

7. Naltrexone Treatment and Implants - Context • Provide blockage of opiates for 6 to 10 months • Readily re-inserted for much longer protection. • Very cost effective compared to long-term maintenance. • Ideally suited for • stable methadone patients • motivated heroin addicts who have invested much in getting clean • chronic pain patients dependent on opiates • Unsupported addicts, eg leaving jail

8. Naltrexone Treatment and Implants - Context • Oral vs Implant Naltrexone Study* • Concord Seminar Series 2010** *Colquhoun, R. M., Tan, D. Y. K & Hull, S. (2005). Comparison of oral and implant naltrexone at 12 months. Journal of Opioid Management, 1(5), pp. 426-439. **Colquhoun, R. M. Paper delivered at the Concord Hospital D&A Seminar Series, 2010

9. Oral vs Implant Naltrexone Study • 42 oral ntx, 41 implant ntx. • Assessments pre-detox found the groups were comparable in terms of sex (63% male), age (mean 28yrs approx) years using opiates (mean 8yrs approx), and psychopathology (BDI-II and SCL-90-R) • Patients and their support persons were routinely contacted via telephone for a period of around 6 months, and compared on a number of outcomes.

10. Oral vs Implant Naltrexone Study • Based on the reports of patients and their support persons at the end of 6 months, it was found that 17 of the 42 people in the oral group had relapsed (60% abstinent). By 12 months 25 had relapsed (41% abst), including 8 who could not be contacted • Only 8 of the 41 people in the implant group were regularly using opiates at 6 months (80% abst), while at 12 months 16 had relapsed (60% abst), including another 8 people who could not be contacted.

11. Oral vs Implant Naltrexone Study • At the end of the follow-up period, patients gave a rating of self-esteem and general relationship quality both before detox and at present on a 0-10 scale (0 = disastrous, 10 = excellent). • The means for the two groups were found to indicate significant improvement in social outcomes as measured by self reports of self-esteem and quality of closest relationships

12. Oral vs Implant Naltrexone Study Self-esteem and general relationship quality pre-detox and 12- months post-detox, compared for oral and implant naltrexone groups (means reported)

13. Concord Seminar Series 2010 Treatments: 295 patients treated in 2009# • Gender: 178 (60.2%) males; 117 females • Mean age: 30.33 yrs • Age commenced opiates: 20.8 years old • Mean Years Using: 8.9 • Mean score on SCL-90-R GSI scale at start of program: 74.5 • Mean score on SCL-90-R GSI scale at 6 months: 47 # Study and counselling program funded by Commonwealth Dept of Health and Ageing and Attorney Generals Dept (Proceeds of Crime)

14. Concord Seminar Series 2010Naltrexone Implants Of 295 patients 177 ROD (60%) • 118 did not a have ROD: 78 Home or in-patient detox (66%); 61 second or more implant • Implants: 275 (93%); Oral Ntx; 20 • Poly Drug in the past: 258 (87.5%) • Poly Drug use at time of entering program: 112 (38%) • Heroin: 177 (60%), Methadone: 77 (26%) (heroin/meth 12%); Bup: 18 (6%) (her/bup 3%); Morphine: 12 (4%); 18 Alc: 6% (implants) • Tissue reactions : 21 (7.6%) • Extrusions: 5 (1.8%)

15. Concord Seminar Series 2010Adverse Events Related to Implants • Specific problems related to implants (only 1 out of 12 reported had implant related adverse evetns -local infection/abscess in Lintzeros Report*) • Rates of infection (very rare); more often inflammatory tissue reaction comparable to the use of testosterone implants** • Rapid detoxification, and naltrexone implants to prevent early relapse, are two different phases of treatment. *Lintzeros, N., Lee,S., Scopelliti, L., Mabbutt, J. and Haber, P. S. Unplanned Admissions toTwo Sydney Public Hospitals after Naltrexone Implants, Medical Journal of Australia, Vol 188 (8) 441-444 **Handelsman, D. J., Mackey, M., Howe, C., Turner l. and Conway, A. J. An analysis of testosterone implants for androgren replacement therapy. Clinical Endocrinolgoy, Vol 47(30), Sept 1997, 311-316

16. Concord Seminar Series 2010Adverse Events Related to Implants • Infection: • Remedy • Use of antibiotics • Rejection: • Remedy • Use of steroid anti-inflammatories (Prednisone) • Very often mistaken for infection • Fibrotic Encapsualtion: • Remedy • Surgical removal of tissue

17. Concord Seminar Series 2010Adverse Events Related to Implants • Overdose: • Nearly impossible while the implant is active • Remedy • Warn about reduction in tolerance to opiates and possibility of overdose even with greatly reduced amounts when implant blocking effect ceases • Very rare – similar rates to those leaving jail or rehabs – good reason to have an implant when leaving jail • Analgesia: • Use of other medications and pain management strategies • Use of non-opoid analgesics • Hyperalgesic effects in chronic pain patients

18. Long Acting Civil Life NTX Implant Trial • 41 participants who had been implanted after detoxification in Sydney as at 23 Feb 2011. • Mean age 29.56 years, • 92% male • 60% employed full-time • 95% using heroin • Mean 9.6 years using • 60% drug related convictions • 17 tests completed at one month, 10 at three months, 4 at six months

19. Long Acting Civil Life NTX Implant Trial Mean self ratings of self-esteem and general relationship quality pre-detox and at 1 and 3 months post-detox (range)

20. Long Acting Civil Life NTX Implant Trial • Mean self rating of craving while using, during detoxification and 1 month post implant (range)

21. Long Acting Civil Life NTX Implant Trial • Mean Liver Function Index pre-implant and one month post implant (range)

22. Serum Blood Levels at 1 month Days Ntx Ntl • 55 6.1 7.9 • 26 5.9 6.3 • 48 9.1 9.1 • 49 4.6 5.9 • 55 6.6 6.6 • 53 3.7 3.3 • 29 3.9 6.4 • 26 12.1 9.1 • 31 19.5 21.3

23. Serum Blood Levels at 1 month (cont) Days Ntx Ntl • 36 5.9 6.7 • 38 2.5 2.7 • 33 0 9.6 • 42 10.1 9 • 29 5.4 7.8 • 29 13.2 25.1 • 30 6.1 7.9 • 30 8 10.4  • Mean 37.58 7.22 9.12 • STD 12.31 4.72 5.74

24. Serum Blood Levels at 3 months • Days Ntx Ntl • 80 4.6 6.5 • 102 4.6 6.9 • 99 9.1 9.1 • 88 0 5.1 • 70 6.1 6.5 • 80 0 4.3 • 66 5.9 6.7 • 70 0 6.2 • 68 3.9 6.4 • 53 2.5 2.7 • Mean 77.6 3.67 6.04 • STD 27.48 1.81 1.45

25. Serum Blood Levels at 6 months • Days Ntx Ntl • 212 0 0 • 170 0 6.6 • 222 0 0 Mean 201.3 0 2.2 STD 101.69 0 3.14

26. NTX Blood Serum levels ng/ml

27. NTL Blood Serum levels ng/ml

28. Blood serum levels at 1 month and LD enzyme levels

29. Discussion • Of the 41 subjects who started the trial only 31 samples had been analysed to date. Of these four had tried using heroin in the first month and all reported that there was no subjective effect. • One started using heroin at 5 months, but reported little effect, but some withdrawal. He has returned to being abstinent and has continued counselling • One subject relapsed to heavy cocaine use after one month, his implant extruded and he relapsed. • Another whose implant extruded after 3 months relapsed to heroin

30. Discussion • There were five tissue reactions and three implants extruded (12% and 7% resp) • Much higher level compared to the earlier Concord study of 275 patients (7.6% and 1.8%) • Management with Cortosteroids recommended • While changes in Liver Function were not significant it was noted that LD levels became markedly elevated in 7 patients. Ethics committee notified and patients being monitored. – early indications show reduction in liver enzyme levels at 3 months

31. Discussion • Research has consistently shown that: • ROD under sedation is a highly effective form of detoxification from heroin and is cost effective; • it is probably more cost effective than methadone; • Slow methadone reduction has a 20% completion rate at 6 moths at an average cost of $100,000 per patient* • ROD has a 100% completion rate and 80% abstinence rate at $8100 per patient when combined with an implant • Other factors effecting long-term outcomes include: • Positive therapeutic relationship, counselling and monitoring of medication compliance (World Health Organisation, 2004). *Roberts, L. MTAR Research, APSAD Conference 2006

32. Acknowledgement • Shenzhen Civil Life Scientific Co and Dr Wayne Moran– supply of naltrexone implants for the trial • www.ntximp.com • Royal Prince Alfred Hospital, Chemistry Laboratory, Sydney analysing blood serum levels

33. Colquhoun, R.M. (1999). Outcomes of a naltrexone treatment program for opiate dependency. Paper presented at New Horizons: Reducing Drug Harm in the New Millennium, Alcohol and Drug Foundation (Qld), Brisbane. • Crabtree, B.L. (1984). Review of naltrexone, a long-acting opiate antagonist. Clinical Pharmacy, 3, pp. 273-280. • Currie, J., Collins, L., Mudaliar, Y., Cox, P., Guant, L., Lutz, P., & Ward, H. (1999). Rapid induction onto naltrexone: A randomised clinical trial of anaesthesia-assisted and sedation-assisted techniques and a comparison with conventional detoxification. Presented at the Western Area Health Service, Drug and Alcohol Service Naltrexone Project. Unpublished paper. • Hulse, G.K., & Basso, M.R. (2000). Reassessing naltrexone maintenance as a treatment for illicit heroin users. Drug and Alcohol Review, 18(3), pp. 263-269. • Shufman, E.N., Porat, S., Witztum, E., Gandacu, D., Bar-Hamburger, R., & Ginath, Y. (1994). The efficacy of naltrexone in preventing re-abuse of heroin after detoxification. Biological Psychiatry, 35, pp. 935-945. • Simon, D.L. (1997). Rapid opiate detoxification using opioid antagonists: history, theory and state of the art. Journal of Addictive Diseases, 16, pp. 103 – 121. • Tucker, T.K., & Ritter, A.J. (2000). Naltrexone in the treatment of heroin dependence: A literature review. Drug and Alcohol Review, 19(1), pp. 73-82. • Washton, A.M., Pottash, A.C., & Gold, M.S. (1984). Naltrexone in addicted business executives and physicians. Journal of Clinical Psychiatry, 45(9), pp. 39-41. • World Health Organisation (2004). Neuroscience of Psychoactive Substance Use and Dependence. Geneva: World Health Organisation Library.