Ross ColquhounD H Sc, M App Sc, B Sc Hons

Addiction Treatment and Psychology Services67 Macarthur St, Ultimo NSW 2007

Phone Number: (612) 9280 2070Email: ross@addictiontreatment.com.au

www.addictiontreatment.com.au

10th Stapleford International Addiction ConferenceLong Acting Chinese NTX Implant Trial

IntroductionSince 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.

IntroductionThe 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

Naltrexone Treatment and Implants- ContextNaltrexone is non-toxic, non-addictive and with few

and no serious side-effectsNaltrexone has never caused anyone to dieNaltrexone does not cause depressionNaltrexone was never a ‘miracle cure’. Good outcomes can be achieved using Naltrexone

Implants combined with counsellingIt is a valuable adjunct to treatment. Addicts know

this; so do experts

Naltrexone Treatment and Implants- ContextThree stage treatment program for Methadone

and Heroin Treatment1. Assessment and Pre-detox Counselling and

Preparation – family involvement2. Detoxification - Rapid One-day, Accelerated and

Home Detoxification3. Aftercare Counselling and Structured

Rehabilitation, Naltrexone Implant Psychological and Medical AssessmentInclusion of FamiliesPre-detox Counselling and PreparationTreatment Planning

Naltrexone Treatment and Implants- ContextThe form of detoxification does not predict 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.

Naltrexone Treatment and Implants - ContextProvide 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 patientsmotivated heroin addicts who have invested much in

getting cleanchronic pain patients dependent on opiatesUnsupported addicts, eg leaving jail

Naltrexone Treatment and Implants - ContextOral 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

Oral vs Implant Naltrexone Study42 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.

Oral vs Implant Naltrexone StudyBased 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.

Oral vs Implant Naltrexone StudyAt 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

Oral vs Implant Naltrexone StudySelf-esteem and general relationship quality pre-detox

and 12- months post-detox, compared for oral and implant naltrexone groups (means reported)

SE pre detox

SE post detox

RQ pre detox

RQ post detox

Oral group 3.8 8.3 2.2 8.8

Implantgroup

3.9 8.7 2.4 8.1

Concord Seminar Series 2010Treatments: 295 patients treated in 2009# Gender: 178 (60.2%) males; 117 femalesMean age: 30.33 yrsAge commenced opiates: 20.8 years oldMean Years Using: 8.9Mean score on SCL-90-R GSI scale at start of

program: 74.5Mean 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)

Concord Seminar Series 2010 Naltrexone Implants

Of 295 patients 177 ROD (60%)118 did not a have ROD: 78 Home or in-patient

detox (66%); 61 second or more implantImplants: 275 (93%); Oral Ntx; 20Poly 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%)

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

Concord Seminar Series 2010Adverse Events Related to Implants

Concord Seminar Series 2010 Adverse Events Related to ImplantsInfection:Remedy

Use of antibiotics

Rejection:Remedy

Use of steroid anti-inflammatories (Prednisone)Very often mistaken for infection

Fibrotic Encapsualtion:Remedy

Surgical removal of tissue

Concord Seminar Series 2010Adverse Events Related to ImplantsOverdose:Nearly impossible while the implant is activeRemedy

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 strategiesUse of non-opoid analgesicsHyperalgesic effects in chronic pain patients

Long Acting Civil Life NTX Implant Trial41 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 convictions17 tests completed at one month, 10 at three

months, 4 at six months

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)

Self Esteem Relationships

Pre-detox 3.36 (2-5) 5.1 (0-10)

One months 7.25 (4-10) 9.2 (7-10)

Three months 6 (4-8) 9.5 (9-10)

Long Acting Civil Life NTX Implant TrialMean self rating of craving while using,

during detoxification and 1 month post implant (range)Craving while Using

Craving during detox

Craving at 1 month post implant

5.8 (3-10) 7.36 (5-10) 0.81 (0-6)

Mean Liver Function Index pre-implant and one month post implant (range)

LFI Pre-implant

LFI one month Post-implant

T-test

0.66 (o.365-1.202)

0.69 (.45- 0.895)

P= 0.78 non sign

Long Acting Civil Life NTX Implant Trial

Serum Blood Levels at 1 monthDays 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

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 9.12STD 12.31 4.72 5.74

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 6.04STD 27.48 1.81 1.45

Serum Blood Levels at 6 monthsDays Ntx Ntl212 0 0170 0 6.6222 0 0

Mean 201.3 0 2.2STD 101.69 0 3.14

NTX Blood Serum levels ng/ml

NTL Blood Serum levels ng/ml

Blood serum levels at 1 month and LD enzyme levels

AC HN MN SC MB DA BB

NTX 2.5 3.9 4.4 3.7 10.1 12.1 6.1

NTL 2.7 6.4 5.9 3.3 9.0 9.1 6.5

LD Pre 137 174 167 172 176 136 156

LD Post

293 462 278 421 270 527 323

DiscussionOf 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

DiscussionThere 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 recommendedWhile 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

DiscussionResearch 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

AcknowledgementShenzhen Civil Life Scientific Co and

Dr Wayne Moran– supply of naltrexone implants for the trial

www.ntximp.comRoyal Prince Alfred Hospital,

Chemistry Laboratory, Sydney analysing blood serum levels

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.