1. Purpose of Outcome Studies
4/23/2017
October 2011
Naltrexone for heroin addiction - oral, depot and implant: behavioral and physical technologies to improve benefit
John Strang & John Marsden
National Addiction Centre, London, UK
Dwayne Simpson

2. Declaration (personal & institutional)
DH, NTA, Home Office, NACD, EMCDDA, WHO, UNODC
Reckitt-Benkiser, Schering-Plough, Genus-Britannia, GW, Diamo, Napp, Titan, Martindale, Catalent, Auralis, Lundbeck, Astra-Zeneca, Alkermes, Fidelity, Rusan, Mundipharma Europe, Lightlake & others
NHS provider (community & in-patient), Phoenix House, Lifeline, Clouds House, KCA (Kent Council on Addictions)
UKDPC (UK Drug Policy Commission), SSA (Society for the Study of Addiction)
Work also with several charities including Action on Addiction, and also with J Paul Getty Charitable Trust (JPGT) and the Pilgrim Trust

4. Tablets
Implant
Depot

6. Tablets
Implant
Depot

8. Implantable Naltrexone: Route and Dosage
PRODETOXON, tablets for implantation mg of naltrexone 8

10. Pharmacokinetics of Prodetoxon (data from the manufacturer)
Concentration, ng/ml 10 20 30 40 50 60 70
Time after implantation, days
Naltrexone metabolite
Naltrexone
Blood samples were collected in one week, one and two months after implantation

14. Extended Release Injectable Naltrexone
Pouder +
Solvent
Microspheres
(Suspension)
Needle
Monthly injection

15. Pharmacokinetics Steady state by 2nd dose
Mean steady-state naltrexone concentration following monthly XR-NTX 380 mg compared to daily oral dosing
XR-NTX 380 mg
Oral naltrexone 50 mg
The study above (Dunbar et al) was a head-to-head study comparing the PK of oral naltrexone to VIVITROL. The steady state data on oral naltrexone was extrapolated from 5 days to about 1 month.
As you can see looking at the gray line, daily dosing of oral naltrexone results in fluctuating plasma concentrations of the drug during the day. Naltrexone concentrations peak within the first hour of oral dosing, followed by a steady decline to below a minimum target level within 8 hours. This pattern recurs each day during treatment.[Dean,644,F1]
In contrast, VIVITROL provides consistent release of naltrexone.[DUN,484,F2]
Transient, initial peak in 2-3 hours [VPI,3,4]
Peak concentrations observed in ~2 to 3 days [VPI,3,4]
Beginning day 14, plasma concentrations slowly decline, with measurable levels for greater than 1 month [DUN,480,Abs; 483,2]
Consistent, measurable plasma concentrations
Relieves the burden of daily adherence decisions
Steady state by 2nd dose
Minimal accumulation 6β-naltrexol
Limited 1st pass metabolism by liver
Monthly naltrexone (380 mg vs 1,500 mg)
Dean RL. Front Biosci Jan 1;10:
Dunbar JL, et al. Alc Clin Exp Res. 2006;30:
Data on File, Alkermes, Inc.

20. Structure of today’s talk
Naltrexone in the UK today
Making oral naltrexone better (NICE)
Oral vs Depot vs Implant
The NEAT trial

21. Structure of today’s talk
Naltrexone in the UK today
Making oral naltrexone better (NICE)
Oral vs Depot vs Implant
The NEAT trial

23. Naltrexone for the management of opioid dependence
Issue date: January 2007
Review date: March 2010
Naltrexone for the
management of opioid
dependence
NICE technology appraisal guidance TA 115

24. Why is NICE so important?
…… because of its central relationship to the NHS.
The UK Government has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE Technology Appraisals normally within 3 months from the date that NICE publishes the guidance.

25. NICE TA-115 Implementation
1.1 Naltrexone is recommended as a treatment option in detoxified formerly opioid-dependent people who are highly motivated to remain in an abstinence programme.
1.2 Naltrexone should only be administered under adequate supervision to people who have been fully informed of the potential adverse effects of treatment. It should be given as part of a programme of supportive care.

26. Naltrexone vs. control treatment Retention in treatment
Cochrane Review: No significant difference in retention for people treated with naltrexone + adjunctive psychological therapy compared with psychosocial therapy alone (risk ratio [RR] 1.08; 95% CI 0.74 to 1.57).
6 of 7 RCTs (3 of which included adjunctive psychological therapy in each arm) reported no significant difference in retention with naltrexone treatment
1 trial reported a significant improvement in retention on naltrexone treatment compared with psychological therapy (RR 0.66; 95% CI 0.43 to 0.93)
A fixed-effect meta analysis of all 7 RCTs showed no difference in retention on treatment with naltrexone, with a RR of stopping treatment of 0.94 (95% CI 0.84 to 1.06)

27. Naltrexone vs. no-naltrexone control treatment Retention in treatment (Relative risk of stopping treatment)
Relative risk meta-analysis plot (fixed effects)
0.2
0.5 1 2 5
Cornish 1997
0.73 (0.44, 1.25)
Hollister 1978
0.97 (0.85, 1.11)
Krupitsky 2004
0.66 (0.43, 0.95)
Shufman 1994
1.14 (0.54, 2.44)
Lerner 1992
0.80 (0.35, 1.73)
San 1991
1.35 (0.98, 2.03)
Curran 1976
1.00 (0.75, 1.33)
combined [fixed]
0.94 (0.84, 1.06)
relative risk (95% confidence interval)
Favour Naltrexone Favour Placebo

28. Naltrexone vs. no-naltrexone control treatment Retention in treatment (Relative risk of stopping treatment)
Relative risk meta-analysis plot (fixed effects)
0.2
0.5 1 2 5
Cornish 1997
0.73 (0.44, 1.25)
Hollister 1978
0.97 (0.85, 1.11)
Krupitsky 2004
0.66 (0.43, 0.95)
Shufman 1994
1.14 (0.54, 2.44)
Lerner 1992
0.80 (0.35, 1.73)
San 1991
1.35 (0.98, 2.03)
Curran 1976
1.00 (0.75, 1.33)
combined [fixed]
0.94 (0.84, 1.06)
relative risk (95% confidence interval)
Favour Naltrexone Favour Placebo

29. Naltrexone vs. control treatment Relapse rates
Assessed by presence of opioids in urine samples
Cochrane review: a significant reduction in illicit heroin use (RR 0.72, 95% CI, 0.58 to 0.90) (NNT to prevent one relpase=8)
Of the 6 RCTs that reported relapse rates, three included adjunctive psychosocial therapy in each arm
5 reported no statistically significant differences in relapse rates with naltrexone treatment.
1 reported a statistically significant improvement with naltrexone treatment (RR 0.41; 95% CI, 0.21 to 0.74)
Pooled analysis of relapse rates showed a statistically significant reduction in the risk of opioid use with naltrexone compared with placebo: RR of relapse = 0.72 (95% CI 0.58 to 0.90)

30. Naltrexone vs. no-naltrexone control treatment Relapse rates (Relative risk of returning to illicit drug use)
Favour Naltrexone Favour Placebo

31. Naltrexone vs. no-naltrexone control treatment Relapse rates (Relative risk of returning to illicit drug use)
Favour Naltrexone Favour Placebo

32. Extent of naltrexone use in the UK
England population – approx 50 million
NICE (2006) reports market value of <£500k per annum (approx €600k p.a.)
11,000-14,000 prescriptions for naltrexone annually
Naltrexone tablet (50mg) NHS cost £1.52 per tablet
Therefore approx 300k tablets annually; hence approx <1,000 patient-years
[[reference comparison – 150,000 on methadone or buprenorphine OST (>80% methadone; 15% bup)

34. Structure of today’s talk
Naltrexone in the UK today
Making oral naltrexone better (NICE)
Oral vs Depot vs Implant
The NEAT trial

37. Naltrexone compliance: effect of added psychosocial element

38. Naltrexone compliance: effect of added psychosocial element

39. NICE Guideline recommendation (Guideline on Psychosocial Treatments, 2007)
8.5.6 Clinical practice recommendation For people receiving naltrexone maintenance treatment to help prevent relapse to opioid dependence, staff should consider offering: • contingency management to all service users (based on the principles described in recommendations and ) • behavioural couples therapy or behavioural family interventions to service users in close contact with a non-drug-misusing family member, carer or partner.

40. Structure of today’s talk
Naltrexone in the UK today
Making oral naltrexone better (NICE)
Oral vs Depot vs Implant
The NEAT trial

42. Structure of today’s talk
Naltrexone in the UK today
Making oral naltrexone better (NICE)
Oral vs Depot vs Implant
The NEAT trial

43. The NEAT trial in the UK (1)
The Naltrexone Enhanced Addiction Treatment (NEAT) Trial for heroin addiction
Advanced planning stage
Chief Investigators - John Strang & John Marsden;
Co-investigators – Ed Day (Birmingham), Mike Kelleher (London), Soraya Mayet (Darlington), Sarah Byford, Caroline Murphy et al;
International colleagues – Evgeny Krupitsky (St Petersburg), Sandra Comer (Columbia, New York)

44. The NEAT trial in the UK (2)
Randomised controlled trial of oral vs implant naltrexone (all receiving best care – psychosocial)
Challenge: Untangling medication from associated psychosocial and organisational elements of care
Health technologies to be assessed: (i) naltrexone extended-release implant; (ii) oral naltrexone (x3/wk); (iii) manual-guided case-work counselling; (iv) voucher-based reinforcement of attendance

45. The NEAT trial in the UK (3)
3-arm placebo-controlled double-blind double-dummy randomised trial (oral vs implant vs placebo)
Patient population: detoxified and returning to community (n=300; 3 x 100)
12-week period of active NEAT trial treatment (medication – DBDD RCT; plus psychosocial)
Open choice re treatment post-12-weeks

46. The NEAT trial in the UK (4)
Research assessment interviews at 1, 3 & 6 months
Primary outcome: number of opiate-negative urines (36 over 12/52); and QALY-based cost-effectiveness
Secondary outcomes: retention in trial Rx; adherence; self-report of heroin use (TLFB); urine (other drugs); heroin craving; psychological functioning; injection risk behaviour; adverse events incl overdose; deaths

47. in conclusion … Naltrexone currently used minimally in the UK
Both behavioral and pharmacological developments have much more to offer – second-generation
Relative cost-effectiveness needs exploration, as well as relative clinical effectiveness
Improved oral vs depot versus implant - ? conclusion
The NEAT Trial is a major step forward in the UK

48. Thank you