naltrexone for heroin addiction - oral, depot and implant: behavioral and physical technologies to...

Naltrexone for heroin addiction - oral, depot and implant: behavioral and physical

technologies to improve benefit

John Strang & John MarsdenNational Addiction Centre, London, UK

October 2011

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

• Tablets

• Implant

• Depot

Implantable Naltrexone: Route and Dosage

PRODETOXONPRODETOXON, , tablets for implantationtablets for implantation 1000 mg of naltrexone1000 mg of naltrexone

Pharmacokinetics of ProdetoxonPharmacokinetics of Prodetoxon(data from the manufacturer)(data from the manufacturer)

Blood samples were collected in one week, one and two months after implantationBlood samples were collected in one week, one and two months after implantation

010 20 30 40 50 60 70

Time after implantation, days

Co

nce

ntr

atio

n, n

g/m

l

Naltrexone metabolite Naltrexone

Extended Release Injectable Extended Release Injectable NaltrexoneNaltrexone

Pouder Solvent

Microspheres(Suspension)

Needle

+

Monthly injectionMonthly injection

Dean RL. Front Biosci. 2005 Jan 1;10:643-655. Dunbar JL, et al. Alc Clin Exp Res. 2006;30:480-490.Data on File, Alkermes, Inc.

PharmacokineticsPharmacokinetics

Steady state by 2Steady state by 2ndnd dose dose

Minimal Minimal accumulation 6β-naltrexol

Limited 1Limited 1stst pass metabolism by liver pass metabolism by liver

Monthly naltrexone (380 Monthly naltrexone (380 mgmg vs 1,500 vs 1,500 mgmg))

Mean steady-state naltrexone concentration following monthly XR-NTX 380 mg compared to daily oral dosing

XR-NTX 380 mg

Oral naltrexone 50 mg

Structure of today’s talk

• Naltrexone in the UK today

• Making oral naltrexone better (NICE)

• Oral vs Depot vs Implant

• The NEAT trial

Naltrexone for themanagement of opioiddependence

Issue date: January 2007Review date: March 2010

NICE technology appraisal guidance TA 115

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.

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.

Naltrexone vs. control treatmentRetention 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)

Naltrexone vs. no-naltrexone control treatmentRetention 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

Naltrexone vs. control treatmentRelapse 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)

Naltrexone vs. no-naltrexone control treatmentRelapse rates (Relative risk of returning to illicit drug use)

Relative risk meta-analysis plot (fixed effects)

0.1 0.2 0.5 1 2 5

Krupitsky 2004 0.41 (0.21, 0.74)

Guo 2001 0.74 (0.54, 1.09)

Shufman 1994 0.77 (0.46, 1.21)

Lerner 1992 1.07 (0.53, 2.14)

San 1991 1.05 (0.64, 1.78)

Curran 1976 0.43 (0.13, 1.29)

combined [fixed] 0.72 (0.58, 0.90)

relative risk (95% confidence interval)

Favour Naltrexone Favour Placebo

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)





• The NEAT trial

Naltrexone compliance:effect of added psychosocial element

Review: DMP: Pharm + psychosocial - ComplianceComparison: 01 (Pharm + psychosocial) vs (Pharm + control) Outcome: 01 Naltrexone doses/days used (completers)

Study Psychosocial Control SMD (random) SMD (random)or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI

01 FTCarroll 2001: CM+FT 48 -19.40(15.40) 44 -14.20(12.40) -0.37 [-0.78, 0.05] Fals-Stewart 2003:FT 62 -102.60(41.30) 62 -79.40(46.30) -0.53 [-0.88, -0.17]

Subtotal (95% CI) 110 106 -0.46 [-0.73, -0.19]Test for heterogeneity: Chi² = 0.32, df = 1 (P = 0.57), I² = 0%Test for overall effect: Z = 3.31 (P = 0.0009)

02 CMPreston1999:CM vsNCM 19 -21.40(15.26) 19 -11.30(13.08) -0.70 [-1.35, -0.04] Carroll 2002: CM 36 -20.90(12.51) 18 -14.40(12.51) -0.51 [-1.09, 0.06] Carroll 2001: CM 35 -17.80(13.40) 44 -14.20(12.40) -0.28 [-0.72, 0.17]

Subtotal (95% CI) 90 81 -0.44 [-0.75, -0.13]Test for heterogeneity: Chi² = 1.15, df = 2 (P = 0.56), I² = 0%Test for overall effect: Z = 2.77 (P = 0.006)

03 CBT (intensive 52 week intervention)Rawson2001:MatrixCBT 41 -78.70(67.60) 40 -34.70(48.30) -0.74 [-1.19, -0.29]

Subtotal (95% CI) 41 40 -0.74 [-1.19, -0.29]Test for heterogeneity: not applicableTest for overall effect: Z = 3.22 (P = 0.001)

Total (95% CI) 241 227 -0.50 [-0.68, -0.31]Test for heterogeneity: Chi² = 2.81, df = 5 (P = 0.73), I² = 0%Test for overall effect: Z = 5.26 (P < 0.00001)

-4 -2 0 2 4

Favours psychosocial Favours control

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 1.4.1.3 and 1.4.1.4)

• behavioural couples therapy or behavioural family interventions to service users in close contact with a non-drug-misusing family member, carer or partner.





• The NEAT trial

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)


• 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


• 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


• 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

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

Thank you

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