Naltrexone for opioid dependence

Dr Martyn Lloyd-Jones

ECHO 24 July 2019

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Naltrexone

a semi-synthetic mu and kappa opioid antagonist

derived from oxymorphone

“no” psychoactive effect

1st pass metabolism to 6-beta-naltrexone

t½ - about 4hrs, active metabolite 10-12 hrs

binds to receptors for 72 hrs

effective orally

can be administered every 48-72 hrs

Naltrexone

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Pharmacotherapy for opioid addiction: Naltrexone

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Benefits

• No withdrawal if stopped

• Also effective in alcohol use disorder treatment

• Medication itself does not cause respiratory depression or sedation

• Not a controlled substance, no restrictions on prescribing

• Retention appears similar to buprenorphine if successful initiation is achieved

Pharmacotherapy for opioid addiction: Naltrexone

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Limitations

• Must abstain for opioids for 3-10 days prior to first dose

• No pain relief, and no effect from opioids

• Non-opioid approaches to pain management

• Long-term studies still lacking

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Use can lead to extinction due to blocking of opioid agonist effects

Reduction in craving

SE- dysphoria, anxiety, elevated liver enzymes

Context

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Heroin dependence carries mortality of 12x that of general population

Methadone OD mortality (Medicaid data) Russolilo 2018 et al. Methadone maintenance treatment and mortality in people with criminal convictions: A population-based retrospective cohort study from Canada 2018

0.3/100,000 in 1999

1.8/100,000 in 2006

1.1/100,000 in 2014

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Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. Sordo L et al

BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j1550 (Published 26 April 2017)Cite this as: BMJ 2017;357:j1550

OD mortality 2.6/1000 person years in treatment with methadone

1.4/1000 buprenorphine

12.7/1000 person years out of treatment with methadone

4.6/1000 buprenorphine

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Nice guideline 2007

[National Institute for Health and Care Excellence]

Dated but no changes needed 2014

Naltrexone recommended as an option for treating opioid dependence

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While naltrexone implant treatment may show some efficacy as part of an integrated program, more research is needed.

Naltrexone implants are an experimental product and as such should only be used in the context of a well conducted RCT with sufficient sample size, appropriate duration of treatment and follow up, regular robust monitoring, provision of a comprehensive psychosocial treatment program, and with comparison to current best practice.

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13 studies

N=1158

Ntx vs placebo/ nil pharmacological treatment- no significant differences

Rates of incarceration favoured ntx (RR 0.47 (95% CI .026-0.84)

No sig diff c/w bzds/buprenorphine (single study)

Inadequate data to draw conclusions about ntx role in treating opioid dependence

Deaths from opioid OD were not studied

Low retention in treatment 28%

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National Guidelines for Medication-Assisted

Treatment of Opioid Dependence 2014

Refers to NHMRC 2011 conclusion that evidence for NTX implants in early stages and that implants should only be used in a research setting

Statements from ANCD in 2012 and RACGP in 2013 that the ongoing use of the TGA SAS inappropriate for NTX implants

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Naltrexone implants

In development since late 1970’s

Theoretically maintain sufficient plasma levels of naltrexone (>2ng/ml) and 6-b-naltrexol (>9ng/ml)

Shape/composition of implant (microspheres)

Erosion of co-polymer

Influence of microenvironment (pH)

Immune response

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Comer S et al. Injectable, Sustained-Release Naltrexone for the

Treatment of Opioid Dependence. Arch Gen Psych 2006

Randomized, double-blind, placebo-controlled trial, 8 weeks

N=60, heroin dependent adults

Retention in treatment, % opioid –ve urines

Time to dropout and retention in treatment dose-related

39% placebo remained

60% 192mg

68% 384mg

27 days placebo

36 days for 192mg

48 days for 384mg

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Injectable extended-release naltrexone (XR-NTX) for opioid depndence:

long-term safety and effectiveness. Krupitsky E et al. Addiction 2013

im naltrexone (XR-NTX) [Vivitrol, Alkermes Inc.]

12 month open label study at 13 sites in Russia

6 months of randomized, double-blind monthly placebo controlled injections patients receiving XR-NTX continued on 380mg/month and placebo patients were switched to active arm for another 12 months

Offered (biweekly initially then) monthly sessions of manualized Individual Drug Counselling

LFT rises in 16.7% (not clin. sig.)

62.3% completed

50.9% were abstinent from opioids (UDS at assessments)

Summary

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Of those randomized to active treatment arm 31% completed 18 months of treatment

Of those who began 12 month extension phase 62.2% completed it

Excess mortality among opioid-using patients treated with oral naltrexone in

Australia. Degenhardt L et al. Drug and Alcohol Review 2015

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Mortality in cohorts treated with oral naltrexone and methadone 1998-2000

WA (ntx) n=1097, all participants in WA n=2520; NSW (meth) n=11,174

Total oral naltrexone mortality higher for ntx (rate ratio 3.5), 95% CI 2.2-5.8

Estimated 25-29 deaths over 2 yrs in oral ntx cohort Due to higher mortality rate post treatment cessation

Norwegian naltrexone study by Tanum, JAMA

Psychiatry 2017

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159 adult patients with OUD detoxed in inpatient or jail setting

Randomized after detox to injectable naltrexone or SL bup/nx 4-24 mg

Followed for 12 weeks, endpoints included trial completion, UDS results, self-reported use of heroin

Naltrexone non-inferior to bup on retention, UDS results, and use of heroin

US Naltrexone study by Lee

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8 sites enrolled 570 adults with OUD Randomly assigned to naltrexone injection

or SL bup/nx in inpatient setting Patients assigned to naltrexone were more

likely to leave during initiation/detox 94% of bup-assigned patients were

successfully inducted, vs 74% of naltrexone patients

For patients who stayed and stabilized on meds, treatment results (retention, UDS, craving, overdose) were similar with bup/nx and naltrexone

Further References:

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Extended release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders. Lee JD et al. N Engl J Med.2016Mar31;374:1232-42

Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Krupitsky E et al. Lancet 2011 Apr 30;377(9776):1506-13

Effectiveness of Injectable Extended-Release Naltrexone vs Daily Buprenorphine-Naloxone for Opioid Dependence: A randomised Clinical Noninferiority Trial. Tanum L et al. JAMA Psychiatry 2017 Dec 1;74(12):1197-1205

Compare effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lee JD et al. Lancet 2018 Jan 27;391:309-318

Acknowledgements

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Miriam Komaromy MD

M E Haque