Naltrexone in response to the heroin “epidemic”.

An ethical and human rights violation in the making

• for sake of ease I will be using the term opioid to cover both opiates and opioids. I will also be discussing Naltrexone as a response to heroin use disorders, and some points may not be appropriate or relevant for prescription prescription opioid use disorders.
• This piece was originally published on the now-defunct “theinfluence.com”

Recently my friend and neuroscientist Marc Lewis allowed president of Assisted Recovery Centers of America, Percy Menzies the chance to guest-post on his blog as part of a series on the “response to the heroin epidemic.” Immediately on reading Mr Menzies post suggesting that Naltrexone, an opiate antagonist, is a “highly favourable alternative” to opioid addiction, I asked Marc if I could provide a brief rebuttal. However, a brief rebuttal is not enough. The promotion of Naltrexone as a viable solution for heroin users is not based on data, and when it is promoted as an alternative to opioid substitution therapy (OST), it is dangerous, unethical and a violation of human rights. Here are the facts.

OST works

The first and most important thing to note is that opioid substitution therapy works. For methadone we have 50 years of irrefutable proof that it works. We use buprenorphine because when compared to methadone in robust clinical trials it is shown to compare favourably (World Health Organisation 2004; Maremmani & Gerra 2010; Lawrinson et al. 2008; Connock et al. 2007; Connery 2015). In some cases methadone is better, in some cases buprenorphine — the pharmacological action differs — but they both work effectively(Mattick et al. 2014; Saxon et al. 2013) and any risks are easily outweighed by the benefits.

OST is shown to reduce mortality by up to 75%, reduce crime, improve health, improve retention in treatment and allow people the space to resolve many of the other issues that have made drug use so meaningful to them, perhaps at the expense of other more beneficial activities. OST also reduces the spread of HIV(WHO 2009) and it is cost effective, saving x for every y dollar spent.

I feel it is essential to say that some people use OST because they like opioids. They enjoy them and want to keep using them, but that basic human right has been removed by these ridiculous prohibitionist policies we have. So to mitigate the harms of uncertain dose, quality and arrest they choose to use methadone for most of the time and heroin at other times. I have no problem with this and neither should anyone else. Some people also have limited access to medical services, and while the privileged access scripts and prescription medications, they use street analogues. This may not be the majority, but they exist and need to be acknowledged.

Why the “epidemic”?

If OST works, why do we still have such high levels of heroin use? Two reasons: Firstly, OST is not widely available and secondly the manner in which it is offered is not welcoming to many heroin users.

Between 2003 and 2013 the use of OST declined from 33%- 27% as first-line treatment for people presenting for treatment with heroin use disorders. Demographically 45% were older than 45 and only 22% were between the ages of 20 -34(SAMHSA 2015). 3% of all US physicians are able to prescribe buprenorphine. The lack of access to OST has been widely reported in the popular press. For example Huffington Post ran a whole series called Dying to be Free. Even more concerning is how judges have even ordered people to stop their OST, as reported by Open Society Foundations.

Regarding acceptability of services: The Federal Guidelines for Opioid Treatment Programmes(SAMHSA 2013) describe what are essentially abstinence-based high-threshold programmes that insist on comprehensive admissions screening, see OST as part of a “recovery orientated treatment plan”, and encourage “substance abuse” counselling, 12-step programmes and mandate continued drug testing through urinalysis (8 per year minimum). None of this is conducive to encouraging active heroin users to start using these OST services.

What are naltrexone and extended release naltrexone (XR-NTX)?

The Assisted Recovery Centres of America (ARCA) website, describes their approach: patients are detoxed “with the help of medications such as Suboxone® (buprenorphine) to relieve withdrawal symptoms. After this first step, you will be ready to begin taking the latest anti-craving medications, such as Vivitrol®(XR-NTX), or ReVia® (Naltrexone) in our outpatient program and continue your daily life with few interruptions.” What are these apparently miracle medications?

Naltrexone has been available since 1984 in the oral form for treating opioid dependence and XR-NTX the extended release injectable version since 2010. Naltrexone is an opioid antagonist. In other words it has affinity with the opioid receptor but has no intrinsic value and therefore no efficacy. It has no effect because although it sits in the receptor, unlike agonists (heroin or methadone) and partial agonists like buprenorphine, it doesn’t cause any response. And because of the high affinity, when an agonist like heroin comes along, there is no effect. The theory goes that if you are taking naltrexone, taking opioids is a pointless exercise. By blocking the normal functions of opioid use, the Pavlovian learning established through cue and reward dissipates over time. In addition to the blocking of opioids, ARCA describes these formulations as anti-craving medications. Naltrexone (ReVia®) is the pill form that is taken daily, and XR-NTX (Vivitrol®) is an injectable form that lasts 28 days. So, if promoters of naltrexone, Mr Menzies and ARCA are to be believed, we have a medication that blocks the effects of opioids and relieves craving, and this should be offered far more widely in response to the “heroin epidemic” being experienced in the USA. But what does the data say?

The data on naltrexone

Various literature reviews show that Naltrexone has little effect on levels of heroin use(Adi et al. 2007; Kirchmayer et al. 2002; Minozzi et al. 2011; WHO 2009) when compared to a placebo. Compliance and retention are cited as the reason for this lack of effect (Minozzi et al. 2011; Johansson et al. 2006). As would be expected in early stages of resolving a heroin use disorder, attitudes and motivations towards abstinence fluctuate. Accordingly, unless closely monitored, people may decide to skip doses, thereby creating the opportunity for the use of heroin. Retention in treatment is often a measure of efficacy in and of itself, and based on this alone naltrexone does not compete favourably with OST(Johansson et al. 2006). A Cochrane review shows no increased treatment retention for psychosocial interventions by adding naltrexone(Minozzi et al. 2011). To address issues of compliance a longer acting version of Naltrexone was developed. XR-NTX (the 28 day Vivitrol injection) guarantees compliance 28 days at a time. This is because the individual is making an irreversible pre-commitment to abstinence. Pre-commitment is when an individual makes advance decisions about their actions when they are aware of possible future failures in will power(Slors 2015; Crockett et al. 2013). Through the pre-commitment to a longer-term antagonist –XR-NTX — the individual mediates the effects of short-term cravings because these cannot be resolved through heroin use. However, this is often “tested” and it has been suggested that this “testing” of the blockade through heroin use is what improves abstinence(Sullivan et al. 2013).

In respect of cravings, studies have been unconvincing. Retention rate alone should be enough to realise that naltrexone in daily dose does not address craving. OST does, hence the far higher retention rates. This is not surprising as naltrexone is an antagonist. However, in some studies with XR-NTX, results have shown a perceived reduction in craving, although closer examination shows that craving diminishes with abstinence independently of naltrexone (Dijkstra et al. 2007).

So naltrexone is no better than placebo unless compliance is enforced and it has no effect on craving. And that’s the good news.

Naltrexone and mortality

The biggest danger of naltrexone, both as oral daily dose or a 28-injectable, is the substantial risk of overdose. Having said this, during initiation methadone is also not without risks, and all OST, when terminated, presents a risk due to reduced tolerance, but Naloxone seems to increase that risk(Davoli et al. 2007). In one study the risks with Naloxone were found to be 7.4 times (high-risk period, p < 0.0001) or 2.8 times (low-risk period, p = 0.055) times higher than with methadone(Gibson & Degenhardt 2007). This study has been criticized by some, but what is in little doubt is that naltrexone reduces tolerance. Some have argued that is leads to upregulation of opioid receptors, and therefore those that stop using naltrexone are at a significantly increased risk of overdose.

Who could benefit?

One cannot simply dismiss naltrexone — there is enough data to suggest that some people would do well: The UK National Institute for Health and Care Excellence (NICE) concludes its guidelines for naltrexone for the management of opioid dependence as follows: “In summary, the Committee was convinced of the clinical effectiveness of naltrexone treatment in a selected, highly motivated group of people. The Committee concluded that for people who preferred an abstinence programme, who were fully informed of the potential adverse effects and benefits of treatment, and who were highly motivated to remain on treatment, naltrexone treatment would fall within acceptable cost-effectiveness limits.”(National Institute for Health Care and Excellence 2007)

These sentiments are echoed by the World Health Organisation (WHO)(WHO 2009). Their guidelines suggest that those who are employed, who have been using for a short time and those with supervision are best candidates for naltrexone. It is people who really are well motivated and who have good support structures, and perhaps a lot to lose that tend to benefit most from naltrexone.

Since compliance is the biggest issue, the question of who is likely to be compliant with XR-NTX has been examined. Those that are less likely to be compliant identify as homeless, injectors or those with co-occurring mental health issues(Cousins et al. 2015). This is clearly not a population wide solution to heroin use disorders.

Reservations around Naloxone research

An important point to note is that there have not been robust clinical trials that compare naltrexone to methadone and/or buprenorphine in the US. A study in Malaysia, comparing buprenorphine to naltrexone found the differences in effectiveness were so great that the trial had to be stopped when it became obvious that buprenorphine was a far superior intervention and to continue with the naltrexone arm of the study would have been unethical(Schottenfeld et al. 2008). A study in Iran that compared methadone maintenance to naltrexone reported: “In spite of the fact that patients undergoing methadone treatment had more severe symptoms and prognoses regarding their age, duration of drug abuse, and number of treatment attempts, these patients showed better general health and social functioning comparing to patients undergoing naltrexone treatment during the 6-month period of this study (P<0.000).”(Sayyah et al. 2013)

Much of the data has been sourced from studies conducted in Russia(Krupitsky et al. 2011; Krupitsky et al. 2015; Krupitsky et al. 2013) where the policy framework excludes agonist or partial agonist interventions and the punitive approaches to addiction treatment find such studies to be constructed on dubious ethical foundations(Wolfe et al. 2010; Cousins et al. 2015).

A confounder to note is that almost all the research on Naloxone was done with concurrent psychosocial interventions taking place(Meyers et al. 1989). As one study concludes: “The improvements in opioid craving, depression, anxiety, and anhedonia among those who remained in treatment and did not relapse are most likely an effect of treatment success and not specifically related to naltrexone since they occurred regardless of medication group.”(Krupitsky et al. 2015)

Pharmacological, philosophical and ethical concerns

The pharmacology of naltrexone is clear — it blocks opioids. But while this may be great for blocking the effects of heroin, this blockade is non-selective, and so all opioids are blocked. In the case of medical trauma it would be very difficult to treat pain, and if high enough doses of opioids were given this could potentially result in overdose. But of greater concern is the blocking of endogenous opioids. Recent literature has shown this to have an effect on the processing of social stimuli(Wardle et al. 2016), and it is something that needs to be monitored over time.

Philosophically I am concerned that by creating a blockade we are potentially seeing this as the resolution of a heroin use disorder. “Addiction” is not merely a function of pharmacology. Addictions are complex matters. To simply block the effects of heroin on, for example, an indigent street dwelling person, is potentially more damaging than allowing the individual to use heroin when they choose. I realise that this thinking will offend some people, and it certainly challenges the presumption that abstinence is a desirable outcome for all heroin users. It may be for some, but for others continued heroin use is a choice and for still others, a necessity. The problem is not the heroin use, or any drug use, it is the context that alienates an individual to such a degree that their identity and vocation is tied to their drug use. The problem is the systemic drivers that make drug use the most attractive solution to cope with daily life. This cannot be addressed by blocking the drug effect. Agonist therapies reduce harms significantly and still give the person the choice to use heroin, although methadone and buprenorphine both out-perform naltrexone when it comes to reduced heroin use(Connery 2015). Of course, heroin users should have the additional option to use heroin safely — diacetylmorphine should be available in safe injecting facilities.

This leads to my ethical concerns around the XR-NTX. When one starts offering XR-NTX to people in the presence of loved ones, or starts over-selling it to people who are desperate but unaware of the full consequences or people who are ambivalent about their drug use, there is the very real risk of coercion. Already we are seeing it being used for criminal justice offenders(Lee et al. 2016). In 2013 a teen was ordered to take XR-NTX, and Ohio courts are ordering heroin users to take it. In a paper published in 2006 Caplan argued that mandated XR-NTX is justified because “heroin addicts” are incapable of making autonomous decisions(Caplan 2006). Prisoners about to be released in Massachusetts are also offered XR-NTX, but only the first injections, and I wonder what the risk is after the first 28 days? A Phase 4 pilot that provided pre-release prisoners the option of XR-NTX on release for 6 months claims that completing the course “may reduce opioid use” although only 37% of the cohort completed the course of injections(Gordon et al. 2015).

My question is why would we even consider naltrexone as a significant option in addressing heroin use disorders? It is a basic principle in medical ethics that when you have an intervention that works you don’t introduce an alternative unless there are significant advantages and/or improved safety. Naltrexone offers none of this. It produces results no better than placebo in randomised samples and it significantly increases risk of overdose on termination. Further, the Phase 4 pilot does not go head to head with OST. The only justification for ethical approval for the pilot was that it took place in Russia where OST is banned. The only advantage that I can see for XR-NTX would be that it satisfies some sort of moral agenda that prescribes that agonist and partial agonist therapies are somehow “less than” or immoral.

This prohibitionist agenda is sickening and deadly, and if policy makers really wanted to address the harm caused by drugs they would first and foremost look at the policies, legal frameworks and agendas that put every drug user at risk. If we are to address this “heroin epidemic” we need to increase access to the interventions we know save lives so that people find the time and space to resolve their addictions and stay safe in the interim. Methadone and buprenorphine need to be accessible to all heroin users with as few restrictions as possible, and if we deliver these in compassionate, person centred harm reduction settings that use the principles of motivational interviewing, where autonomy is respected and a person is considered the expert in their own lives, we will see results.

Naltrexone for heroin use disorders should perhaps be available for those who really want it and are fully informed. However, if the current attempts to mandate use of XR-NTX to already vulnerable populations, as we are seeing in the criminal justice system, continue, it will be seen by future generations as another example of how prejudices and stigma have yet again resulted in a gross violation of medical ethics and human rights.

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