Filling the prescription

BuprenorphineThis article is the first in a series examining the past, present and future of buprenorphine in the treatment of opioid dependence. Buprenorphine is a medication used in opioid substitution treatment (OST), and it has also been used extensively for the management of pain. The surge of buprenorphine prescribing during the COVID-19 pandemic triggered a reflection of its journey, and with the recent introduction of long-acting injectable buprenorphine we question what its future is within drug treatment services.

Development

In the USA, the Committee on Drug Addiction was created in the 1920s where it studied the morphine molecule, searching for medicines which would not cause addiction. It was hoped that they would find a medicine which could be used in the place of opium based medicines.

The search to find a non-addictive analgesic began in the 1920s following increasing concerns that opioid addiction was resulting from iatrogenic prescribing. The opioid agonist methadone was initially developed during World War II and it was prescribed minimally in the 1950s. Due to the lack of agreement on its safety and its inability to produce the desired effect without addiction, the search for opioid antagonists commenced.

The concept of ‘substitution treatment’ was first developed in response to the opium and morphine addiction epidemic in the USA. It was fully recognised by then that even if a safe and side-effect free alternative was discovered, the addiction problems countries faced would not be resolved in totality due to the complex factors that influence addiction. Therefore, it was suggested that antagonists may assist in managing the problems associated with addiction, rather than completely resolving them. During the 1960s there was a shift from attempting to cure addiction to finding a medicine that alleviated some of the risk. Naltrexone, an opioid antagonist, was produced in the 1960s but only used as a supplementary treatment from the 1980s.

Discovery

John Lewis Buprenorphine PioneerIn the mid-1960s buprenorphine was discovered. Longer acting relapse prevention methods such as antagonist depot injections were studied in the 1970s, while researchers also explored whether naloxone could be added to opioid medicines, and it was around this time that the search for a medicine with both antagonist and agonist properties began to really accelerate. Methadone maintenance was largely looked upon as a solution to treating opioid-dependent veterans and crime in the USA. Despite its support, its limitations were recognised fully.

By the late 1970s it was assumed that buprenorphine could effectively replace methadone as a treatment in opioid dependence because of its low misuse potential – essentially it was thought to have the benefits of both methadone and naltrexone but fewer drawbacks.

Treatment

Although sublingual buprenorphine was launched from 1982 for analgesia, it wasn’t until 1998 that it was licensed for the treatment of opioid dependence in the UK as an alternative to methadone.

Despite the support buprenorphine gained as having the potential to be the next major medicine for treating opioid dependence, it took three decades to be fully approved and utilised in drug treatment services. The development of buprenorphine met with political and social challenges and as an additional option for opioid substitution treatment it has had mixed responses from patients. The dismantling of the barriers that can exist for opioid substitution treatment, as seen with the widespread use of buprenorphine in France, have led to innovative ways of tackling overdose, treatment and retention rates.

In the next article we will look at the introduction of different buprenorphine preparations, its use during the COVID-19 pandemic, and its safety and cost in comparison to methadone.

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What do patients think about buprenorphine?

We asked some patients what their experience was of being prescribed buprenorphine and received both positive and negative feedback

Positive experience of buprenorphine

‘Buprenorphine is far better than methadone – when I came off it [methadone] I had to go through six weeks of hell. I felt like an old man, with aches and pains, hallucinating. I did a 14-day detox. When I came off buprenorphine it was much easier, just a few days of restless legs and that was it If I’d have known what it was like coming off of methadone I’d rather have just stopped off the heroin. Methadone is worse than heroin itself. I went down to 2mg on methadone – three weeks after coming off methadone I felt so bad I took a total of 100mg diazepam, and they didn’t even touch the sides.’

‘You feel like an old man, the pain is unbelievable – 18 years ago this happened, they kept me on maintenance.’

‘I came off buprenorphine a few times, no issues like I said, just restless legs the first night, then the second night a full night’s sleep. I was a lot younger back then, the helpful thing is to exercise.’

Negative experience of buprenorphine

‘I didn’t get on with buprenorphine at all, although most people I know have got on with it. The first time they didn’t bring me down to 30 mg of methadone before I switched onto it, I was on 70mg. I left it two to three days to be in withdrawal, took one and then I was ill, I was actually going to a job interview that day – 20 minutes before I went for the job interview it felt like a super cluck. I had to go out and get something.’

‘I tried to get onto buprenorphine three times. This was seven or eight years ago.’

‘I prefer the methadone. It’s something mental I suppose, I’ve been on it for so long.’

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Buprenorphine Chemistry

Buprenorphine is a partial agonist at the mu opioid receptor and an antagonist at the kappa receptor:

μ-opioid receptor

Buprenorphine has a very high affinity, a low intrinsic activity, and a slow dissociation at the mu receptor.

It has unique and clinically desirable pharmacological properties: lower misuse potential, milder withdrawal symptoms on dose reduction than methadone and a ceiling effect at higher doses (meaning that an overdose of buprenorphine is less likely to cause fatal respiratory depression than an overdose of a full mu opioid agonist like methadone).

Buprenorphine produces a dose-related blocking of drug ‘high’ from ‘on-top’ use of heroin, making it particularly appealing to well-motivated patients.

However, if taken too soon in opioid-dependent patients, buprenorphine can displace heroin and other opioids from the receptors, yet not provide the equivalent degree of receptor activation, thereby leading to a rapid drop in opioid effect and the onset of opioid withdrawal symptoms (‘precipitated withdrawal’).

κ-opioid receptor

The high-affinity kappa receptor antagonism of buprenorphine is involved in reducing stress-induced drug-seeking behaviour. Also, kappa antagonism has demonstrated antidepressant properties.

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The french model

In France in the 1980s, the widespread off-label use of buprenorphine was being used to treat addiction. In 1995, it was the first country to approve the use of buprenorphine for the treatment of opioid dependence.

There was an acknowledgement at the time of increasing levels of overdoses and it was suggested that the majority of people who were opioid dependent were not receiving treatment. GPs were enabled to prescribe buprenorphine and they adopted a low threshold, far-reaching approach.

This approach incorporating GPs had the benefit of normalising addiction treatment into mainstream care. Financial barriers were reduced for GPs and patients. The outcomes were:

• The number of people treated for opioid dependence with buprenorphine vastly overtook the numbers prescribed methadone.

• The majority of buprenorphine treated patients in Europe were in France.

• Overdoses reduced enormously.

• Pharmacists saw an increase in retention into treatment rates.

• HIV infections in people who injected drugs fell dramatically.

• However, France saw a higher number of patients injecting their buprenorphine, particularly when lower dosing was used.

The French model is an example of where reducing the financial, procedural and stigmatising barriers associated with treatment has resulted in positive outcomes for patients.

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What did clinicians think about buprenorphine?

We asked Dr Emily Finch, vice chair of NHS APA, vice chair of the Addictions Faculty at the Royal College of Psychiatrists and clinical director at South London and Maudsley NHS Foundation’s Southwark Central Acute and Addictions Directorate.

When buprenorphine first came to the market as an addiction treatment option in the UK, what were the fears and expectations in drug and alcohol services?

Discussions were dominated by cost when it first came in. It was initially much more expensive. So there were many thoughts about who was most suitable for it – essentially we were rationing it. The first person I gave it to [in 2004] went into precipitated withdrawal. It probably made me very cautious. Over time prescribers and service users gradually understood the need to be in withdrawal when given the first dose.

There were concerns about the difficulties supervising it. It took longer. It was a time when methadone maintenance was not very old in England and most methadone was supervised. At that time we also had lofexidine which we were using for detox. Service users did not like it at all initially.

We were sceptical about the evidence from France, where methadone was not an option, and the US literature where it was introduced because they couldn’t use methadone in ‘office based’ settings – effectively primary care. We knew about its reduced overdose potential but we weren’t that convinced.

In your opinion, has buprenorphine reached its initial expectations of being a safer and preferred alternative to methadone?

I don’t think that was the initial expectation – perhaps by the drug companies, but not by most UK prescribers. It has revolutionised opioid detox and has been successful where drug use may be less chaotic. That is its biggest impact – it is safer but only if the service user will take it. All of my prescribing and the policies I have written have emphasised offering buprenorphine as an option equal to methadone – maximal patient information and influenced by the NICE technology appraisal. Often this means prescribing buprenorphine first, then if that is not successful they’re prescribed methadone.

How do you explain that buprenorphine prescribing has not become the ‘gold standard’ in opioid substitution therapy, as it was originally predicted to be?

I don’t think it was predicted to be the ‘gold standard’. Perhaps it is because it doesn’t make service users intoxicated. So, they stop taking it. The fact that they need to be in withdrawal for induction is a barrier. Other barriers can be the perception that you cannot ‘use on top’ and the fear of not being able to use.

Additionally there has been diversion of buprenorphine in prisons because of the inability to supervise it and the difficulty in induction for many. This can reduce retention rates. The reality is that many people who use drugs in the UK carry on ‘using on top’ of their opioid medication. Does that say something about the adequacy of the rest of the treatment system?

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Dr Georges Petitjean is the substance misuse medical lead for Inclusion, part of Midlands Partnership NHS Foundation Trust.

Deanne Burch is the hepatitis C elimination coordinator for the NHS Addictions Providers Alliance (NHS APA).

Inclusion: www.inclusion.org

The NHS Addictions Provider Alliance: www.nhsapa.org

The authors have not received any financial or other support from pharmaceutical companies and the articles are their own opinion. See the February 2022 issue for part two.

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