Introduction to depot buprenorphine in the treatment of opioid dependent patients

Samantha Milat: Good evening everybody and welcome to our Introduction to Depot Buprenorphine In the Treatment of Opioid Dependant Patients webinar. My name is Samantha and I will be your host for this evening. Before we start, I would like to make an acknowledgement of country. We recognise the traditional custodians of the land and sea on which we live and work and we pay our respects to elders past, present and emerging. 

 I would like to introduce our presenter and our facilitator. This evening we are joined by Professor Nicholas Lintzeris as our presenter, and our facilitator, Dr Hester Wilson. Nicholas has worked in addiction medicine almost 30 years and is currently director of DNA services at South Eastern Sydney Local Health District. He is a contract professor at the University of Sydney, president elect of the chapter Addiction Medicine at RACP. He has been involved in several trials of Depot Buprenorphine products and is lead author of the recent New South Wales guidelines regarding Depot Buprenorphine for the treatment of opioid dependence, so welcome and thank you for joining us Nick. Hester Wilson has a Masters degree in mental health and 25 years’ experience working in the primary healthcare setting. Hester is also a staff specialist in addiction at Sydney's Langton Centre Drug and Alcohol Clinic and has facilitated training for doctors and other healthcare workers since 2001- so welcome and thank you for joining us Hester.

Dr Hester Wilson: Thank you so much Sammi- appreciate it.

So looking at the learning objectives, by the end of this webinar we hope that you will understand a little bit about the clinical situations, the guidance that’s available for you around injectable depot buprenorphine, the evidence base, the pharmacology and the risks associated, so that you'll be able to identify who of your patients might be appropriate for this injection, and have clinical conversations with your patients around the pros and cons of depot buprenorphine for them. 

To understand that depot buprenorphine is an opioid agonist for the treatment of opioid dependency and understand a little bit about the prescribing, how to start people, look at those alterations and when you might actually reduce someone to complete treatment or take them off the drug. 

Be able to administer subcutaneous injection of the depot buprenorphine and be aware and be able to comply with the regulatory requirements of prescribing and storing. 

So that there are requirements in New South Wales, and they may be a little bit different to the ACT, and we’ll come back to that a little later on.

So yes, now I must just acknowledged professor Adrian Dunlop who is also a director of drug and alcohol services at the University of Newcastle, was involved in writing some of this presentation that Nick will be giving. 

Our disclosures- all of us have been involved in depot buprenorphine studies and had some consultation and participation that advisory boards. Just also note that there are two brands of depot buprenorphine and because they are specific, and there are some differences between the medications, we will need to use the brand names Buvidal and Sublocade, and Nick will explain more about that for us. Nick would you like to take it from here. 

Prof Nicholas Lintzeris: Let me introduce the summary of the presentation. So many of you will be familiar with buprenorphine- it has been around now for about 30 years in medicine. We have been using it as in the treatment of opioid dependence for around 20 years now in Australia. Until very recently it's only been available as a sublingual formulation: either suboxone film which is a product in combination with naloxone, or in the mono, buprenorphine mono product Subutex. So they are the formulation had available to us up until now. Both those medications require patients taking the medication on daily basis- patients actually turned to either a pharmacy or a clinic either on a daily basis or several times a week, and they may get takeaway doses on the intervening days. 

The introduction this year of two Depot subcutaneous injection formulations really is a significant sort of a difference in the model of care and the implications for patients and for services. There are two products: there is the Buvidal products and they come either as a weekly or monthly subcutaneous injections, and then there is the Sublocade product and that is a monthly or for weekly injection only. The big difference really is the way that the depot treatment will change a lot of the inconvenience and stigma for patients, and obviously without issues having to attend daily to pharmacies or clinics that will reduce the cost of treatment, hopefully increase medication adherence and reduce some of the concerns around non-medical use, of people offering products. For some of you that may or may not be aware that in Australia patients themselves are actually have to pay community pharmacies for the labour associated with supervised dosing, and so most patients are paying around 40 dollars a week is fairly standard and most community pharmacies. Whilst most products are on the PBS they’re section 100 so there's no dispensing for pharmacists, there's no dispensing fees for pharmacists, so the pharmacist end up charging the patients. So this treatment approach will have a significant change also for the cost of treatment for patients. So that's an overview of what we'll be looking at today, and back to you Hester to introduce some of the cases.

Dr Hester Wilson: Thanks Nick- so we're going to be looking at two cases which we'll just flag at the beginning, and then get Nick to have a run through the information and then come back to the cases at the end. I would just flag at this moment guys if there are any questions that come up during Nick's presentation, please put it in the chat box. If it feels like it is a good place to actually ask it at that point I will interrupt Nick and asked him the question, otherwise we will come back to them at the end. As Sammi said we do try and answer all questions - if there are some that we can't get to or we will follow up with you afterwards, so let's come to Joe.

So Joe is a 50 year old man with a history of anxiety, depression, asthma, hypertension and non-insulin-dependent diabetes. I do not know about you guys, but this presentation of someone like Joe with these morbidities is really common in my general practice setting. Joe was also injured in a motor vehicle accident five years ago and as a result has some chronic back pain. He was started on OxyContin at the pain clinic, and the dose increased over time to 150 milligrams daily- so 225 milligrams or a morphine equivalents. He found he was running out early and started seeing a number of doctors to obtain scripts, and despite this his severe pain was actually not being very well managed and it was interfering with his ability to work. His previous GP told him he could no longer assist him. On advice of a friend he sought help from you. You assessed Joe and suggested that he had developed an opioid use disorder and referred him to your local drug and alcohol treatment service for further assessment.

So moving on now- Joe commenced on the sublingual buprenorphine naloxone combination through the drug and alcohol service and has continued seeing you as his GP for his general health needs. He was initially very reluctant to start treatment- you know there's a lot of issues that come around –‘geez you know I have a problem with pain- I don't have a drug and alcohol problem’- but the reality is with some conversation it became clear that the medication wasn’t assisting and that the buprenorphine naloxone combination was a really good option. So he started treatment and he's feeling much better now- his pain has decreased, his mood and anxiety levels have improved, and he's gotten back to work. He finds a regular attendance of pharmacy a struggle at times due to work commitments, and the cost of his medications is a financial burden, so these are issues that Nick has raised. His regular medications- so he's on some asthma medications, he's on the buprenorphine naloxone combination (16 milligrams daily), plus an antihypertensive and an antidepressant, and generally his blood pressure, his asthma and his depression are pretty well managed at the moment. He's doing very well- he comes in and sees you in your general practice for his usual medical review and says he's heard about a new treatment with injections instead of sublingual buprenorphine. Okay so keep Joe in your mind as we go through the presentation- so is someone that is stable or stable on treatment, but is looking at the cost and going to pharmacy, and he's looking for something- he's interested in in changing and having a chat about the changes.

So we come to Mary who is a 50 year old woman with significant anxiety, depression, history of alcohol dependence, morbid obesity and osteoarthritis that greatly limits her mobility- she has a lot of pain from the osteoarthritis, particularly in her knees. She started using heroin 30 years ago and has been in and out of opioid dependency treatment throughout this time- so she's injected heroin over that time. She's had long periods of abstinence from alcohol but relapses when she feels too distressed and overwhelmed with stressful life events. She's tried methadone multiple times but finds it hard to attend daily dosing due to her limited mobility- she relapses back to heroin use when she misses dosing. Interestingly it's easier for her to access heroin and get it delivered to her home and pay for it than it is for her to actually stay in treatment. She was admitted to hospital three months ago with pneumonia and was commenced on sublingual buprenorphine in hospital. On discharge she's continued to struggle to attend daily dosing but she says she prefers the buprenorphine to methadone and she doesn't use heroin as much now. One of the things about a dose of buprenorphine, particularly the larger doses is that other opioids have little effect and certainly for Mary having the buprenorphine was great because it meant if she tried to inject heroin it had very little effect and so it helped her to not use heroin and she was very keen not to. But she's really struggling once again with her mobility and her other health issues to get to the pharmacy or to the clinic for dosing. She’s keen to stop heroin completely but just isn't able to get to the dosing and asks if there are other options. So back to Nick.

Prof Nicholas Lintzeris: Thank you, thanks Hester. Before we sort of get into the presentation- New South Wales Health has been very proactive and has put together a set of guidelines that describe the use of the depot buprenorphine products. They're available at that website and as an interdisciplinary working group that put those together based on best available evidence. The guidelines come in two versions- so there's the long guidelines they go for about 80 odd pages and they're really oriented for specialists working in the sector and address a lot of sort of minutiae around treatment. But we've also recognized that not everyone likes reading 80 page guidelines, and there is the brief guideline document that's also been developed that's what gives a summary of the guidance and around about 10 pages 12 pages, so if you want to read the full guidelines by all means feel free, but there's also the the abbreviated guidelines. Now those guidance documents very much focusing around the depot buprenorphine products- they're written in conjunction with the broader New South Wales guidelines around the treatment of opioid dependence, and those were released last year in 2018 and they're also available as websites there. So they will describe in greater detail things around the use of methadone sublingual buprenorphine and also the use of naltrexone and some of the other issues around withdrawal management and so forth. So this presentation is an overview and if you really want more information I would strongly urge you to go and look at those guideline documents.

For those of you who may not have a lot of experience with the opioid dependence, opioid dependence is a chronic condition and in fact it affects somewhere between 0.1 percent to 1 percent of the adult population. We say somewhere between there because it depends on how you assess opioid dependence. Historically, we always used to think of opioid dependence around heroin use in Australia, and as always that focus around illicit heroin use and injecting heroin use. Increasingly now what we're recognizing is the increasing number of patients who were prescribed opioid medications, used in the context of pain, and with chronic opioid medication we estimate somewhere probably in the range of 10 to 15 % of patients prescribed opioids long term develop a dependence diagnosis. So that means that now in Australia illicit heroin use probably accounts for the minority of all the opioid dependence that we see in Australia at this time . Dependence itself across all drugs is more or less characterized by diminished control over the use of your drug- it means basically you can't control / you don't control your substance use as well as you would like to, and that's often associated a range of physical psychological and social harms for the individual and for the people around them-families friends and also for the broader community.

On the right there you can see in the figures of the main treatment pathways available for patients with dependent opioid use- so patients can either go through the withdrawal pathway- so withdrawal is that period generally most opioids were looking at a one-week two-week period of patients stop the use of opioids and there is a characteristic withdrawal syndrome that occurs generally. Most withdrawal is managed as an outpatient but it can also be managed as an inpatient, and we use a number of medications. Sublingual buprenorphine has pretty much become a standard medication now for the management of opiate withdrawal in Australia, but there are other symptomatic medications that sometimes get used. On occasion we use methadone as well, now many patients after withdrawal will be looking then at moving on to drug-free treatment programs or Medicare, or medication-free should I say, and that generally involves counselling programs using outpatient basis. But there's also residential rehabilitation programs and we also actually do have opioid antagonists available in Australia- so oral naltrexone is licensed for treatment of opioid dependence. It works well for patients that are highly motivated and with very good support structures around them, but unfortunately the outcomes for most patients with naltrexone is problematic if they're poor outcomes. Naltrexone is also very difficult to use in patients with comorbid chronic pain, because if you're on naltrexone its an opioid blocker, and it actually really limits the ability to get any opioid analgesia on top of the naltrexone.

Now that's the pathway on the left, the pathway on the right is patients entering directly into opioid agonist treatment. This is a treatment modality which generally we would like to think of lasting for months to years- again we have to remember opioid dependence is a chronic condition and generally we treat chronic conditions with long-term treatments. Generally the evidence tells us that the longer patients stay in opioid agonist treatment the better their outcomes. The main medications we use in Australia are methadone and buprenorphine- sublingual buprenorphine to date and in Australia about 70% of patients on opioid agonist treatment use methadone and about 30% use buprenorphine. At the end of opioid agonist treatment patients look to come off their methadone or the buprenorphine and there is a withdrawal program so there is a withdrawal syndrome associated with stopping those medications as well. After opioid agonist treatment and likewise we would often recommend the patients look at some form of ongoing aftercare- be that counselling or at least follow up with GPs and primary care providers.

So that's a quick snapshot of opioid dependence- now a quick overview of buprenorphine the medication. So as we said before buprenorphine has been available for about 30 years in Australia. For 20 years we've used buprenorphine and we tend to use high-dose buprenorphine for the management of opioid dependence. Some of you will be familiar with low dose buprenorphine-so that’s in the form of sublingual tablets (so that's the Temgesic) or in the topical patches (that's the Norspan), for both of those the indication is for pain management. The buprenorphine is a very good analgesic, as well as our use for it in treating opiate dependence. Now the reason we like buprenorphine is that it is a partial agonist at the Mu receptor- so the mu receptor is where most of the action is when we're thinking about what opioids do, so if we think about things in analgesia, sedation, and unfortunately overdose- those things are all mediated through the Mu opioid receptors and buprenorphine is a partial agonist there. Now a partial agonist means that you take a dose it has an effect, but ultimately there a ceiling effect so once you start getting certain dose of buprenorphine more buprenorphine will not trigger more opioid receptors, and most importantly that's really important for reducing the risk of toxicity and overdose to buprenorphine. So unlike with methadone or other opioids such as morphine, oxycodone, if you take too much methadone or too much morphine we are all familiar with the risk of overdose. With buprenorphine its not a big concern for us so even at really high doses buprenorphine on its own is usually not associated with overdose.

The other sort of key aspect with the pharmacology of buprenorphine is that it has very high receptor affinity- what that means is it will preferentially bind to opioid receptors ahead of other opioids. So what that means is that will it will reduce the effects or block the effects of other opiates such as morphine or heroin that may be used on top of the morphine. So that's the key pharmacology. As we said there before, been available in Australian as sublingual tablets or film for opioid dependence for about 20 years now, and really the depot formulations is the new development that we're talking about.

So in a nutshell- what are these formulations and what's been the rationale for their development? So we're seeing in a moment you will walk you through the two formulations available and they come as either weekly or monthly subcutaneous injections, and the rationale for developing these products really was around addressing the barriers to treatment and the problems of the regular attendance and daily dosing of buprenorphine. So as we said before, there's the model in Australia's meant you have to attend either a clinic or a pharmacy on a regular basis- usually means daily attendance when patients start treatment- and then once they stabilize in treatment and they reduce their use of other opioids then patients are attending less often but still that frequent attendance is a real problem for many patients in their ability to stay in treatment. And then there's the cost associated with that and that's the labour of the supervised dosing- so you can see how a depot product which only requires attendance to a health care provider once a week or once a month will have a huge impact on the convenience for the patients but also for service providers. Depot also means we should see fewer missed doses- that's where patients don't get their normal dose- and that's important because if a patient misses their normal dose of sublingual buprenorphine then many of them will either get cravings or their use of other opioids, or will go into a full-blown withdrawal and so that sort of impairs treatment outcomes because often we see other drug use occurring on occasions of missed doses.

Then the other key advantage of a Depot product means that we're not giving the medication to patients, which means that there's less risk of the medication being diverted to other people- other people not in treatment and then some of the concerns we have with diverting medications where some people then go and inject their doses are buprenorphine and so forth. So overall, we're confident we should be seeing less non-medical use with the depot formulations and that ultimately enhances the safety of the medication but the community perceptions around some of the problems of non-medical use and diversion.

All right next slide- okay so now let's look at the two formulations so the two products are available. The first product is a product called Buvidal- now Buvidal is manufactured and distributed in Australia by a Swedish company, and this is really their first product anywhere in the world actually as a medication –so they are a new drug company and they specialize in depot formulations. So the Buvidal product is available either as weekly or monthly doses. The product comes in a ready for use prefilled syringe and you can see there is relatively low dose, low volume doses so 0.16 up to 0.67 mils so that's a pretty small dose. It's a subcutaneous injection, its administered by a healthcare professional-that generally means doctors or nurses- and one of the key things around all these products is these medications are never to be dispensed or supplied to a patient or their carer.

 So one of the key issues around the use of these medications is that the medication is either supplied directly to the clinic or medical practitioner from the from the drug company warehouse, or alternatively can be supplied to a community pharmacy but then the pharmacist must supply the medication to the doctor or the nurse so there's no dispensing to patients. The Buvidal is stored at room temperature, so it makes storage quite simple, and subcutaneous injections- it's going to be injected in multiple sizes around the body.

The way this medication works/these depot products work- so prefilled syringe once it's administered subcutaneously, once it comes into contact with water the matrix in which the buprenorphine is embedded in slowly starts to dissolve and slowly dissolves then over the period of the either week or month according to whether or not you're using a weekly or a monthly formulation. On the right you can see there some of the modelling around the kinetics around the buprenorphine plasma concentrations, and you can see there the top right hand figure demonstrates sort of the difference between a daily dose (you can see there's a daily increase and then the plasma level goes down and get the next dose so that's what happens with your standard daily sublingual dose) and the difference there with the weekly product is that you get your peak effects over the first 24 hours and then they slowly subside over the subsequent week. You can see what happens with the monthly product, very similar profile, we see peak dose or a plasma concentration c-max in the first 24 hours and then slow sort of taper off over the subsequent four-week period. The half-life of these products roughly coincide with the dosing duration- so with the monthly product the half-life is around 20 to 25 days but the plateau with the weekly product’s about 5 days. So it's not as though buprenorphine plasma levels have hit zero at the time of the next dose.

This is really about how we dose patients with Buvidal. Now patients with opioid dependence can either be already on sublingual buprenorphine and patients already on buprenorphine can very easily switch the weekly or monthly Buvidal and we do this according to the dose conversion table there. So it's very simple- you just align what the daily dose of sublingual buprenorphine is and then you can see there the corresponding weekly dose or monthly dose. So patients can go directly onto a weekly or monthly dose. What we find is most patients are a little bit anxious about this idea of depot lasting a whole month, and so most clinicians and most patients generally will start a patient weekly dose for the first one or two doses. Once they're comfortable, once the patient is reassured that the depot actually works for the full week, then most patients will transition over to the monthly product for long term. But it is possible to go straight to monthly and as the Commission's have been using this products get more comfortable with the product and there's sort of the word of mouth that the Buvidal monthly works amongst patients we're seeing more and more patients going directly from the sublingual onto the monthly Buvidal.

If a patient is only using heroin or short-acting opioids such as morphine or oxycodone generally we would say ‘look transition over to sublingual buprenorphine for the first week and then switch over to Buvidal’. But it is possible if the patient doesn't really want to go via sublingual for a range of reasons, it is possible in Australia to go directly onto the Buvidal weekly without having to go buy a sublingual. So if you're commencing a patient say from oxycodone or from heroin or from morphine for example, it is possible to initiate directly with a Buvidal weekly product and we would usually say start with their 24 milligram Buvidal weekly product.

Now some patients are already on methadone- a methadone patient must transfer to the sublingual buprenorphine before they can go over to the Buvidal. The frequency of injections- there is a bit of flexibility there. You can see whilst we say that the weekly dose should be every seven days, patients can either come in a couple days early or a couple days late- five to nine days and it really has minimal impact upon the efficacy of the dose. So patients can have a bit of flexibility and that you can see that it's important- either patients miss an appointment or you may routinely be running a clinic on a Monday for example, but Monday is a public holiday and so you might bring the patient in a couple days earlier or a day or two later. Likewise we've got that flexibility with the monthly dose-we say every four weeks but again it can be at you know every three to five weeks and quite easily there the dosing.

Ok lets walk you through the Sublocade. Sublocade is distributed by Indivior, Indivior is the company that makes our Suboxone and Subutex so they’re the sublingual and buprenorphine products currently available. Now the Sublocade is also a prefilled syringe- there's only two doses available of the Sublocade- either a 100 milligram or a 300 milligram dose, and it only comes as the monthly dose. These are bigger injections- so you can see the 100 milligrams is a point five million it seems that's all quite fine. The 300 milligram is a 1.5 mil dose so it's a larger subcutaneous injection. Likewise, this product can only be administered by a healthcare provider (a doctor or nurse). This product though does require cold storage requirements, so it needs to be stored to at 2 to 8 degrees Celsius which means it needs to be in a refrigerator in a safe room. So cold storage Schedule 8 drugs are actually very difficult to handle outside of sort of hospitals and clinics- there's not a lot of facilities that actually do cold storage Schedule 8 so the drug company is actually or will be organizing and facilitating direct delivery to medical practitioners into clinics. The product can be stored at room temperature for seven days. The drug company will be orchestrating delivery of the products to, for example, medical practitioners if they sign up the system and they'll deliver the product and then it'll be able to be stored up at standards or schedule 8 and storage conditions for up to 7 days. If it doesn't get used within the 7 days then it has to be discarded-you can't put it back in the fridge. Another point of difference with the Sublocade is that this is an abdominal site only- so we don't put it into the thigh or into the buttocks or the upper arm as we do with the Buvidal. Dosing with the Sublocade -these are pretty simple- patients to be eligible to Sublocade must be on sublingual doses for at least seven days of buprenorphine. So you can't initiate a patient from heroin or morphine directly onto Sublocade and patients must be on at least eight milligrams of sublingual buprenorphine. So if you have patients on low dose buprenorphine, say two milligrams or four milligrams, then Sublocade is probably not the preferred medication and the Buvidal probably is better suited to low dose patients.

The dosing model here is slightly different to the approach with the Buvidal. With the Buvidal we match the Buvidal dose to the sublingual dose, with the Sublocade it’s a little bit different. What we do is we start all patients on 300 milligrams for the first two months and that gets the plasma levels up, and thereafter patients can be maintained either on 100 or 300 milligram doses according to the response. Likewise there’s a little bit of flexibility here with the dose, and doses can be administered about every four weeks but you can see there you can go up to two days early, 26 days, and up to six weeks after the last injection. So 26 to 42 days is pretty standard for the Sublocade product.

The studies that have been done looking at the evidence for these products are very similar, and so similar studies have been done both for the Buvidal and Sublocade, and we can cluster the evidence around three domains. The first is the issue of blockade- now when we use methadone or buprenorphine to treat opioid dependence one of the effects that we want from the medication is we want it to reduce the effects of additional opioid use, so both methadone and sublingual buprenorphine you can often achieve that at high doses, and this is important because what it does is it reduces continued opioid use on top of your methadone or on top of your buprenorphine .

 Because patients will go and inject their heroin or use oxycontin on top and they'll just find that it just doesn't work that well, and so I love the positive rewards of continued or persistent opioid use are not there with this blockade effect. So studies have been done both for Buvidal and Sublocade and they have demonstrated in laboratory studies that they do reduce the effects of additional on top use, but in some cases it's either full blockade (so there's no effects) or at least an diminished effect. So that's the blockade and it can give both products the big tick when it comes to blockade effects.

The next is the issue of efficacy. This has been looked at in two big randomized control trials. For Buvidal it was an active comparator so the comparison was Buvidal versus sublingual buprenorphine. That paper was published in JAMA and the reference is there, and basically that study demonstrated that Buvidal was as good as sublingual buprenorphine. It was a non-inferiority study so it was as good as buprenorphine in both retention and reducing on top opioid use and the Sublocade study was a as a US study (the US like studies where the comparators placebo) so it was comparing Sublocade to placebo and the Sublocade was demonstrated to be far more effective than placebo in the outcomes of hidden retention and reduced opioid use.

We've also looked at effectiveness- now effectiveness is not under saw double-blind randomized control conditions, but effectiveness studies actually look at open label studies (that means doctors and patients know what they're getting that's not blinded) and we allow the doctors and patients to use the medication under natural conditions. Now we in Australia were participated in a big study looking at that- there was long term treatment- and what we found in that so he says the first time we started using the Buvidal product in Australia- we did that at one of those clinics in New South Wales. What we showed (our site and South Australia as well) and what we showed that the medication the Buvidal was easy to use (so effect welfare was good we'll look at that in a moment) and really good treatment retention, and you know, clinicians and the patients who are using and we actually quite liked the medication. So we thought this is a good medication and we can't wait for it to be licensed and that's what's happened. So that's another view of the evidence and we've references in the slide deck later and anyone wants to go and chase up those references, they're available there as well.

In terms of administering the products- these are very simple medications to administer. They are subcutaneous injections. If you go a little bit too deep in you and you go into a muscular that seems to be far and it hasn't been any problems with it. Really what I just want to reiterate the issue around this medication should never end up in the hands of the patient and this is a TGA requirement around these medications. The concerns are that if you've gone to the hands of a patient and someone was to inadvertently or maybe not, if they were to go and inject it intravenously then that could cause some real problems in terms of the depot then a sort of forming either on tricuspid valves or hitting pulmonary vascular beds, and we really don't want those things happening. So that that's why the TGA has registered both products to only be as supplied to the healthcare provider who must administer the medication. Now there are some useful videos that both companies have provided. The Camurus product is available online, so if you go to their website and if you google search Buvidal you'll find the website, and you need an APRAH login number and once you've put in your APRAH login (because they're not doing direct marketing to patients) you will then see all the materials available from the Buvidal product.

I should have said Sublocade product- actually it's licensed but it doesn't have a PBS listing yet and so the company has not made it available for use in the community yet. There is one study currently underway with the Sublocade product and there's a number of sites in New South Wales that are currently recruiting (so North Sydney st. Vincent's and Newcastle are the three sites in New South Wales). So you may be coming across patients on Sublocade but it's not really available outside of research context at the moment.

Adverse events- so the most of the adverse events that we need to concern ourselves with these products are the local injection site issues, and generally with both products we say about 10 to 15 percent of patients reporting transient and usually mild adverse events- a bit of pain, a little bit of swelling, a bit of redness. It almost always subsides, you know the pain usually subsides a matter of hours, the swelling and redness within one to two days. Very rarely of the other local injection site problems longer-term problems. The Sublocade is associated with a bit of a lump, that's not uncommon when using Sublocade (so a little lump in the abdomen) and that generally settles down over the first one three weeks. Both these products - they're not like implants their patients could surgically try to cut out themselves- there's nothing there to really cut out and we haven't really seen those kinds of problems occurring or patients trying to cut out the depot so to speak. There's also the broader range of side effects that one can get to buprenorphine and the most common side effects we see with buprenorphine are opioid related, so nausea, constipation, sedation. All opioids can cause this sort of paradoxical poor sleep, and it seems to be more of a problem on buprenorphine and people often also seems to have this particular adverse event of headache which tends to be commonly reported.

Finally I guess on the key issues around what to our patients think. So in the study that I was referring to before- which was the open label study- that's really the first study where patients receiving buprenorphine and have actually been asked to tell us about their ratings of satisfaction with the medication. You can see there that there was quite high levels of satisfaction with the depot product compared to the sublingual. Still there, to highlight though there still was around 10% of patients who actually said no I preferred the sublingual to the depot, so whilst we can expect the majority of patients to actually be happy on the depot products let's not forget there are some patients that still will prefer the sublingual. So there really raises, you know highlights, that whenever we're talking to our patients around these products those three points are really important. So this remiss be informed decision-making with our patients and we need informed consent. So the decision to try the depot really should be the patient to be involved in that decision. In order for them to understand what's involved it means we have to give clear and easy to understand information to our patients, and patients should always have the opportunity that if it's not working there's always the option that can go back to sublingual.

 I think that should be it okay. Then again, the summary of the advantages and disadvantages we've spoken at length about the advantages, so I won’t go over those again, so instead highlight why some patients may not like the depot. So we may find that some patients who currently, for example, get a lot of takeaway doses that being on the depot means that they will reduce the autonomy over how they use their medication. For some patients the daily attendance for dosing, or the frequent attendance (sometimes a week), means that some clinician is actually looking at them and reviewing them on a regular basis, and there's moment if you do lose that daily contact with the patient with the depot product. Now of course if you're concerned about patients going, you know, missing for a month or so, you've always got the weekly products, and if you've got patients that you're concerned about them the weekly is a nice kind of option there. We mentioned that some patients will get side effect to the depot products.

Key issue there- we should always remember treating patients with opioid dependence is never just about the medication. We also need to be encouraging our patients to participate in counselling and other psychosocial interventions. Patients need to be reviewed regularly and as Hester highlighted most patients with opioid use disorders also have a range of other medical, mental health, and social comorbidities and so effective treatment means we also have to attend those comorbidities. Now what we've generally found with the depot treatment is that when patients are turning up for their depot injection, that's when you get to do the case management, the clinical reviews and that's when you can get to follow-up the mental and all those other issues.

Safety issues- we've mentioned adverse events, driving- probably not as much as much of a concern with buprenorphine as we have with methadone. The key concerns with the depot's that patients may experience some sedation in the first couple of days after injection, and so they should be warned that over the first few doses just be prepared that the medication may be a little bit sedating and not to drive if they feel that the medication is affecting their ability to drive with the sedating them. Drug drug interactions is the same as other buprenorphine products, most of the concerns are overdose related and that's about the risks of mixing other sedative drugs, alcohol and benzos, on top of any opioid. Pregnancy- the medications, Buvidal- the TGA listing is that it is not recommended in pregnancy but that's not the experience of buprenorphine more broadly, and in Europe and in the US both products are actually have been licensed suitable for use in pregnancy. So generally what we consider is thinking about a risk benefit assessment for any patient, and if any concerns are on the depot you can always put the patient back to sublingual. There's always going to be concerns around pain management for patients on depot, generally what we finally it's not really different to managing any other patient on sublingual buprenorphine, and the management strategies for patients with pain on buprenorphine. Most non pharmacological- so there's all the standard non-medication approaches. When it comes to medication- your options are all the non-opioid options, so nonsteroidals and those kinds of medications, paracetamol. If you have to use opioids, you can achieve opioid analgesia either by giving higher opioid doses than usual, so you know just increase the dose of oxycodone or morphine-it will work, or alternatively, you can use the super agonists such as fentanyl- those kinds of medications. They’re usually required only in a severe acute plane and that's really done by anaesthetist in hospital settings.

Dr Hester Wilson: Nick, can I just interrupt? There was a question from one of our GPs around ‘does this buprenorphine injection work as well as other opioids if you've got someone that has chronic non-malignant pain?’

Prof Nicholas Lintzeris: Yeah thank you. So, most of the research that has been done, all the research around opioid dependence, has been on looking at opioid populations and outcomes. Now, clinically many of us have been using this medication in patients with concomitant pain and opioid dependence, and I think to date, I think all the clinicians have been using it in those kinds of patients, the opioid dependent chronic pain patient. We've all been pleasantly surprised about just how well this medication works, and many of us actually, we're actually feeling quite confident that the depot actually probably provides better analgesic cover than some of the sublingual doses where we're having to use, often split the dose, and a whole range of other issues.

 I'd only give you all a heads up that the Buvidal product, actually there are trials underway in the US, where they're looking at the Buvidal product purely as an analgesic medication- so purely for a pain indication. So the Buvidal, we expect one day, should the trials prove to be effective, and should the company (I'm sorry guys as an ambulance going by), should the company pursue a registration then that one day may will be that we actually have Buvidal both as indicated both for pain management and up your dependence. But that is in the future. So buprenorphine is a very useful analgesic medication and so far we're confident about its use for chronic pain as well.

I might just quickly add though, when we use suboxone, for example, you know sublingual high-dose buprenorphine often in patients who have chronic pain, we really only its indications for patients who have opioid dependence- so you can have of course both pain and dependence. So at this point in time, using Buvidal or Sublocade, Buvidal is the one that is currently available on the market. Buvidal. if you want to use it for a patient with pain, you need to be confident the patient also has opioid dependence- so if they don't have opioid dependence then really it's not the current indication for the depot products.

Dr Hester Wilson: So Nick I've got another question here which is one of our GPs saying what they've understood is that the higher dose buprenorphine sublingual of 32 milligrams, what their what they found in Adelaide was that moving it to the injectables, actually the patient wasn't being held by that dose. They were having withdrawal symptoms- have you noticed that at all in Sydney?

Prof Nicholas Lintzeris: Yes, so these are the studies that we were looking at in terms of those issues, and then the doses. So this is one things to be aware- that many patients will come back after their first injection, several days later, and say ‘I'm in withdrawal, its not holding me, this is not holding me’. When you actually sit down you go through it what you find is actually they're not so much in opiate withdrawal, but there's a lot of anxiety associated with their presentation, and a lot of it is I haven't had a medication today or yesterday or the day before that, and I'm used to taking a medication every day. So there's a lot of this anxiety associated, and that almost always settles down after a couple of doses, as the patients actually then sort of realize actually no the medication is holding me, and I shouldn't get too anxious about it. So a lot of the things that get called withdrawal in the first dose or two actually tend to turn out to not be withdrawal. As for the higher doses, look there's always the opportunity you can do top ups with the Buvidal, so the highest dose we have available licensed in Australia is 128 milligram dose, but you can do top up doses on top of that if it's not holding a patient.

If it turned out though that a patient genuinely was not being held on the 32 grams of Buvidal, so from high use sublingual- if they've moved over to the Buvidal and they're not being held on the high dose even with top up injections, then should that happen then that's the type of patient where you may consider moving them over to the sublingual 300 milligram. How often has this happened? Yet to be experienced really, in most of the trials. Put in context, the Adelaide clinicians I think actually only ever recruited a sum total of six patients on Buvidal, so I think it's fair to say that there's limited experience of Buvidal in Adelaide. They've had much more experience with the Sublocade product.

Dr Hester Wilson: So Nick, just coming out of that was a question about what were you were saying before- the Sublocade and Buvidal are not equivalent but what if you want to transfer from one to the other what are what are the issues there?

Prof Nicholas Lintzeris: Yeah so generally, if you’re on Buvidal stay on Buvidal, if youre on Sublocade stay on Sublocade. Clearly drug companies, when they do their research and they list the products they don't really want patients swapping to the competitor drugs- so if you looked at the product label it says nothing about going from one to the other. Clinically however, there may be circumstances where a patient is treated with one medication and for one reason or another you want them to move to the other medication. So it could well be for example that they say they're on Sublocade in Adelaide, they do a temporary transfer into your service but you've only got Buvidal available- can you treat with Buvidal? The answer is yes, you can there is guidance available in the New South Wales guidelines- we have written a section in there that describes the process there, and generally what we say if you're on really high dose Buvidal then you go to the 300, if you're on lower doses of Buvidal you would go to the 100 milligram and vice versa. So there's we've provided bias in the guidelines how you can do those transitions.

Dr Hester Wilson: Okay Nick, sorry I am aware of the time- there's lots of great questions which we're not going to be able to get to because we've only got a little limited time left. So can I ask you to move on- sorry for my interruption.

Prof Nicholas Lintzeris: Yes, let's go quickly you know- no they're good questions. Very clear coming off depot, when patients come off buprenorphine we expect there to be some withdrawal. To date it hasn't been well characterized so we don't know how severe it's going to be. The few cases that we've been following up- generally what most patients have been describing is very mild withdrawal occurring weeks - months after the last dose. But these are not formal studies, we're talking about a handful of cases, but it's looking optimistic about what the withdrawal profile might be. So I might just move on and I think we're going to move on now to some of the regulatory requirements.

Now this is important to understand. In NSW when the TGA licensed these drugs and registered them they actually put some of our caveats around there their registration- so both products are restricted to specialist rehabilitation settings as the way the TGA turned it for the first six months of their registration. So Buvidal we expect from around January 2020 onwards will be available outside of specialist clinic settings- so if you work in a public clinic or a private clinic in New South Wales you can access these medications, but if you're a GP you actually can't start prescribing these medications until early next year- will be January/ February next year. To prescribe- if you've already got a permit for the patient for buprenorphine, you don’t need a new permit, just contact the PRU and let them know I'm transferring of the patient from sublingual to the depot. If you're going to commence a patient though you need to get your authority for buprenorphine. As for writing prescriptions it's all the standard schedule eight requirements, you know words, letters, numbers all those kinds of issues.

Dr Hester Wilson: So Nick, okay New South Wales regulations for us GPs working in New South Wales, can do an OTAC course which will allow you to prescribe for up to two hundred people in the community setting, or you can now in New South Wales prescribe for up to thirty people (that's 20 people on suboxone and ten people who are stable on methadone). Now as you were saying before Nick that at the moment GPs cannot prescribe until we hope the changes happen early next year, and will that mean at that time that a GP who is not approved (is not an approved prescriber) can actually commence people on buprenorphine and then transfer them or start them on the injectable if they're in that group of GP is to do a little bit of this work but are not authorised prescribers?

Prof Nicholas Lintzeris: So the current wording that we've been following is that if a doctor is eligible to get a permit for buprenorphine sublingual, then they will also be eligible to get a permit for depot. So whilst we say you can prescribe sublingual buprenorphine without having done the full OTAC course they still have a number of requirements of you. So if any of you ever try to do this, prescribe without having done the accreditation course, the health department will just give you a call- make sure you haven't had your schedule eight prescribing restricted and just make sure that you know there's no sort of warning signs from their end. So they've got a checklist that they follow. So if you are eligible to prescribe sublingual buprenorphine then the current logic that New South Wales health are working upon is that they will do the similar kinds of texts and allow you to do a depot. Having said that, New South Wales Health reserved the right to change their minds, so in the new year once it comes off the restrictions I think they will pay closer attention to this and they may fiddle with that, but that's the current model that we're working on.

Dr Hester Wilson: Fantastic. Just moving on to this next slide, so I just want a flag for any of our GPs who are working the ACT, we currently have Megan Arnold from ACT Health who's on line. So if there are any specific questions from an ACT point of view, if you just send a send a question and she will answer that in the chat back to you. So what we have on the screen now is the ACT Health authorities advice around depot. They're considering request for primary care services as to where they'd be considered or approved as a specialist rehabilitation clinic, and so people that are practicing in approved services or clinics can apply. At the moment there are no additional restrictions on supply of depot buprenorphine products- no additional training is required in the ACT over what the sponsor has provided, but any particular issues that you want to raise, if you flag that say you're a GP from the ACT and ask Megan in in the chat she can respond directly to you. Thanks Nick, moving on, we've got two minutes left.

Prof Nicholas Lintzeris: Back to the cases now

Dr Hester Wilson: Yeah so just coming back to Joe. So Joe is the guy that we're seeing our general practice- there's lots of other health issues- he's really stable on his sublingual buprenorphine and he's interested in finding out whether the injectable would be an option. Nick, what would you say if you got a call from a GP saying ‘look this is a situation, is it appropriate?’ What would you say to the GP?

Prof Nicholas Lintzeris: There’s all these issues going on for Joe, but overall he's doing well in treatment but is struggling with, you know, the payment and having to turn up for dosing. So the depot I think would be a good medication to trial, obviously you'd have the discussion and say look here the potential advantages from using it and I would probably be looking at transitioning Joe from the sublingual 16 milligrams a day (I believe he was on- this on the next slide) and I'd be recommending a weekly Buvidal weekly to begin , and if you go back into your conversion tables (from memory don't quote me on this) I think it's the 24 milligram. I would give that a try, review him a week later. Tell the patient, tell Joe, ‘look if it's not holding you, if your anxious, if you’re worried give me a call let's talk about things. You can always get top ups if it's not holding you’. But generally most patients are fine- they come back with you a week later and if the dose is about right, so again good pain control, no side effects, no other concerns- stay on the same dose and you could even offer whether or not the patient want to move over to the monthly dose. Then you use the same conversion table and the 24 weekly then turns into 96.

Dr Hester Wilson: So, I mean certainly for you guys as GPs if you do have a Joe where you're looking at that at the moment, you can't do the transition yourself but have a talk to your local drug and alcohol clinic and see how they can assist you. Or plan to have that conversation again in the new year.

Moving on to Mary, so Mary is a different patient that you're seeing in your general practice for her for her other health needs, but she's a patient that's been seen in the specialist setting. She's on long term heroin user, finds it difficult to get in for dose of daily dosing. She has significant respiratory issues so moving to buprenorphine is a very good idea generally for her, but she's once again struggling to come in for daily dosing. She’s complex, she's still using heroin, there's lots of other health issues going on for her- Nick is she an appropriate one to trial on the injectable Buprenorphine?

Prof Nicholas Lintzeris: Look, we've had really good success with these kinds of patients with the depot and a lot of it has to do with when patients miss their normal dose the drug doesn't work, so if you're missing doses and Mary's got problems with mobility and actually finds that easier to sometimes miss a dose and just use heroin instead. So for Mary I think a trial of the depo is worth considering- no guarantee it's going to work, but as with all these medications, you know give it a try, if it works good! If not you always go back to the sublingual.

Dr Hester Wilson: Terrific- we'll move on to the last case study. So Julie- so Julie has been stable in opioid dependency treatment for some years. She works full-time, she's got kids, or two younger kids live at home with her and a partner, she's not used any psychoactive substances for years, her general mental health is good. Hepatitis C has been treated- she's hepatitis C negative. She commenced on an injectable buprenorphine as part of a clinical trial and now continues on monthly injections. She's not using any other medications- she wants to decrease and cease treatment. Nick how would you talk to Julie about how she could do that with the injectable buprenorphine or would she need to change her medication?

Prof Nicholas Lintzeris: So the key thing about talking to patients that coming off treatment is being being ready and being prepared. Basically you want patients have a good prognosis because what we know what happens is when patients come off their methadone or buprenorphine they're always at risk of relapse, both to heroin use or to other substance use. Also the real concerns are also with patients coming off methadone or buprenorphine is the risk of overdose. So mortality rates go up again when patients come off their methadone and buprenorphine. So the big discussion there is about the challenge is about coming off buprenorphine altogether. We think the depot is going to be a good medication because if you think about it, what we'd like to do when we bring patients off methadone or buprenorphine, we'd like to slowly bring the dose down gradually over time. And that generally requires patients to change the dose regularly over time. If you think about with the depot, the drug is doing that itself- so it's automatically slowly reducing the plasma concentration over time. So it's all sort of like automatically doing its own reduction. The other advantage that we think with the depot buprenorphine products is that we've broken that cycle of the patient taking a medication every day- so they're no longer in that behavioural ‘I've got to take a pill or else I'm going to feel unwell’ and the medication is slowly tapering off. So pharmacologically we think this is a good medication option, but what we really would be emphasizing with all withdrawal- you've got a plan. The plan should be good assessment, good prognosis. Make sure you're reviewing the patient regularly look at what's like psychosocial supports, counselling maybe worth doing, review the patient regularly and if things aren't working be prepared to step in and pause the reductions and stabilize the patient again.

Dr Hester Wilson: Fantastic so look I am aware of the time we move on from that slide. So there were some questions about where to go for further resources- fantastic. Once again did these will be available to you after the webinar. Next slide- okay some references- again they'll be available, and back to the learning outcomes. So we will be finishing up the webinar now- you guys have asked lots of fantastic questions, and there hasn't been time to answer them all. What we will do is I'll ask Sammy to send them out to Nick, and I will answer them in email form and then Sammy can send them on out to you. If there's any additional questions that you want to ask, ask afterwards of course- that's great as well. So I'm hoping that this has been a useful conversation and Nick thank you for giving us some information. You have a lot of experience with the injectibles- probably more than anybody else in Australia, so you're the go-to person for this, and really, look, this is a really fantastic drug that assists people to get on with their lives. We hope in the near future that it will be something that us as GPs can actually prescribe for our patients. I would also say to anybody to get to know your local drug and alcohol clinics, where you can actually access help and support to assist your patients at any time as well.

So thank you to Sammy and the RACGP for running the session. Thank you to all our people who attended-it's brilliant we had a hundred and fifty people attending and Nick thank you so much for your time we really appreciate it.

Prof Nicholas Lintzeris: Pleasure- thank you.