Sammi: Good evening everybody and welcome to this evenings twilight online Understanding Cannabis Medicines (Part Two) Prescribing in General Practice webinar. My name is Samantha and I am your host for this evening. Before we make a start, I would just like to make a quick 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 and present. So, to introduce our presenters for this evening, we are joined by Dr Jan Fizzell. Jan is a public health physician, working as a medical advisor in the Office of the Chief Health Officer at the New South Wales Ministry of Health. She has been working on facilitating the New South Wales clinical trials program for medicinal cannabis and cannabis-derived products and assisting in cannabis therapeutics policy development in New South Wales. Jan also has a keen interest in health technology assessment and population based screening programs. And our second presenter and facilitator for this evening, is Dr Harry Nespolon. Harry is the current Chair of Sydney North PHN and Principal of two general practices in Sydney. Harry is also a Fellow of the RACGP and has been a Quality Assurance Examiner for the OSCE component of the Fellowship Exam for the last 10 years. So thank you for joining us and welcome, Harry and Jan.
Harry: Thank you. With that great introduction, I am just going to hand over immediately to Jan to present Cannabis Medicines – Prescribing in General Practice.
Jan: So good evening, everyone and thanks for joining us. So we have some learning outcomes for this evening’s session, and we are hoping that at the end of the activity, you will have some better ideas about the pathways, requirements and processes to lawfully prescribe and supply cannabis medicines in New South Wales, that you will have a better idea of where some of the reliable information is and what kind of cannabis medicines to prescribe. You will also be able to discuss the ethical and legal responsibilities, plus the liabilities that apply to prescribers when using unregistered medicines, and that includes thinking about informed consent processes and precautions when using unregistered medicines, and explain the different roles of GPs and specialists in cannabis prescription and the requirements for ongoing patient monitoring. So, we will do a very quick review of the session that we had a couple of weeks ago just looking at the cannabis medicines. And then we will have a look at the regulation prescribing pathways, have a look at some of the medicines that are available, then thinking about what to consider when prescribing a cannabis medicine, working as a prescribing and monitoring team. I will briefly go into the informed consent processes that are expected by TGA as part of prescribing unregistered therapeutic goods, and also talk about driving and heavy machinery, or just the workplace THC testing that some patients are encountering. We will also talk about monitoring outcomes of the treatment and think about some of the reliable sources of information.
So, cannabis as a therapeutic has been used for thousands of years. It was used widely in the 19th Century for many different things, including palliative care of patients with rabies. It was regulated worldwide from the late 19th Century, such that wide spread medical use had really ceased in the 20th Century. Research in Israel in the late 20th Century helped us identify an endogenous cannabinoid system and showed that this cannabinoid system has an influence on disparate body systems including neurological. It modulates immune function and gastrointestinal effects. The other thing to consider is, that previously when we were using pure plant derived products, that cannabinoids that people ingested or inhaled were particularly THC, but as commercial investigation goes for other cannabinoid uses, we are starting to see larger doses of these other cannabinoids being used in therapeutic terms and to some extent they are not things that people have been exposed to through recreational use. So, we have got two main compounds of that available to prescribe in Australia at the moment. Many of the cannabis medicines in Australia are plant derived products, so they also have a spattering of other cannabinoids and terpenes and other things that can have some biochemical and pharmacological function. We have got Delta-9 THC which is the most studied phytocannabinoid. It is responsible for the psychoactive effects of cannabis. It can help reduce nausea and vomiting and in fact a synthetic THC, dronabinol is registered in the US and Canada for that indication. In animal models of pain, it is a reducer of pain. It may improve appetite. People are famous for the munchies, but unfortunately in clinical trials in cancer patients it has not worked so well, so we are looking again at how that might be working in our clinical trials. It has got anticonvulsant and proconvulsant dose-dependent qualities and the oral doses are usually starting quite low and a recommended maximum is about 30 mg a day.
Cannabidiol is the other, next most studied phytocannabinoid. It is not intoxicating. It can be sedative. It is really good at interacting with the cytochrome P450 system and so it is important to consider other drugs that patients are on when prescribing cannabidiol. We are seeing quite large doses being used in paediatric epilepsy. We do not have good evidence around cannabidiol alone having a clinical effect in low doses and that is mostly because the clinical trials have not been done. In models, it is antioxidant, anti-inflammatory, it may be neuroprotective and it may modify some of the psychoactive effects of THC, but it is important to understand that just because you give somebody cannabidiol alongside their THC, does not mean that they are free of the chances of having an unfortunate adverse event.
So, things that your patients might be asking you about or considering include the ongoing cost. So, to say that there is a standard cost is not correct. It is quite variable depending on the condition and dose required, because the charge is usually for the amount of cannabinoid used daily rather than because of all the drug development costs and so on. So, a patient who is on 5 mg a day will have a very different cost to somebody who is on 2 grams a day, and that is just how the pricing model is at the moment. And that is why you see these widely varying costs quoted to patients. Most unregistered medicines, if they are supplied out of our hospitals have been evaluated by a drugs and therapeutics committee, and they will usually often be funded at the same time. At the moment, for most cannabis medicines, there is not the evidence of efficacy such that they could be considered cost effective, and so the medicines are normally not being provided by hospital and LHDs, which is why GPs are starting to see patients seeking use of unregistered medicines in general practice. Because I do not think it is particularly common, is it Harry, for unregistered medicines to be being used.
Harry: That is correct. Often you will be approached by a patient rather than the other way around.
Jan: Yes. Pharmacies need to be identified to order in the medicine. They generally do not hold stocks of the medicines, so that is usually about a two to three day delay in the medicine actually getting from you having an approval to actually someone shipping the medicine into the pharmacy where it can be dispensed. The other thing is, that unlike other medicines where you can give a patient the consumer information, there is no reliable consumer information for the unregistered therapeutic goods. A lot of the cannabinoid companies have brought stuff in from Canada that has not been reviewed by a regulator. There is no quality control on it like you see with consumer medicine information in Australia, so you just have to be slightly cautious about what information people are getting and what information you are giving to people.
Harry: Is it easy for the pharmacies to get the product if it is here in Australia?
Jan: It is, so it is relatively easy I understand for a pharmacy to get the product in. A lot of the goods are held at standard wholesalers around Australia and the challenge can be if there is a cold chain requirement of shipping the good and different cannabinoid products have different stability testing about how well they go outside of being kept cold. So that can be a bit challenging.
There is also the fact that we have been given in New South Wales Health, the advice from an expert group that you really should not be driving with THC on board. There is no defence under the Drug Misuse and Trafficking Act for being caught with THC in your oral fluid just because it was prescribed, because the levels at which we see clinical effects of THC are also the levels at which we see impairment from THC.
We also know that some workplaces do on the spot drug testing and then that is up to the doctor and the patient and perhaps the place of employment to negotiate well how much does that particular drug impair that patient? Is it safe for them to operate heavy machinery? Or is it safe for them to be making important decisions even, if they may have some impairment. And that is a similar assessment that you would be doing with any other medicine that can cause significant drowsiness or impairment of cognitive function. One just needs to be really careful about talking it through with your patients, about you know, you may have a limit on what you can actually do at work and we should not just confine that to forklift trucks. If you have got to make important financial decisions, it is important that you are clear thinking as well.
So, a lot discussion is about the regulation of cannabis medicines and they are in a really unusual place because we have got a demand for unregistered medicines and they are also regulated by both national processes by the Therapeutic Goods Administration and then by State processes, where we are interested in safe use of controlled substances, so S8 drugs. So, nationally there is the National Scheduling Committee, a group of experts that provide advice about which schedule a particular pharmaceutical might sit in, and so we have S4 prescription only medicines and cannabidiol only medicines that have only a trace of THC if you are into the S4. S8 medicines which are the controlled drugs, and then S9 are prohibited drugs, and anything with cannabis that is not actually coming in under TGO 93 is likely to be prohibited still. We then have the decision by the TGA to list or not on the Australian Register of Therapeutic Goods, we then have, assuming the sponsor makes an application, for the medicine to be listed or not on the Pharmaceutical Benefits Scheme. Looking at the cost effectiveness of those particular medications for a particular condition. The TGA has developed a standard for medicinal cannabis which talks about making sure that we have got a certain amount of cannabinoid in each product, that it is free of heavy metals and that it is free of contaminants. And that is what TGO 93 looks at. We have national decisions about import and export, but most products that people would use are on-shore. And then we have the use of unapproved medicines which is a TGA decision.
In New South Wales, we need to adhere to a number of different parts of legislation. So we have the Poisons and Therapeutic Goods Act which is mostly around looking at how we package labels, store, write prescriptions, make sure that we keep records of supply, particularly of controlled substances. We also have the Drugs Misuse and Trafficking Act, and a person who is lawfully prescribed a prohibited drug is not committing an offence. So if a person has been lawfully prescribed a cannabis medicine if the doctor has received an authority from the New South Wales Ministry of Health to prescribe an S8 drug, then that person is not committing an offence. We also have in New South Wales the Care and Protection of Young Persons Act, and this is about protecting vulnerable people from doctors doing things to them that they perhaps should not do. And so, within that we should not carry out special medical treatment on a child, so that is defined in this Act as a person under 16 years otherwise in accordance with this section, and that means we should not be prescribing a psychoactive drug to a child for more than 10 days in any 30 days. We also have the Guardianship Act and that has a protection for vulnerable people who are unable to consent regarding special medical treatment, so again using psychoactive drugs that are not endorsed by a professional group or standard. And so for patients with dementia who are actually unable to consent, you are probably best off going and talking to the Guardianship Board, because a relative cannot consent for you to do special medical treatment on a vulnerable person. So, if there is any concern that the person may not be competent to consent to the treatment, I would really encourage people to get guidance.
So, doctors applying for authority for prescribing in New South Wales, so this is completely different to the PBS authority system, there is too many words with “authority” in them at the moment and it all gets very confusing. I am sorry, I have come in on the end of lots of people naming things all the same thing, so I can only apologise for my forebears. But an authority to prescribe in New South Wales is about prescribing certain controlled substances, and that includes Schedule 8 opiates for a drug dependent person. It includes the prescription of certain benzodiazepines. It includes prescription of an unregistered or extemporaneously compounded Schedule 8 product. So, for example we have had previously people are trying to compound ketamine injections. Those people would now have to get an authority to be able to prescribe those compounded ketamine injections. Schedule 8 cannabis medicines including nabiximols and there are certain other restricted products, mostly to do with reproduction hormones and things that can be easily diverted.
So who is looking at what in brief? So if you have a look at the Commonwealth. The Commonwealth is looking at the product, is it a product that complies with TGO 93, or is it a registered medicine overseas. The Commonwealth looks at the patient, including the seriousness of the patient’s condition, and they also look at the health practitioner applicant’s qualifications, expertise and also how long they have had a therapeutic relationship with that patient. Within the State, we still look at issues of diversion, so if there has been a history of practice such that it is likely that a patient could have diverted opiates from the same practice for example, or a patient has a history of drug dependency that the doctor may not have been aware of. There are issues of appropriate use of an unregistered controlled drug, so generally speaking we leaving the clinical assessment to the TGA, but if we start seeing for example THC being prescribed for hangnails, we might have something to say about that. And also, we do check to see if say for example, an application went through to the Commonwealth to prescribe a THC product for a 15-year-old, we would then have to say to that doctor, did you realise that we have now got to go and talk to the Department of Family and Community Services about this? And that is not, and that is just to get permission to prescribe that.
So, we have medicines that are on the Australian Register of Therapeutic Goods which includes nabiximols which is Sativex which is marketed in Australia. You do not have to apply to the TGA to prescribe nabiximols to patients. You do need to notify New South Wales Health and get an authority to prescribe. And it is available in Australia, it is registered, it has got a huge amount of safety data behind it, and so you are on fairly solid ground as far as being able to look up product information, having appropriate consumer medicine information. So you are on fairly safe ground with nabiximols as far as looking at the evidence, because a lot of the clinical trial evidence is generated using Nabiximols. But also you have got evidence against use, you know, where a clinical trial is not showing a benefit.
Harry: One of the questions is, is there much inter-batch variability in the quality of the product?
Jan: So, with each batch, the supplier has to provide a certificate of analysis with the batch. There can be some batch to batch variability. I was really surprised to find out that standard pharmaceuticals can have plus or minus 10% of what is on the label, and for cannabis medicines it can be up to plus or minus 20% because they are plant-derived products. So it is about making sure that you are aware of the quality. You could even ask, so can you show me more than one batch certificate and you might get an idea of who is providing stable batches versus who has got widely varied cannabinoid content. So, it is, they have within plus or minus 20% of what they have got on the label.
Harry: Does that have much of a clinical effect that you know of?
Jan: I think at the moment, we are not at precision dosing levels with many of these things because the absorption of these medicines is so variable from person to person. I am not a pharmacologist but my understanding is you know, different people will process them differently. So, I think individual person to person variation is almost as important as batch to batch variation. But having said that, if we are looking at something, someone like a small child with epilepsy, where cannabidiol can increase the levels of their other anti-epileptic drugs from a therapeutic range to a toxic range, we have got to be particularly careful about trying to get as much as a standardised product as possible. You know, particularly if we are dealing with small children who require you know, large doses of cannabinoid and are not going to tolerate variations as much potentially.
We have also got medicines registered with the overseas regulators, dronabinol which we are seeing some applications for being used here, and Marinol is the usual trade name for that. There is nabilone which is a THC analogue that is also registered in the US and Canada. And there is a cannabidiol product called Epidiolex which we are currently using in our compassion access scheme for kids and it is heading for RDA approval. It has recently passed one of the big hurdles and so we are expecting to hear something in June about it potentially being registered in the US. So, there are registered medicines available, though sometimes more expensive than the plant medicines. But you do get, you know for something like dronabinol which is a synthetic, there is no batch to batch variability beyond any other standard pharmaceutical.
So just to speak a bit more about nabiximols and the reason why I am talking about it, is it is actually registered. So you have got lots of information there. You have got drug-drug interactions. You have got lots of things available to you. It is actually registered for use in refractory spasticity and multiple sclerosis here. It went to PBAC for a decision and it was not considered to have significant enough clinical efficacy to then go on and assess the cost effectiveness, so at the moment it is not available on the PBS. It has been used in lots of clinical trials as I mentioned before, some of which are quite small, so I think the rheumatoid arthritis trial had less than 50 people on it, but it still had some effect. And I have provided the link to the New South Wales notification required and that authority gets transmitted back to you so that you can send off the information to the wholesaler and you can get it in for your patient.
So, then we go onto our unregistered medicines that are available, and this is that Therapeutic Goods Order 93. They are currently all imported from overseas, however some of the production companies are saying they will have local products soon. They are manufactured under good manufacturing practises of pharmaceuticals. There are different levels of GMP. One is for food standards which is where you see a lot of the products coming out of Europe are compliant with the food standard which is nowhere near as rigorous as the pharmaceutical standard. So they do have a known cannabinoid content. They are free of heavy metals. Any information a supplier may give you has not been assessed or approved by a regulator. You will not get any information generally about the product-specific absorption dose side effects. Some of them have actually been used in clinical trials overseas where an ethics committee has had to review and investigate a brochure, so that might give some comfort that there is some of that data available. They have not been assessed by TGA for safety or efficacy and a lot of their use is extrapolated from registered medicines or studies in other countries.
So when we think about the unregistered medicines, their safety and efficacy data is often not available, or if it is available, it has not been reviewed by a regulator. They are often in carrier oils and it is important to understand each one, so if you have got somebody who is intolerant of sesame or coconut or lots of different oils that they are in, you need to understand which oil they are in, so you need to ask the question. Some people would like to vape the products. There are no actual devices registered with TGA to vape medicines. There are some devices registered overseas. One thing to keep in mind though with vaping, is that we do have a Clean Air Act, and it is very difficult to tell whether you are vaping medicinal cannabis or doing something else, and so there are some limits. And then there are the hard limits of the fact that you know, something that is potentially flammable and oxygen just do not mix. So you know, there are all of those considerations as well.
There is no need for these products to have an ongoing supply guarantee. They are available and as long as they are in stock they are in stock, but there is no guarantee that they are going to be re-supplied from overseas and there is no published product information for your consumers. So if you wanted to know all about the different medicines that are available, there are over 50 I think I counted today that are currently available. This is where you can go and see the full list of products. They are usually manufactured in Canada. They have been imported. They are on-shore and they are dispatched from the importer to the nominated pharmacist.
So, when we talk about prescribing unregistered medicines, it is usually done through three major routes. One is the clinical trials route and TGA has two particular schemes, the clinical trial notification where an ethics committee signed off that the product is appropriate to use in a clinical trial, and the other is the clinical trial exemption where the TGA actually does the assessment of the products. Most clinical trials using cannabinoids are using the clinical trial notifications scheme, so an ethics committee has reviewed it. The Special Access Scheme where there is category A, you still need State approval for an S8 and category B which is your standard pathway where TGA does it. I would really encourage people to use category B. There is no true advantage to using category A for cannabis medicines with our single notification pathway.
Authorised prescriber is yet another pathway which involves having an ethics committee endorse a particular plan of treatment. So the Special Access Schemes legislation to ensure medicines, Australians can access medicines prior to registration or for example, if a drug company choses to withdraw a registered medicine here and a patient was using it, they can have a supply imported from elsewhere in the world where the medicine is still available. It is administered by the TGA. For us it is a single form to the TGA and TGA sends to New South Wales State Authority. And you can see TGA has put this illustration around you know, trying to balance how much evidence you have to provide to use a particular medicine versus the clinical need of a particular patient. And so my poor hangnail patients will probably need very high evidence before TGA approved use of an unregistered good to treat hangnail.
The Special Access Scheme, so the TGA advises that if you are considering using the Special Access Scheme to prescribe, you need to understand that it has not been evaluated for quality, safety or efficacy and it is not an approval by TGA. They are looking to see is it within the realms of safety and not so inappropriate that it is unimaginable. They are not looking to say, yes this is good. They are not endorsing your practice. They cannot guarantee the quality, safety or efficacy of an unapproved product. They have tried to put some safety there by saying here is the cannabinoid content. It is free of this and it is free of that, but they cannot say somebody is not going to have a paradoxical reaction or even an expected reaction to the medicine. And the thing is, you do not have to prescribe an unapproved medicine if you do not think it is right to do so. It is really important not to feel pressured into doing that. So, the TGA is quite explicit about the obligations of informed consent. The product, so your patient needs to know it has not been approved by a medicines regulator. They have to understand the benefits of treatment, now you know the risks and adverse effects, the possibility that there could be things that we have not known about, or late adverse effects, and the patient should also be aware of other treatments that are available to them. TGA advises that consent should be recorded and written if possible. The patient should probably think about the cost of treatment before you send off their data to the TGA, so you need to have a good conversation with the patient before you start talking to organisations like TGA and New South Wales Health. We do not need to know about your patients if once they are told about the cost they are not going to want it. So have that good conversation with your patient before you submit their data. Some companies are promoting their website as a great pathway to easy prescribing. I would really suggest that you think about your patient’s privacy and make sure that they consent if you are going to use any of those private prescribing services, because if their data gets leaked from one of those services, you need to be sure that it is going to be secure. And just a reminder around do not drive if it is a THC containing product.
We need to make sure that we have got appropriate clinical tools to monitor the health of your patient and that usually would involve having a treatment plan, so that if an agreed outcome is not being met the doctor could consider discontinuing the treatment. You have actually got an objective measure that has been negotiated between you and your patient. And sometimes that is really important because we have seen that often cannabis medicines, because they are what is being tried after everything else has failed, there is a great temptation to keep going even if the treatment outcomes are not being met. But this is coming at a physical risk to the patient, a financial risk to the patient, and so it is really important that we have got some good way of having that conversation right up front that if we have not met these treatment goals and have them agreed on. Now, that is not to say that you might not reassess the treatment goals because whilst you know, the pain was not a lot better I was sleeping a lot better though doctor, I feel better because of that. You might consider in that clinical consultation that that is a worthwhile treatment outcome and on the basis of that, you are ready to go. But to capture that treatment outcome you have got to think about it as you start or as you are titrating the dose of cannabinoid. It is important to remember that you need to report serious adverse events to the TGA and to whoever supplied you with the medicine. And the TGA is going to look for your objective evidence of how you have been monitoring the patient and how they are going along and making sure that things are being monitored and you know, that may also include patients being willing to keep a pain diary or a seizure diary, or you know, there are lots of clinical tools for monitoring how people are feeling and it is about using ones that you are familiar with and you are happy to educate your patients on.
So, the Authorised Prescribers Scheme. We will just touch on that. So this actually involves you developing a clinical protocol that talks about how a particular drug will be used in a particular population of patients who have particular condition. It has a defined dose regime where you escalate according to a particular dose. It has got defined monitoring and defined starting and stopping rules. It is usually endorsed by NHMRC-endorsed or a College ethics committee. My understanding from looking at the RACGP website, is currently the RACGP’s ethics committee is not looking at authorised prescribers at the moment for anything, not just cannabis. It is just not a thing they have capacity for at the moment. And authorised prescribers still need to notify New South Wales Health for each patient to get an authority for each patient, because again there is that potential where a person has a particular history of drug dependency that a prescriber may not be aware of, so we still need to make sure that we minimise the risk of diversion for the community.
Harry: Just going back to the nabiximols, when, because it is an S8, they need an authority from the beginning. It is not just the dependent patients. You will need that combination TGA, New South Wales Health.
Jan: No, no TGA, just us. It is just New South Wales Health to do the authority for nabiximols, and it is a registered medicine and we are turning those around in a matter of hours.
Harry: But it is from the very first one.
Jan: From the very first go. And that is simply because we are still monitoring the uptake in the community. It is an S8 controlled drug. We are hoping that like overseas we will see that there is, you know, a fairly small risk of diversion, fairly small risks and then we can talk about rescheduling things. But at the moment it is an S8 drug and so we have got the fairly tight controls at the moment.
Harry: And just before you move on, is there any protocol regarding ongoing management of the patient in terms of regular blood testing or those sorts of issues?
Jan: So, it very much depends on what you are prescribing for a patient and why you are prescribing it. So, for example for a child with epilepsy who is having high dose cannabidiol, they are having their liver function regularly monitored. They are having therapeutic drug levels regularly monitored. If you had a patient for example, who was having a combination product with cannabidiol who was on warfarin you would want to watch their INR very closely. They do not seem to be causing a lot of renal impairment and as I say, the cannabidiol we are not sure whether it is only in the very high dose patients who tend to have their liver function go off. And so it is more about monitoring the clinical condition and seeing how your patient is going and if you have got any concerns, just checking in. But I will talk about a service that is available to help doctors later in our presentation.
So at this point, having given you all the bad news, we are getting to some of the better news. So, this is when it is a reasonable time to talk about prescribing cannabis medicines with your patients. So, you have looked at the therapies with better evidence. You have used them or they are contraindicated for this particular patient. A good example is we have patients who do not tolerate megestrol acetate for simulation of appetite in palliative care patients. So, they have sort of done step one, and they could not tolerate the steroids because they stayed up all night awake and not tolerating it. They could not tolerate the megestrol or it was contraindicated because of the type of cancer they had, and so to stimulate appetite we would really like to try some THC containing products. And so, that is reasonable. They do not have to have had a new episode of steroid psychosis to qualify if that is it, it is a past history of intolerance is all people are looking for. We are not looking for people to get tortured in the line of getting approved. It is helpful if there is high quality evidence of efficacy or for example, where we are looking at something like spasticity in multiple sclerosis, spasticity in spinal cord injury, spasticity with a similar pathophysiology. You can reasonable extrapolate it is likely to be effective for your patient. You might have a significant number of case reports with good pre-clinical evidence of likelihood of efficacy for some patients, because you know, for some people with rare diseases we will never get a large cohort. But the really important thing is that both the patient and doctor are aware of the uncertainties and willing to proceed.
So, one of the key questions is, who is best suited to lead prescribing of the cannabinoid, and that comes down to a really important consideration of how confident are you as practitioner in managing this patient with this particular disease. Some patients are incredibly complex. They have got rare diseases. They have got refractory disease and normally I think most people would say well that is in the realm of a specialist or even a subspecialist for some patients. You need to be very sure that you are very familiar with all the prescribed and other therapies for that particular patient. So we know with the kids with epilepsy for example, you know if their liver function tests are going off, do you cut back on their sodium valproate or do you cut back on their cannabidiol. But that is something that the paediatric neurologist understands, but because they have worked a lot and become authorised prescribers for cannabidiol for these kids with epilepsy, so they are aware of all the pre-clinical work, they are aware of the current clinical work. So, it is that question, if something is starting to go off once they start prescribing a cannabis medicine how comfortable am I that it is either a different drug or the cannabis medicine that I am prescribing. How familiar are you with other options for therapies? So, you know, I would suggest that most general practitioners are fairly comfortable working around palliative care to some degree with chronic pain. But even so, it is around for a chronic pain patient signing them up to a psychoactive long term drug is not a small decision. Similarly to you know, prescribing opiates long term now that we have got the evidence that it is not a particularly helpful thing to do, is a big decision. And so, working through all the other ways of looking after that person first before you explore cannabis medicine. Thinking about how much evidence can you hang your hat on that this is a good thing to do, probably Wikipedia is not the best place to go hunting for evidence. The ability to manage side effects of the medicines, so you know as I said the drug-drug. And again, even though dependence is not a particularly high problem with cannabis medicines, if there is already evidence of dependence and considering polypharmacy. So considering about how confident you are managing those issues and having those conversations with at the end of 12 weeks. You are not convinced as the objective practitioner that it is making that much difference. Are you really happy to have that conversation that it is time to stop?
So, I did mention earlier that there are commercial operations that are here to help, but we are really quite concerned about how some of them are promoting themselves in New South Wales. I would point out that across Australia, less than 500 approvals have happened, so no one has got a huge body of practise at this point and the products as I say are expanding greatly, so I do not think anyone is across every single product that is currently available on the market. Also, how confident you are in referring someone to a different general practitioner for example, because a lot of these services are staffed by general practitioners, to manage significant health conditions, as compared to you as a general practitioner who is aware of this patient, who has been working with this patient seeking advice and support which we will supply from New South Wales. We have funded a cannabis medicines advisory service. We will talk a bit more about it later. So, if the problem is that you actually do not think this is a good idea, we would really promote you actually saying to your patient, this is not a good idea and saying why and being open about your concerns because sometimes what we are being told is that it is too hard, there is too much paper work. Underlying all that is actually I do not want to do it because I do not think it is a good idea. And if say it is too hard, you will not be surprised when you get a call from one of these prescribing services saying your patient has come to us, will you help us support their application? You are kind of jammed then, if that is what has happened. But also, we have got a publically funded service there to help you and we will do pretty much what the commercial operations are offering to do if you are willing to put that time into that patient, and we are there to help. And also, it is really important that everyone is on the same page when we are prescribing, because if you have got one doctor who is trying really hard to reduce the polypharmacy in a patient and you have got another doctor saying here is a new drug, it is not good for the patient, it is not good for anyone.
So, I will just put up the slide that we used last time just to talk about some of the things that you, that physicians in Canada have suggested that they are comfortable about. In Australia, generally for neuropathic pain they would like to know that somebody has actually seen a pain clinic and has engaged with a pain medicine program. For palliative pain though, people recognise the expertise of general practitioners in managing palliative care patients. For chemo induced nausea and vomiting, again I suggest some caution to make sure that the patient’s treating oncologist is also on board with it. If they are on board, that is no problem, but considering there are lots of different reasons why a chemotherapy patient might be vomiting, it might not just be because they have had a lot of emetogenic chemotherapy and they are saying well I am vomiting because of the chemotherapy it might be something else going on, so it is really important that everyone is on the same page with that. And again spasticity and multiple sclerosis when a neurologist has been looking after the person and you have sort of got to that point and you and the neurologist are happy to work together, that is a recognised indication, no problems.
So, thinking about contraindications. So, I have taken this from the product information of Sativex. So, thinking about hypersensitivity. So, somebody said I had a really bad trip once and I thought I should you know, go and jump off a balcony, you might suggest to them that this is not the best thing for them to do. Also, the excipient, so understanding how something, what carrier oil, those allergies I was talking about. Now, the known or suspected history or family history of schizophrenia or other psychotic illness. There is a really complex relationship between cannabis and schizophrenia. We are even investigating cannabidiol as an anti-psychotic. So, the real thing is though, given the narrow evidence base, if you have a patient who has had past psychosis, you would be a very brave person to be prescribing a THC product at the moment. Again, it is around the ability to work with a person with severe personality disorder, around cannabis prescribing and managing drug dependence and polypharmacy and cannabinoids are incredibly lipophilic and so if the person is breast feeding, you probably do not want to be prescribing cannabinoids. Similarly, pregnancy, not a particularly good idea.
Precautions, so things that you want to think about are people, older people who if they get a mild or moderate dizziness may wind up falling over, so you can make somebody dizzy because you know, it is not uncommon. There are differences of opinion around THC and what the appropriate age is. There are rat models of rats being exposed to THC as adolescent rats and having brain development issues. There are cohort studies were there are concerns and again it is a chicken and an egg thing, are you using cannabis because you are more likely to have a problem, or do you have a problem because you are using cannabis. The Canadians suggest that it is inappropriate to use a THC containing product for those under 25, the Israelis are using some THC containing products for kids as young as five, but generally speaking, you probably do not want to be using a THC product in that age group.
Cannabis can give some people a bit of a stress test, particularly THC and so if somebody has got serious cardiovascular disease, probably not the best thing. There have been you know, reports of acute stroke and acute AMI after using cannabis. But again, we have not got consistent concerns. You know, it is there, it is a possibility. So certainly not for unstable angina patients. For epilepsy and seizures, as I said for some people THC is proconvulsant so they will actually fit more with THC containing products, and again, generally with older people because, you know and delirium is bad news if you are an older person, and so giving somebody something that can cause a delirium is a concern. So, then different people will find THC, you know they will either feel good with it or they will feel terrible, you know two people same effect, one person’s happiness is another person’s misery. The pregnancy, we do not have a lot of safety data in pregnancy and again the work and driving issues. And even cannabidiol which is not going to be on the test, if you have got somebody who has previously been stable on all their medications, you put them on cannabidiol, it inhibits their metabolism of their benzodiazepine, they can suddenly be drowsy when they did not used to be. So it is important to remember that because they are a fairly new drug, sedation from normally, you know, from drugs that people are normally tolerating quite well, can occur including some tricyclic antidepressants for example.
So, monitoring adverse effects. Something that the TGO will ask you about. It is about some effects that are common, especially the dizziness. It is important that people understand the oral absorption and the fact that it can take more than an hour to actually get an effect, because there are horror stories from doctors who initiated somebody and said we will just titrate it up gradually and the person took it, did not get any effect for half an hour, took another one and was starting to feel a little bit funny but did not think it was really working, took another one and wound up completely stoned and very unhappy at the end of that hour. So just to make sure patients are educated that it can take time for oral absorption to work. Again, drug levels of drugs that interact with the cytochrome P450 system, and recognising that you had one patient that tolerated a dose could be a completely different situation for the next patient. So there is a lot of person to person variability.
We have talked about negotiating those clear outcomes, and there are some standard assessment tools. The Palliative Care Outcome Collaborative have got a really nice symptoms assessment scale for your palliative care patients, and that will also help you pick up on things, you know, your target symptom might have been anorexia and anxiety. But it will also pick up on anything else that is improving as part of the treatment that you are giving, and there is a whole wealth of information around pain diaries and monitoring chronic pain patients on the Agency for Clinical Innovations Chronic Pain Network site.
Harry: One of the questions Jan, is how old is old?
Jan: I think that is a really good question, and I think it comes sometimes back to physiological age, doesn’t it? So, if you have got a very frail 49-year-old, then they are a frail 49-year-old with lots of health conditions. If you have got an incredibly sturdy 70-year-old, you have got an incredibly sturdy 70-year-old. So, it is not a hard and fast rule as such, it is really though recognising that you know, the old-old are particularly vulnerable because we do not have the information and it is very much, you know, it is a therapeutic decision how old is old. It is not like I can say never prescribe to an over 85-year-old.
I just wanted to talk through some myths and legends at the moment about cannabis prescribing, because I think these are the things we see in the media, we see picked up from people’s letters to us about what their concerns are. So I just wanted to try and put some of the myths and legends to bed. The first myth is that there is actually a list of conditions that will be approved. There is no set list of conditions. It is all about each case by case application to the TGA. It is about knowing that standard evidence based therapies have been tried and that the person who is making the application has thought about the likely efficacy of the product. You know, we have seen applications approved where the doctor has said, look you know, I have got very little evidence that it is likely to work, however I have thrown everything else. There is a theoretical benefit and I would like to try it for my very sick patient. I have seen those approved and I have seen other applications where somebody is very passionate about it and the TGA has been very concerned about what was being initiated when other therapies that were standard and routine had not been tried. So, there is no standard list.
One of the other things patients get confused about is cannabis medicines and they are all synthetic. So, as I have discussed, there are a couple of synthetic medicines, but most medicines both the registered medicine nabiximols is plant derived. It has got traces of other cannabinoids terpenes and it is standard. Every time that patient gets that, they get exactly the same mixture. The goods imported under TGO 93 are plant derived and synthetic THC products. They are not commonly used in Australia. They are available, but they are not, TGA does not say no to plant.
Pharmaceutical cannabis is more expensive than the black market, and I, you know, I am quite honest in saying that it is cheaper to grow things in your own back yard, just like it is cheap to go and harvest the bark off your own willow tree to get your aspirin. I would not recommend that. So, for palliative care indications, the cost could be as low as $3 to $10 a day. And I know that is a significant amount of money for some patients, but considering if they go down to the pub and try to buy a gram of cannabis a day or two grams of cannabis a day, they will be out of pocket a lot more than having a pharmaceutical grade product that you as a doctor have confidence in prescribing to them.
My patient will die before they get approved. At the moment for palliative care patients with complete applications by their usual treating practitioner, we have got an average processing time of about six hours. So you put an application in at 6 o’clock one day, it will be approved by 4 o’clock the next day for sure.
You cannot get high on medicinal cannabis and that is something that we see a lot promoted through the media. You can get high on medicinal cannabis. Sometimes we want you to get high on medicinal cannabis as a therapeutic effect. It does depend on the dose of THC. Cannabidiol can decrease the degree of euphoria or dysphoria, however on a 1:1 ratio cannabidiol and THC, 3% to 10% of patients on nabiximols still feel high. So it does not completely get rid of the sensation of intoxication. And we can if we give you enough nabiximols, make many, many people have an acute paranoid psychotic reaction.
Which leads us on to you cannot die from a cannabis overdose. So, this is a bit like saying people who die in a drunk driving car accident have not died from their alcohol consumption. You can actually have such an altered behaviour that you do die from trauma, for example somebody has a hallucination that they are being chased by something and jump from a balcony. And we do know that overseas, that kids are getting admitted when they have consumed products that were either prescribed by a doctor that had an undisclosed THC content or where they have accessed some of their parent’s stash of edible gummies and so on, and so those kids have wound up seizing. They have wound up in ICU. They have wound up ventilated which to me is not too many steps from dying from a cannabis overdose. We also have had people who for example have been so delirious from self-administered cannabis medicines they have required admission because for example they needed their diabetes insulin and because they were so delirious that was not safe to be administered and so they have wound up admitted. So, again, they might not have died from the cannabis but you know, problems with DKA for example. So it is really about trying to say, yes they are fairly safe in large doses, but they are not completely safe, and as I say remembering that morbidity is not just from direct overdose it also from what happens.
So, we have drawn a pretty complex maze at the moment so let us see if we can help get to the other end of the maze. So last December the Government announced that we were funding a cannabis medicines advisory service. It started operation in February. It has a clinical pharmacologist, so an expert in medicines and drug-drug interactions and has senior drug information pharmacists working there. It is a New South Wales Health service. It is free of charge. It is available to you 9-5 Monday to Friday and it is there to help. And they can help you with the latest evidence. They can help you through the regulatory environments. They can help you with tools to monitor progress. They can help you with dosing, titration. I have started my patient on this, this is happening I am not sure what to do, all of that – they are there to help. They are also very aware of which clinical trials are recruiting. So, if your patient is eligible for a clinical trial, they can help you refer your patient to a relevant clinical trial. They will even fill in your paper work for you. So, this is the email address, the telephone 49236200. They are there 9-5 Monday to Friday and they are there to help. They will usually help you the same day and if not it will be a next day service because depending on the volume of enquiries and depending on how unique your particular enquiry is, they go away and you have got a patient with a unique issue, they will go away and they will have a look in the literature for you, to you know, what evidence is there to use particular cannabinoid combination for this particular type of patient. And they have also got the network of the whole Hunter-New England Local Health District specialist network if they just need to ask a colleague who is a neurologist or something for some advice as well. So they are there to help. You have got a specialist drug person there to help you.
We have also got the TGA guidance that we talked about last week. It has the systematic reviews of the evidence. It does not actually give you so much about use 2.5 mg twice a day for whatever, but it does give you some idea of where the wind is blowing as far as what to do and perhaps what not to do. And also, I am just mentioning the Australian Centre for Cannabinoid Clinical and Research Excellence, because we have provided quite a bit of funding to them. They are actually developing clinical guidelines, flow charts like the Canadian ones for Australian circumstances. They are also there to help with how the clinical trial will come out. How do we put that information into clinical practice? We have also funded them to be able to perform drug levels of cannabinoids and their metabolites. So if you ring the cannabis medicines advisory service who work hand in hand with ACRE, they are happy to work together with helping you if you need that particular thing. So a particular thing might be, I have got a patient, I have only given them a small dose. They are off their head. I want to know what is going on with them. Then they are there and they can help. You know, particularly if you know, things have been going quite well for a little while. It is not an instant service, it is more of a, you know, what has happened can I get some idea of what is happening. But again, the clinical pharmacologist is there to help understand it.
I think that is me done.
Harry: Well done. One of the questions is, if you have got a patient using black market cannabis, have we had any applications to use medicinal cannabinoids to presumably treat them and help them get off their high use of black market cannabis.
Jan: So, nabiximols has been trialled in Sydney for cannabis withdrawal and reducing cannabis. If it is a straight substitution as a harm minimisation, we have not got the evidence yet that that is a reasonable thing to do. So if it is just a straight substitution because we have not got you know, like a methadone program for cannabis where you go from black market cannabis to lawful cannabis. However, if a patient has been using a product and if it has been grown in Australia, it is likely to be a high THC, low CBD product as we discussed at the last seminar, and they have had some benefit and say they were managing a particular symptom and you and perhaps their specialist in that symptom had an agreement that this was a useful thing, moving them on to a legal cannabis product is not such a bad idea, and probably you need a THC only product to start with because they are using a high THC product in the community. Or, you could move them on to a registered medicine like nabiximols and see if you got the same effect. So, we have certainly had people approved who have used unlawful cannabis products to self-medicate who were seeing success whose doctors supported their move to a lawful product for the same symptoms because they could see that it had benefitted that person. So it is not, it is actually evidence to support that that has happened, but at the same time, it is really about thinking about, is that the best move for that patient or are you just continuing a dependence condition when you should actually be discussing about how to stop.
Harry: The other question that has come up is probably a more typical patient that GPs would see, which is the chronic non-cancer pain patient who has tried almost everything or has been on usually the opioids. Where would you put that sort of patient?
Jan: And I think this is a really hard one. If we are talking about a patient with neuropathic pain, there is some evidence of benefit. There is also a significant, you know, bNNT to NNH ratio is not fantastic but then possibly a lot of other manoeuvres that have happened for that patient were not fantastic either. So, I am assuming that that person has probably been reviewed by a pain clinic or been participating in you know, all the other things, then it is there as if you like a last line to help. For the other non-neuropathic pain patients, the Faculty of Pain Medicine really recommends that this is probably not a place you want to go at the moment. They are suggesting that the potential harms are outweighing the benefits. So I am relying on the assessment of professional colleagues to suggest that looking at the evidence, the Faculty of Pain Medicine people say probably not for non-neuropathic pain, but again there is always exemptions to every rule, but it would have to be a fairly rare and special case.
Harry: So even substituting out opiates for cannabinoids.
Jan: We are not there yet. Look it is a really interesting area and people are really interested about the opiates varying effects of cannabinoids and I think that is a really interesting thing. What we have not got is really excellent RCT evidence regarding a standard chronic pain non-neuropathic pain patient and whether we are actually able to consistently reduce their dose of opiates. We have got conflicting evidence I think from population studies, where in some populations, use of cannabis reduces use of prescribed opiates, and then in other studies and it is self-report, and there are other studies where actually the person was not using that many opiates anyway when they started on the cannabis medicine when you got back to prescription reports. So what looks like a big decrease in self-report was actually not. They were already on a fairly low dose of opiates when they were personally substituting. We have had that interesting epidemiological phenomenon in America, where in some states where they have liberalised cannabis use the rate of opiate overdose has gone down, but at the same time usually when they liberalise cannabis use, they start clamping down on opiate prescribing so, you know is it because the liberalisation of cannabis came at the same time as a clamp on opiate prescribing? Is it the clamp on opiate prescribing that is decreasing the deaths or is it the cannabis? Or is it both? And we are not there yet, so I do not think the Faculty of Pain Medicine are there.
Harry: I think that covers most of the questions that we have gotten for tonight’s presentation.
Sammi: As you can see on your screen at the moment, they are the learning outcomes that we went through at the beginning of the session, so we hope that we have covered those for you. I just want to say a big thank you to Jan and Harry for presenting at this two part series. We hope you have all found it very interesting. Thank you all for joining and thank you again, Harry and Jan.
Harry: Thank you.