Transcript

MIC CAVAZZINI:               Welcome to Pomegranate Health. I’m Mic Cavazzini for the Royal Australasian College of Physicians and this is the second episode of our IMJ On-Air series.

In the November [sic, October] issue of the Internal Medicine Journal we have a Clinical Perspectives review dealing with a scenario you’ve probably already encountered. Patients who are taking complementary or alternative medicines, whose benefit you’re not too sure about. About two thirds of Australians use CAMs but only around half of these people will mention it to their doctor. This can complicate management of patients in palliative care particularly, as they’re less resilient to the outcomes of drug interactions.

To discuss this I’ve got the article’s authors with me in person and online. But I’ll leave the introductions to the journal’s clinical pharmacology section editor Jonathan Brett, in whose office we’re sitting at St Vincent’s Hospital, Sydney. Jon tell us where we are and what you do, as well as volunteering your time to the College publication.

JONATHAN BRETT:          Thanks, Mic. So I'm a clinical pharmacologist, toxicologist and addiction specialist. And I'm also a senior research fellow at University of New South Wales. And we're sat here in the bowels of St Vincent's Hospital in the clinical pharmacology department in my relatively small office. But it's a great pleasure to be with you today. And thank you, Jenny, for coming in person. Could I ask you to introduce yourself?

JENNIFER MARTIN:         I'm Jennifer Martin. I'm a general physician and a clinical pharmacologist, and have a role with the College in terms of training advanced trainees in general medicine and pharmacology to be specialists. And I'm really delighted that Dr Jo Patel, who's a palliative care specialist, came and trained with us in clinical pharmacology for a year. And we realized that that time, I think that there was quite a lot of overlap with drugs and drug development and the clinical pharmacology area.

JONATHAN BRETT:          Thanks, Jenny. And, Jo, would you like to add to that?

JOANNE PATEL: As Jenny said, I'm a palliative care specialist up in Newcastle in New South Wales. And I'm also a dual training and advanced trainee in clinical pharmacology. And I've worked with Jen before.

JONATHAN BRETT:          Fabulous. So I'll launch straight into the paper, which I read with great interest. Just to get a sense of perspective, in your clinical practice how often are you having conversations about complementary or alternative medicines.

JOANNE PATEL:                 In my clinical practice doing palliative care, regularly. So every patient that I would see I would have the time to do a medication review, and ask patients what medications they're taking. And that would include over the counter and otherwise-sourced medications. Complementary and alternative medicines traditionally are thought of as medications that are not necessarily prescribed by a physician, and that maybe have limited evidence base but patients use either to augment and help with their symptoms or to help manage an underlying diagnosis. And that can either be alongside traditional prescribed medications or sometimes instead of.

JONATHAN BRETT:          Is it something that comes up quite frequently in your practice people ask you about this, or does it often just come up when you ask them?

JOANNE PATEL:                 To be honest, even when you do ask them often it doesn't come up because people often don't recognize that that formulation they're getting from a health food store that we would class as a complementary or alternative medicine, people think of as a dietary supplement or otherwise. So sometimes even doing what we think is a comprehensive medication history we can still miss these things that are what we're interested in. And I would say that frequently, patients who I see—by the nature of being in palliative care people have complex symptoms, and will have usually tried several things prescribed or non-prescribed before I get to meet them. And they may have self-discontinued, you know, there's a cost associated with these medications. They may have self-discontinued if they've not found that they're helpful, or they may still be taking them. The thing that I probably get approached about most regularly in this space would be cannabinoids, and I think a lot of my colleagues would say the same.

JONATHAN BRETT:          Thanks. I'm glad you brought that up. Because you gave in the paper some great examples of complementary medicines including capsaicin, ointments, evening primrose, and melatonin. But I think it's interesting to focus in on cannabinoids, and I am aware that there have been previous podcasts on this. But I’ll go to Jenny, what do you think are the sort of major issues with cannabinoids in the palliative care space at the moment?

JENNIFER MARTIN:         I think the field’s moved on since we last spoke on this a few years ago. I think there's a lot more access for patients to getting cannabinoids and they can access those through the special access scheme, and either through their own doctor or if their own doctor is unwilling to prescribe often these patients are actually sourcing external help in terms of the cannabis clinics, which are often online. So patients or people have got more access to cannabinoids, but I think there's a lot less regulation around what's happening with those cannabinoids and just to follow up on the clinical care aspects of the patient.

So just as an example, we had a patient, probably several months ago now that rang our research centre because they had been given a cannabinoid for symptoms in a palliative care setting. And the patient was getting quite nasty serotonergic symptoms but didn't actually know the name of the prescriber, or where they could get help. And because they hadn't had them described through their GP, they didn't feel comfortable going back to their GP to explain this problem. But I guess that highlighted for me something that we've seen a lot of and heard a bit about, which is that there's a lot of fragmentation of care and easy access to these products. But these patients, they're actually not all that well, and when they get into problems, it's very difficult for them to get them get the medical help that they need in a timely manner.

JONATHAN BRETT:          That's a pretty unfortunate situation, that. Just to take a step back and remind listeners, what we're talking about when we talk about cannabinoids, because it's not a simple area; would you mind just sort of giving an overview

JENNIFER MARTIN:         Yeah that's a good point, actually. People think that it says one thing. But as we know, the plants got a number of different chemicals. And there are two that are commonly used in the palliative care setting; That's THC or delta nine THC. That's the active component that people used to smoke recreationally to claim the benefits from it often gives people dissociative, some almost psychotic—and psychotic sometimes—symptoms. And I think people feel that that might be helpful, sometimes, if they want dissociation and end of life setting.

Then there’s cannabidiol, which is the second major component of the cannabis plant. And although that said to be non-psychoactive, I'm not actually sure where that wording came from. Because we know that people feel quite sedated, they often use it for sleep, people feel that they get relief from anxiety symptoms with cannabidiol. So it's really those two components of the plant, which are the major constituents. I think the thing is that people are often not all that aware of what the two different components are when they're buying it. And they often might change the combination and the relative proportions of those two compounds in the product that they're seeking. So they might, for example, they might source one combination somewhere, that's got a lot of THC, and then source it at the cannabis clinic, which has got a different amount. And then they're getting into all sorts of problems with through other medications.

So I think it's just that whole thing of awareness for patients not really sure what they're taking. And then if they go to smoking, which we've often seen particularly as symptoms worse and towards the end of life, and so they’ll start off taking our medical product that might be prescribed appropriately, and then they'll smoke as well to get additional benefit from the cannabis. And then we're getting a whole lot of other extracts from that joint, essentially.

So the problems I think, are just all the problems that we always have with medicines around the education, around the oversight and the governance of medicines. And then that whole thing of bringing in clinical care so that the patient's doctor can actually identify that there's a problem here or drug interactions are to do with a part of the cannabis. So I think that's probably more the situation we're seeing now. Whereas in the past, I think the issue was that patients actually couldn't get access to a cannabinoid at all, even if it was felt by medical practitioner that they might benefit.

JONATHAN BRETT:          Since the rescheduling the cuts really out of the bag, I think, isn’t it?

JENNIFER MARTIN:         I think I mean, some of the community thinks that the rescheduling has been good because it has enabled a commercial business to develop in terms of the cannabis clinics. And it has made it easier for people with long standing chronic pain and other issues to access a quality cannabinoid as opposed to smoking something that might have a lot of other chemicals in it. So I think that that part of the community might feel overjoyed by a change in the scheduling from Schedule 9 to 8. But I think from a medical perspective, we've seen a lot of harms and it's also made it quite difficult from a clinical research perspective to either get funding for research or also to get patients to enrol in trials. So I think it has been difficult from that perspective because we've actually lost a really good opportunity to get quality data both in an observational setting but also in a randomized controlled setting to find out how to use these cannabinoids optimally. And because of that we’re now left with this rather veterinarian situation where patients, the onus is on them to ask a practitioner to prescribe something that they think might be beneficial, but they're doing that without all their other medical notes and clinical care. And just that relationship with the doctor that would often change, I think the way drugs were used in that setting.

JONATHAN BRETT:          So generation of new evidence has become a real challenge.

JENNIFER MARTIN:         Yeah, it's a shame really.

JONATHAN BRETT:          Just in terms of evidence. Joanne, you noted in the paper that the Number Needed to Treat for post-herpetic neuralgia for pregabalin was 4 and for cannabis-based products is 20. But in terms of palliative care indications what—do you have a sense of, what they are and what the level of evidence is for cannabis-based products for those things.

JOANNE PATEL: The evidence base is poor, I suppose. It's growing all the time, there's a lot of people doing a lot of work in it. But as Jenny said, it's really hard to recruit patients to any large study in palliative care. And by nature, the patients we look after in palliative care are usually excluded from most traditional clinical trials. They’re often, but not always elderly; They're often poor functional status; on multiple other medications; it's hard to control for those confounders. So the evidence base is lacking but I don't know that we're ever going to achieve hugely high-quality, highly-powered studies in the palliative care space. And that's the true of a lot of the medicines we use, to be honest. in palliative care because of all those challenges. And so we do use, also, a sense of—there's an anecdotal bias to all of our prescribing, probably, in terms of what we've seen work and what we haven't.

In terms of the question of how do I think it compares to the other agents as an analgesic. There's no perfect analgesic, particularly for neuropathic pain and poorly opioid responses pains. I don't see that cannabis, or cannabinoids any better than any of the other things that we prescribe. I think that the efficacy as an analgesic in my practice, what I've seen, supports what the data shows, which is that I think it's less efficacious than other things that we've tried and can have harms. But that doesn't discount the fact that some patients have tried everything. And occasionally, it does have a big benefit for a patient whether that's part of the psychosocial context and a placebo response or whether that's just that person's biochemical makeup that they respond well to the cannabinoids. And you don't want to exclude patients trying or having an attempt if it's really important to them, because that can also harm a therapeutic relationship, if they really want to try something.

MIC CAVAZZINI:               Can I just chime in there to zero in on the indications, the uses that are most common. So we know that there are TGA-listed products Epidiolex, which is liquid cannabidiol, and Sativex, which is an oromucosal spray. There are in the indications for childhood epilepsy or Multiple Sclerosis spasms. In the palliative setting, is it pain that they're most often coming to you about? And is it hard to get that prescription? Or would many clinicians be inclined to give that prescription off-label?

JOANNE PATEL: In practice, I think, it isn't just pain. I think people have a sense that cannabis or cannabinoids are a one-size-fits-all kind of medicine. And that whole sense of general wellbeing; improvement in nausea, improvement in appetite, improvement in sleep. There's some perception that there's no side effects, I think, among the general public. And I think there's a perception that if they can use cannabis it might replace some of that other medications, which although they also have side effects are probably doing a better job of improving the pain. So I think in my practice, what I've seen, I think it gets prescribed probably more for appetite and wellbeing, possibly, nausea rather than for pain.

There are certainly prescribers of cannabinoids amongst us, but it's very dependent on the patient. It's not really a standard approach because it doesn't fit in with the evidence. In terms of off-label use, in the palliative space a lot of the medications we use aren’t indications that are PBS-listed for, in terms of antiemetics and things. So I don't think it's necessarily about the PBS and the regulations that puts people off prescribing. I think it's more concerned about that benefit-harm ratio with the particular drug.

JENNIFER MARTIN:         So there's only two products that actually have data that supports a TGA registration listing,  and you've identified those. So that's the Sativex oromucosal spray for spasticity in MS, and the Epidiolex which is cannabidiol for rare forms of paediatric epilepsy. But patients can access through the SAS-B scheme—and it was actually set up for patients to be able to get access to off-label drugs—usually as a single drug, not as a class of a drug like the cannabinoids have become. But people can get access through that pathway for any symptom, as long as a doctor is willing to write a script for it.

And I guess that's another really important point just for this podcast, that if we're thinking about where was the need, where was the unmet clinical need, I think we all felt that a quality cannabinoid product might relieve symptoms at the end of life. But when we look at the TGA data, we can see that their highest users by far, like, almost all of them, are scripts actually for chronic pain. And they're actually in a patient group, which is aged 18 to 45, and males. So it's a male chronic pain population that's accessing SAS-B. Eighteen to 45 year olds, our most productive people in the workforce, and we've now given these people another chemical that we know has psychoactive effects. And that's a separate issue, I don't really want to go into that so much today, but the TGA data suggests that the people that are accessing it are not necessarily those that the clinicians felt we had a an unmet need to fill in the clinical space.

JONATHAN BRETT:          Great, thanks. Actually sticking with regulation, because I think this is a really interesting topic. Thinking about complementary medicines as a whole, you did talk briefly about how they're registered in the paper. Would you mind just stepping us through that?

JENNIFER MARTIN:         Yeah, so there's two pathways for registration of a product. There's one, which is an AUST-L, and that’s a listed product. And that usually does cover complementary medicines, but you still need a level of safety and safety data for that drug to be considered to be registered with an AUST-L label. And then have AUST-R, which is the registered medicines, and that's most of the medicines that we would prescribe on a script as a doctor. But I know that with cannabinoids a lot of the community wanted to push for an AUST-L listing for cannabinoids, but because of the space in which they were used, so vulnerable populations, because of the risk of drug interactions and because of a whole lot of other issues around efficacy and quality of the product, it was deemed at these would go down the standard evaluation process for standard medicine. And the TGA expected that these will be used as a medicine.

JONATHAN BRETT:          Just following on from a couple of things you just brought up there, I want to pick up on the safety around interactions but also around purity, excipients, and contaminants, I think that’s a really important consideration. What are the requirements for the TGA to test for SAS-B imported products for cannabis, for example, on those things; purity excipients contaminants.

JENNIFER MARTIN:         So that was a big thing, I think that people hadn't quite thought about initially. People thought that, you know, we've been growing in our backyard for years, so how unsafe can it be? But I think actually, when people started testing it, they realized that, particularly the area that Jo and I work in Newcastle, there's a lot of heavy metal in the cannabis. And in some parts of the world, the cannabis plant is used to sort of clean up the soil after mining—so very high levels of lead and arsenic and other compounds.

So the TGA did bring in a standard called TGO-93. So TGO-93 regulates a lot of that stuff around quality of the products for cannabinoids. And essentially if you're importing it, all imports have to meet the standards, which tell you, you know, that you've got no fungus, there's no insecticide, there's no heavy metals on it, and what sort of percentage of the plant is THC or CBD. We're not really using so much of the imported dry product anymore, because I think it is difficult to standardize it.

And just as an aside, we went down that pathway to start with doing vaporized studies with dried products because you couldn't actually get synthetic extracts or other extracts. And we were finding that the composition of the product at the start of the trial was actually quite different to the end. And I think if you're trying to help get these products registered by the TGA and the products actually changing during the trial, that's not great. But the TGO standard doesn't really look at the shelf life and stability, so much, so that issue could still be there and researchers have to do their own work in that area. But it does just check that it's pretty safe and all of those toxins—the aflatoxins and things that we're worried about and not present.

And it's actually fascinating because I sometimes get emails or phone calls from someone out in the public, who says something like, “Hey Jen, you're the researcher up In HMRI doing lots of research, and I've got the script, and I've gone and spent all this money, and I don't think this is the real deal. So I'm wondering if I can just drop it off at the hospital get you to test it for me?” So I don't know how many of those we've had, maybe a couple of dozen of people just bringing up their research centre, and offering to drop the product off. The problem being that, obviously, they're dropping off a product that has a whole lot of legal and security issues in a hospital. And I'm a medical practitioner, so there's a whole lot of duties of care when I receive a product and then find out it's not good in terms of my requirements to manage that patient. So it has been a bit fraught.

But yeah, we just give the advice that for people to be very careful. And there is a list of quality products that are well documented and people have used in clinical trials. And they've essentially pharmaceuticalised their product. We have also set up a Drug Information Service, which is for the state, but run at the Hunter and that's again—we can say to the patients, please just ask your doctor to bring our service. And we can give them information about a quality product. Because not all of that stuff that's important is actually quality.

JONATHAN BRETT:          That sort of leads on to a question around interactions. So Jo, I might ask you about this. I think cannabis products are a good exemplar of, 1) how important it is to ask about whether people are taking anything else and, 2) about potential drug interactions. Could you give us any examples from your clinical experience?

JOANNE PATEL: Yeah, I think of a couple of examples. And it sort of highlights the differences in the healthcare space as well. So we do supportive care; so I have seen a lot of patients who are on palliative chaemotherapy with an intent that's going to prolong their life and we see them in a supportive care space. And we see patients who are on cannabis and it could either be prescribed or it could be sourced themselves, who are also on immunotherapy with intent of life prolonging. And we know that there is a drug-drug interaction, that's been demonstrated in studies, between immunotherapy and cannabis, and that cannabinoids may actually impair overall survival and shortened time to tumor progression.

And often, that's something that people are unaware of. So part of my history taking when I ask about cannabis is I highlight that reason why? I'm asking because it can interact with other medications, and just encourage patients to talk to their oncologists about that to get the best advice that they can have. I suppose with anything we prescribe, it's a risk benefit ratio for any drug for any indication?

In the other space of palliative care where it is very end of life, and it's purely symptom control that we're looking at, and there's not active anti-cancer medications or whatever other malignant disease it may be, the aim is to make people feel better each day. And that's where my job is quite easy, because I don't have to wait for scans to know whether treatments working, I can just ask someone whether they're feeling better. But often they're not feeling better after they start a new drug. And that could be anything, but with cannabinoids or other complementary or alternative medicines, there's interactions with other medications they might be taking. So if they're on, for example, an SSRI, a serotonin reuptake inhibitor for depression or anxiety and they start a cannabinoid, there can be an interaction there which may worsen their symptoms. It could precipitate nausea, it could make them feel anxious. So there's just two examples of different spaces where the reason we ask and explaining to patients why we're asking.

JONATHAN BRETT:          Thanks, Jo. So my understanding is that with CBD in particular, cannabidiol, you have both pharmacokinetic and pharmacodynamic interactions. So what is perceived as a fairly benign treatment can actually have fairly clinically significant interactions. Would either of you like to step us through what the P450 interactions might be and what the potential pharmacodynamic interactions are?

JOANNE PATEL: Yeah, so with CBD in particular, I suppose the somnulents, the anti-anxiety, all of those things. If someone's also on for example, opioids, or benzodiazepines, to help manage their anxiety or make them sleep, it can actually be really quite sedating. And it just potentiate those effects.

JONATHAN BRETT:          And often people in palliative care are already on a number of sedatives.

JOANNE PATEL: Yeah, and it also may be that the CBD may be the long-term medication that that patients been on, but then we decided to add a sedative as the patients getting closer to the end of life. And the risk-benefit ratio means that we think they may benefit from that. But just to be aware that maybe we need to use a lower dose, because if that patient's already stable on CBD, you want to be cautious in case you're going to potentiate those effects. Jen, do you want to talk about the pharmacokinetic interactions?

JENNIFER MARTIN:         Yeah, so cannabidiol, it's a really fatty drug because it comes from a plant. And so you can't excrete fatty drugs without making them water-soluble. So you’ve kind of got an alarm bell ringing already that you're going to have to metabolize this and you're going to have to add lots of things in the liver to make it water-soluble. And I guess that means that there will be a lot of drug interactions and cannabidiol does get broken down through the P450 system, but it also acts as an inhibitor. So it blocks the enzyme that breaks drugs down as well. And probably a pan-enzyme inhibitor, but it probably does have particular effects on drugs that are broken down through the SIP2D6, which is the one that breaks down most of our neurology and psychoactive drugs, so a lot of our antidepressants are broken down through that pathway, and antipsychotic drugs. And it probably inhibits SIP304, which is essentially the enzyme that breaks down the rest.

So really, if you're on cannabidiol, levels of other drugs that you're on that are broken down through the P450 system will become quite high. And so, again, Jo's already given a really good point with the benzodiazepines that actually, if you need to use them, if the cannabidiol is not providing the sedation that you need, and you're wanting to use a benzodiazepine, you can use it but just go very carefully with the dose and just start on a very small dose. Because I think one of the studies with Dravet syndrome, the paediatric epilepsy syndromes, the children were given cannabidiol, they were quite sleepy, everyone thought it was probably the cannabidiol. Except the levels of the Clobazam, which is a benzodiazepine were very, very high. And in subsequent studies between five to eight-fold higher. So there's still an uncomfortableness, I guess, amongst the epilepsy community that maybe the benefit of cannabidiol in that setting was just because the benzodiazepine level was so high. And there's quite a lot of literature around that.

My colleagues say maybe it doesn't really matter what the mechanism was, because you've actually reduced the seizures. But I think that you might be able to get away with a lot lower dose of those other drugs if you're starting with cannabidiol. And coming back to that earlier case that we discussed where the patient from a cannabis clinic rang our research centre, they were actually on a serotonergic antidepressant and were getting quite significant serotonergic symptoms. And I can't actually remember the dose that I recall it not being that high, it's not at a dose that you usually expect serotonergic symptoms just from that SSRI alone. So I think really, it is a cause for concern. And I think just, you know, go low, go slow.

JONATHAN BRETT:          Yeah, interesting. So I imagine it's often quite challenging to unpick symptoms at the end of life. And we want to make damn sure that we're not contributing to that.

JENNIFER MARTIN:         I mean, if you can measure levels that’s really helpful. Because we have researched into this aligned to the back of our campus, we can we can measure concentrations. And so we can see that, particularly in our clinical trials, that the levels do correlate with symptoms. But I think you can tell just clinically from the symptoms that people have, and probably as the palliative care fraternity tell us, and Jo's already outlined, that if you ask someone every day, and they and they tell you how they're feeling, and you actually listen, then you can probably do that without measuring levels. And that whole mantra of actually, “Well, if you take the history properly.” So go back and retake the history and ask the things that weren't taken initially. And the medications I think are often done very quickly, there's sometimes written in the margin of a written report, no one has written and when the drugs are started when they're stopped, what happened last time they were in hospital, when they stopped and started the CAM medicine as well.  Yeah, I would just support that.

MIC CAVAZZINI:               I’ve got a got a question for Joanne, actually. Back in episode 33, the last time I spoke to Jenny, I also interviewed Professor Mira Agha, who's a palliative care specialist doing trials of cannabinoids for cachexia. And she had an interesting point that while, often, patients and families at the end of life are willing to try anything as a sort of Hail Mary intervention for their symptoms, she took a much more conservative approach, because these people are so frail and so vulnerable to dosage errors and interactions. So maybe Jo, do you want to talk talk from your experience about the frailties of these patients and how unpredictable outcomes might be?

JOANNE PATEL: Patients at the end of life are very vulnerable. Just thinking of it from a pharmacology point of view, there's often rapid weight loss, they're often not eating and there's big changes in their diet and their oral intake of water. All of those things impact all of the drugs that they're taking and their general sense of wellbeing, and I feel that they're just a lot more vulnerable to side effects. And often the side effects of whatever CAM it is, you know, often is the symptom you're trying to treat.

Like, people get debilitated by nausea occasionally, and any medication you look at, you go on MIMS or AMH, any medication has nausea listed as a side effect. I think if you talk through that with patients, if they come to you with concerns or questions about a CAM, is being open and honest with them, that there's a good chance this might make it actually worse. And unless we're in an evidence base that we know it's going to be better it is trial and error. And being open to trying things if patients want to, but having a low threshold to stop them, if we think it actually might be making them worse because of their frailty, the changes in their, their pharmacodynamics and pharmacokinetics towards the end of life.

JONATHAN BRETT:          Thanks Jo. It’s sort of reminiscent of opioids in some ways, isn't it? The sort of, you know, we talk about universal precautions with opioids. You know, only prescribing as necessary, having a treatment goal and having a sort of de-escalation strategy. So I think it's probably even more relevant with the sheer number of medicines people might be on at the end of life.

But I just wanted to sort of follow on to I think, what's probably one of the most important interactions, which is the doctor-patient interaction. And, Jo, just in terms of the conversations you're having with patients, could you tell us the kinds of things that come up and some of the challenges, particularly around complementary medicines?

JOANNE PATEL: Yeah, absolutely. I'm really fortunate, I get a lot of time with my patients. And I know that my general medicine colleagues, and especially my general practitioner colleagues don't get the privilege of the time I have with patients. But people, they just want to be heard. And if they've had ideas or suggestions from people in their lives about things that might work or make them feel better, or, you know, the huge Holy Grail of, “It might cure my cancer,” they want to talk about it, and they want to feel heard. And they don't want to be dismissed or have that dismissed.

I just talk to patients the same way I talked to medical students and junior colleagues. If they want to go to that level of evidence I'm happy to sit down and break it down with them, you know, “These are the things that this medication might be good for. These are the harms we know it might have. These are the interactions,” and just being honest that all the other things that I'm prescribing, you know, the opioids or the pregabalin, or whatever it may be, there's risks and benefits to those too, I just understand them a bit better, because I'm a bit more familiar with them, and we've got a higher evidence base for them.

If it's really essential to the therapeutic relationship, then I'll try and support it but just put in safe parameters and make them feel comfortable with coming to me or their GP with concerns. A lot of people, especially if they've gone to a prescriber or gone online, to buy their medications may feel like they've been dishonest or they don't want to impair the doctor-therapeutic relationship as well. So I think you've just got to be open and honest with people and just be kind and compassionate, that they're in a space where they're also trying to do their best. And we've just got a little bit more knowledge to guide them, hopefully.

JONATHAN BRETT:          Yeah, absolutely. Mic, was there anything else you wanted to ask? Yeah, I might.

MIC CAVAZZINI:               I might just throw one grenade in there, before we go. Jenny and Joanne, you wrote in the paper that “the annual Australian private expenditure on complementary and alternative medicines is $4 billion.” And so this prompted me to look up from a federal government report from several years ago that the gross out of pocket spent on listed pharmaceuticals was only $1.7 billion. So what do we what do we make of that and how can you frame that for patients? Where to put their bang for buck, where to put their value for money?

JENNIFER MARTIN:         So I think it's a fascinating question too, because often, like, I used to sit on PBAC and quite a lot of issues would come into the media on the day that PBAC actually was meeting. And they'd be a patient that would be out of pocket if the PBAC didn't, didn't list this drug. And, you know, obviously it hurts a lot to think that someone can actually get medicine that might benefit them if a public subsidy is not provided. But then on the other hand, I actually am always surprised at how much people will spend on, for example, cannabinoids and a medication that's not funded.

It is an interesting psychological kind of dichotomy, isn't it? And maybe it's that there's an entitlement, maybe we feel that government should pay for all of our medicines costs. And I think that's what we've grown up with, that's what we expect. But then it's interesting that people do seem to have a lot of funding, not always, but in some cases to actually pay for that out of pocket. But I guess, the other thing is that  as I said, before, drugs are not listed or not funded on the PBS unless there's enough evidence to know that an investment by the taxpayer in this drug will buy a health outcome for the country, that is a good investment. So if it's not listed, most of the time, it's because it's not perceived by that committee to be a good investment and the health outcomes of the country.

JOANNE PATEL: It’s just interesting as humans, and as a society, I think, the things that we know, work to prevent cancer or to keep us well, or to treat pain or good diet and exercise and stuff. And it's a privilege to have the time and the energy to be able to do that. And I think if you can bottle something in a pill, and tell somebody, “Oh, this will have the same effects, this will help your pain, this will replace all that time and energy you'd have to spend otherwise,” it's quite appealing to people. And people who maybe don't have the scientific background to balance the evidence which we were very privileged to have that health literacy. I can understand why the expenditure is so high. It's pretty shocking. But people want to feel well.

JONATHAN BRETT:          Really good points. Medication of distress is certainly a big issue in the community as well. But I think you make a really important point in the paper around, sometimes patients come to you sceptical of conventional medicine, because it's a big industry. And I think it's a really important point that you know, it seems like the complementary industry is four times as big.

JENNIFER MARTIN:         I think that is actually interesting point as it relates to the cannabinoids as well. Because in the study that we are recruiting for still, we have over 100 people recruited around New South Wales at the end of life that have taken different cannabinoids. And we are doing the deep listening that our palliative care colleagues do very well, it's fascinating, just talking to people about why they're taking the cannabinoid. And so sometimes we get to the point where people are taking their exogenous cannabinoids, so they're smoking joints three times a day, as well as taking a very small amount of medicinal product. And so I say to them, “Do you still want to be on this trial? Because you're taking tenfold what I'm giving you in a tablet, every time you smoke a joint and your symptoms are still there, and it might be good to withdraw from the trial. And then you can actually access other medicines for your symptoms.” And there's certainly a sense of. “I like being on the trial,” because they basically get a bottle of stuff that they can take as required. So whenever they feel they're getting a twinge of something they can take something under the tongue. And I think there's definitely control and being able to manage my symptoms.

JOANNE PATEL:Do you think that also might be—we know that part of the placebo responses is that psychosocial context of health, and that actually being in the trial, regardless of the medication might be giving some benefit because of those interactions, and that sense of monitoring.

JENNIFER MARTIN:         People say that as well. And they definitely like the research staff and the research nurses who contact them, you know, quite frequently.  I think you're spot on job. It's giving people a sense of doing something positive and being in control of their current symptoms and doing something that might make them feel better.

JONATHAN BRETT:          It's interesting, what's coming across to me is with distressed people, particularly the end of life, the importance of just a good therapeutic relationship and listening to people and helping them feel supported. But I'm also interested in, you know, you brought up the word placebo. If we're thinking about complimentary medicine that, we were pretty happy, it's safe, but we're not sure are as effective, is there an important role for placebo effects in treating that population?

JENNIFER MARTIN:         I think there is that we're interested to see what Jo thinks about this. I mean, in the actual clinical trials that were done with cannabinoids, like, for example, in the Lennox-Gestault and the other forms of epilepsy, the Dravet syndrome, the placebo response was incredible. So up to 40% of people got benefit, they actually got a reduction in seizures, even though they were not taking active drug…

MIC CAVAZZINI:               Not just people but children.

JONATHAN BRETT:          Absolutely. My understanding is with children, it's often mediated through the parents. And actually there's a lot of—there's emerging evidence of open label placebo. You give people a sugar pill, and you say, “ there's nothing active in here, but it might help you symptoms.” And it's actually almost as effective as a placebo for some indications. Yeah. So it's really interesting. Jo, did you have anything to add about that?

JOANNE PATEL:I think there's a there's a huge placebo effect with any of the medications we use. You could use IV morphine aAnd the evidence shows that a lot of a lot of the response to that is the placebo effect. And it makes complete make makes complete sense to me. It’s that feeling of being safe, and someone taking your concern seriously, and feeling nurtured and supported. It's just the ethics of the openness about that. So you know, if someone's taking a medication to help them sleep, well, whatever that may be, or a supplement, a dietary supplement, because I think this is going to help my immune system, I'm happy to support that as long as I'm being open that I don't think there's scientific evidence to support that. But if it's making you feel better, and it's not causing side effects, and you can afford it, go for it. I think it all just comes back to that benefit-harm balance. And absolutely, if you think something's causing harm, because of a drug interaction or a side effect, then we have an obligation to counsel the patient on that and to stop it. But I think we also need to be open to the fact that just because there's not a scientific basis to benefit doesn't necessarily mean that that patient doesn't feel better on it.

MIC CAVAZZINI:               I think that's a good place to finish that, you've described her even for people taking complementary and alternative medicines, the relationship with their physician is important and can be valuable and and can steer them in the right direction. So rather than is this being a beat up on cannabinoids or any other CAMS, I think you've just pointed out that there's no reason to treat cannabinoids more lightly than we treat any of the other scary Big Pharma drugs, like you were saying, John, in the regulation and safety testing. So with that, I want to thank Jenny Martin for coming down to Sydney from Newcastle. Thank you, Joanne for squeezing us in online. And thank you, Jonathan, for having us in your office and pleasure conducting a studio interview like a natural. Great job, everyone. Thank you.

You can read Jennifer Martin and Joanne Patel’s paper in the November issue of the Internal Medicine Journal. It’s titled "Complementary and alternative therapies in the palliative setting." Every member of the RACP has access to the IMJ included in their membership. Simply go to racp.edu.au/fellows/resources/journals to find the login page.

At our website I’ve linked to a few tools that can help you predict what drug interactions are associated with CAMs. These include the Australian Medicines Handbook, the MIMs Drug Interactions database, the TGA’s Medicinal cannabis hub and the About Herbs page from the Memorial Sloan Kettering Cancer Centre.

Go to racp.edu.au/podcast and click on the episode you’ve just listened to find out more. You can also go back to episode 29 of Pomegranate Health which deals with the pharmacokinetics and dynamics of drug interactions in more detail, with a focus on deprescribing in the elderly. And episode 33 gives a pretty good review of the evidence base for cannabinoids up to January 2018.

Don’t forget that any time you spend listening to these podcasts, reading associated literature, or attending real life lectures can contribute to your continuing professional development, and I’ve provided a quick link at each podcast page that will automatically populate your MyCPD profile for convenience.

To make sure you don’t miss an episode of IMJ On-Air, look for Pomegranate Health in your podcast browser. Most iPhone users listen via Apple Podcasts, while other popular apps are Spotify, Podcast Addict, Overcast and Castbox. Or for the late adopters, there’s a mailing list where you’ll get an email when each new episode is published. That’s at the top of the podcast web page.

Pomegranate Health is just one of many online learning resources provided at elearning.racp.edu.au. I want to draw your attention particularly to the Medflix video library, where many of the webinars presented by RACP experts are archived with new recordings added every month. And if you come across any great content you’d like to share with your colleagues, please submit it to the database by clicking on the link titled “the Resourceful Physician”. There’s something there for every specialty.

I’m Mic Cavazzini, and this podcast was produced on the land of the Gadigal people of the Eora nation. I pay respect to the storytellers and the healers who first walked this country.