Episode 33: Early Days for Cannabis Therapy

Episode 33: Early Days for Cannabis Therapy
Date:
30 January 2018
Category:

Cannabis is a plant rich with potential therapeutic compounds and centuries of cultural resonance. At this moment in Australia, media accounts are full of patient stories and lab data suggesting benefit from cannabis for scores of different conditions, while politicians discuss laxer regulation of the drug and a new lucrative industry.

However, only a few of the claimed medical effects of the plant have been proven by rigorous clinical trials in people. Nabiximols is the only medicinal cannabis product currently registered in New Zealand and Australia, and it’s indicated only for­­ the treatment of spasticity in patients with multiple sclerosis (MS). Systematic reviews of the research note strong evidence that cannabis can also help with the pain associated with MS, the nausea induced by chemotherapy and some cases of epilepsy. But for many other conditions like post-traumatic stress disorder, irritable bowel syndrome, immune disorders and Parkinsonism, reviewers concluded that meaningful clinical recommendations could not be made—there simply aren’t enough studies of good quality.

Cannabis is complex. The flower bud contains mostly cannabidiol and tetrahydrocannabinol (THC), but there are about 100 other cannabinoid compounds. On this episode, Pomegranate Health guests explain how important it is to separate the effect of these various components in a systematic way, and why well-regulated research and prescribing will be safer for patients.

Guests: A/Prof Peter Grimison FRACP (Chris O’Brien Lifehouse, University of Sydney), Prof Meera Agar FRACP (UTS, USNW, IMPACCT), A/Prof Carolyn Arnold FRACP (Monash University, Alfred Health), Prof Samuel Berkovic AC FRACP (Epilepsy Research Centre, University of Melbourne), Prof Jennifer Martin FRACP (Australian Centre for Cannabinoid Research Excellence, University of Newcastle, John Hunter Hospital).

Claim CPD credits via MyCPD for listening and using resources related to this episode listed below.

Medicinal Cannabis Guidelines

Medicinal Cannabis Guidance Documents [TGA]
Prescribing Cannabis-based Products [NZ Ministry of Health] 
CBD Products [NZ Ministry of Health]
Accessing Unapproved Products: Authorised Prescribers/Special Access Scheme [TGA]
Legislative Framework and Commonwealth Access Schemes Relevant to Supply of Medicinal Cannabis [RACP Congress 2017]
Cannabis and Cannabis Products for Therapeutic Purposes [NSW Health]
Cannabis Medicines [NSW Health]
Statement on 'Medicinal Cannabis' [Faculty of Pain ​Medicine, ANZCA]

Journal Articles

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence [National Academies of Sciences, Engineering, Medicine]
Cannabinoids for Medical Use: A Systematic Review and Meta-analysis [JAMA]
Systematic Review and Meta-Analysis of Cannabis Treatment for Chronic Pain [Pain Medicine]
Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome [NEJM]
Cannabidiol in Patients with Seizures Associated with Lennox-Gastaut Syndrome [Lancet]
Opioid Abuse in Chronic Pain — Misconceptions and Mitigation Strategies [NEJM]
Pharmaceutical Opioid Use and Dependence among People Living with Chronic Pain: Associations Observed within the Pain and Opioids in Treatment (POINT) Cohort [Pain Medicine]
Compassion and evidence in prescribing cannabinoids: a perspective from the Royal Australasian College of Physicians [MJA]

News Media

Why Is It Still So Hard for Patients in Need to Get Medicinal Cannabis? [​Wodak, The Conversation]
Why So Few Australians are Using Medicinal Cannabis on Prescription [McGregor, The Age]

Related Podcasts

Medical Marijuana [Pediacast CME]

Credits

Written and produced by Mic Cavazzini. Additional audio recording from James Milson. Music courtesy of Blue Dot Sessions (“Cloud Line”), 4T Thieves (“New Times”), Mystery Mammal (“Asylum”) and Jahzarr (“Please Listen Carefully”). Image courtesy of iStock. Executive producer Anne Fredrickson.

Editorial feedback for this episode was provided by RACP members Dr Michael Herd, Dr Pavan Chandrala, Dr Marion Leighton, Dr Rosalynn Pszczola, Dr Mahesh Dhakal, Dr Rhiannon Mellor, Dr Rebecca Grainger, Dr Philip Gaughwin and Dr Paul Jauncey, as well as Louise Hardy (Manager, RACP Policy and Advocacy) and Ms Joanna Harrison (Senior Adviser, ACRE).

Declarations of Interest

A/Prof Grimison is lead investigator on a study of chemotherapy-induced nausea and vomiting funded by NSW Health and Tilray®.

Prof Agar is lead investigator on a study in palliative care funded by NSW Health using a product purchased from Bedrocan®. She also receives funding from Cancer Australia, the National Breast Cancer Foundation and the Australian Cancer Research Foundation.

A/Prof Arnold receives an honorarium from the Victorian Department Health and Human Services for her role on the Independent Medical Advisory Committee on medical cannabis.

Prof Berkovic is lead researcher on a study of CBD gel in adults funded by the National Health and Medical Research Council (NHMRC) and Zynerba® Pharmaceuticals.

Prof Jennifer Martin is lead investigator with the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) funded by the NHMRC, and a pragmatic observational study funded by NSW Health. She is also a member of the ministerial appointed Australian Advisory Committee on Medical Cannabis.

Transcript

CAROLYN ARNOLD: It’s not as great as we would like, really. So that means you’re going to have to treat 22 patients and one will have a 30 per cent reduction of chronic non-cancer pain. That’s a lot of patients to treat with not much impact.

MEERA AGAR: My view is that people at the end of life deserve the best evidence to guide their care because you have often one chance to get it right and to do it really properly, quality of life is so important.

MIC CAVAZZINI: Welcome to Pomegranate Health, a podcast for physicians of the RACP. I’m Mic Cavazzini, and today we’re talking about cannabis—a plant rich with potential therapeutic compounds and centuries of cultural resonance.

Just type ‘medicinal cannabis’ into your web browser and you’ll find tantalising patient accounts and lab data suggesting benefit for scores of different conditions. You’ll also find impassioned pleas for laxer regulation of the drug, and politicians promising a lucrative industry. However, only a few of the claimed medical effects have been proven by rigorous clinical trials in people—a fact not helped by the prohibited status of the drug over the last century.

Currently, nabiximols is the only medicinal cannabis product registered in New Zealand and Australia, and it’s indicated only for the treatment of spasticity in patients with multiple sclerosis. But there is no government pharmaceutical subsidy because symptom improvements were shown by self-report but not by objective clinical measures in the few studies that showed an effect.

Systematic reviews of the research note there’s strong evidence that cannabis can also help with the pain associated with MS, the nausea induced by chemotherapy and some cases of epilepsy. But for many other conditions like post-traumatic stress, irritable bowel syndrome, immune disorders and Parkinsonism, the reviewers that concluded you couldn’t make meaningful clinical recommendations. There simply aren’t enough clinical studies of good quality.

And cannabis is complex. The flower bud contains mostly cannabidiol and tetrahydrocannabinol (or THC), but there are about a hundred other cannabinoid compounds. Today’s guests explain how important it is to separate the effect of these various components in a systematic way, and why well-regulated research and prescribing will be safer for patients. We’ll hear from a palliative care physician, neurologist, a pain medicine specialist a clinical pharmacologist.

But first, oncologist Peter Grimison who’s directing a trial to study cannabis as a treatment for nausea and vomiting in patients undergoing chemotherapy. 

PETER GRIMISON: So, I’m Associate Professor Peter Grimison, I’m a medical oncologist at the Chris O’Brien Lifehouse and I’m a researcher at the University of Sydney with a particular focus on quality of life.

Probably about these days a third of patients or relatives will ask me, “Well, should I be taking medicinal cannabis?” or, “I’d like to take medicinal cannabis.” And I guess my first question is, “Well, why are you wanting to take it?” And I tell them, “Why you don’t try the proven treatments first—which generally the side effects are manageable—and only take medicinal cannabis if you’re still having problems at that point?”

Other people want to take medicinal cannabis to treat or cure cancer and I have to say, “Listen, I’m quite a sceptic about that. There’s some very preliminary laboratory research for brain and certainly I support doing research,” but at the moment I tell people there’s not good evidence at all that cannabis will cure cancer. There is a lot of hype about medicinal cannabis but I think most of my patients are interested in my perspective to explain where there is some evidence and where there’s some evidence that there’s not going to be a benefit.

MIC CAVAZZINI: There have been a number of trials previously looking at chemotherapy induced nausea and vomiting and these were systematically reviewed by the Cochrane Group and the US National Academy of Sciences Medicine and Engineering (NASME). The reviews describe the evidence for a benefit of medicinal cannabis in this field as moderate to conclusive, but what is missing from the data that we don’t yet have a registered product?

PETER GRIMISON: Yeah, there’s obviously a disconnect there, you know, what’s the problem? And one may be doctors’ scepticism but I think another is that the products that have been tested are quite toxic. They’re generally synthetic cannabinoids which is very high concentrations of THC and patients to find that quite intolerable. Feeling dizzy, disorientated, stoned. And I think most patients with cancer on chemotherapy are actually wanting to be as active as possible so they can go to work, so they can, you know, participate in family life and so on.

You know, since those trials were done there’s been more progress and more tolerable products so I think that’s an argument that the research needs to be redone in patients who are having best standard anti-emetic therapy which wasn’t available back in the 1980s when the trials were done.

MIC CAVAZZINI: Yeah, the reviews referring to previous research say that THC was better than placebo and as good as prochlorperazine as an anti-emetic. But this is no longer the first therapy, is it?

PETER GRIMISON: That’s right. Current anti-nausea medications are actually very good and most patients these days on chemotherapy don’t have significant nausea or vomiting. If you just restrict it to the people having, you know, very potent intravenous chemotherapy the literature would say there is still probably about half of people who have need.

So, our trial is only for patients who are still having significant nausea or vomiting despite best therapy and as part of the trial they will continue the standard anti-emetic therapy. In addition to that for one cycle of chemotherapy they’ll get medicinal cannabis and for another cycle they’ll get a placebo and then we compare levels of control of nausea and vomiting, we compare side effects. It’s a capsule containing a one to one ratio of THC and cannabidiol which is CBD and the idea is that the CBD one can reduce side effects of the THC. And my personal experience with some patients on the trial and off the trial, it’s again there’s a small group it will help.

MIC CAVAZZINI: Do you think it’s appropriate that at the moment it’s still in the hands of doctors with a specialist interest in one of these few conditions or do you think, you know…?

PETER GRIMISON: You know, the other argument having the unfettered access which is sort of the California model where all you need is a note from your doctor that you have significant nausea or chronic pain or a headache. But there’s a lot of risks as well because there’s very little oversight, there is virtually no research in North America trying to find out which patients will most benefit from cannabis. And that ultimately will harm patients because there’s patients having cannabis who aren’t going to benefit from it, who are getting side effects, who are having to pay for it.

I think the argument that it will be cheaper to get non-pharmaceutical products is probably not true. I guess my sense just from talking to patients is it’s about $200 a month whether you’re getting legal or non-legal product. I think many patients, particularly cancer patients, particularly those on chemotherapy, actually want to get a safe regulated product. They’re very keen that there’s not impurities, they want to have a proper graded product that will give consistent results over time.

MIC CAVAZZINI: While intensive chemotherapy can cause nausea, some advanced tumours release inflammatory markers that trigger loss of appetite and muscle wasting in their own right.

The 2017 NASME review did identify some studies looking at wasting disease in patients with cancer, anorexia nervosa and AIDS. But these studies were typically of poor quality, and only one of the four studies in patients with AIDS actually demonstrated weight gain in those taking THC.

Whenever we talk of low grade evidence, it means for example, that the trials didn’t have enough subjects enrolled to show statistically that most patients would benefit. Or that the studies were unblinded, meaning the psychology of patients and clinicians could have biased the results. Another problem in previous cannabis research is the lack of consistency in the products being used or the way they were delivered, making it hard to compare outcomes.

Professor Meera Agar is an academic at UTS and UNSW, and clinician in south west Sydney. She is a lead researcher with IMPAACT, or improving palliative care through clinical trials

MEERA AGAR: So, I think prior studies often have just measured appetite rather than a broad range of symptoms. I think taste, smell and food enjoyment are particular aspects of the experience that cannabinoids may make impacts on so we think it’s important to measure that in a much more nuanced way.

And we know, that eating is not just a medical system, eating is part of our social life, our family life. You know, if you imagine sitting down, you know, we do it without thinking every night with our families having dinner. Imagine if one member of your family was not able to participate or feel able to be part of that experience day in day out, that profoundly affects not just the wellbeing of that person providing food is one of the ways we show love in our relationships.

MIC CAVAZZINI: So, the delivery method in your trial will be as a vaporised cannabis flower bud. Why choose this delivery model rather than one of the more purified formulations, like dronabinol is pill formulation isn’t it?

MEERA AGAR: So, the prior studies did use dronabinol. Our concern was around the bio-availability of that product and eating is a spontaneous activity in that you need to have quite a rapid peak in THC so that’s why the vaporised route in terms of being able to get a rapid onset of that THC. But then also it to be quite rapidly removed from the body so that you don’t have THC hanging around when you’re not trying to actually get appetite stimulation was the theory.

And most studies in this area have not taken any pharmacokinetic data so that we have no idea when the drug is ingested what actually happens in the person’s body in terms of absorption, the peak levels, and how that relates to the change in symptoms and when people are telling us that they’re experiencing side effects.

So, the product we’re using is one of the sort of moderate range THC products so that we’re hoping that that minimises the significant side effects but we need to remember that people with advanced cancer have quite altered metabolism of drugs due to the weight loss. They often have brain effects of their cancer and other drug interactions that make them more vulnerable to medication.

MIC CAVAZZINI: So far from saying that “These patients are approaching the end of life, we should let them take whatever chances they want”—they actually could be quite vulnerable to side effects that don’t emerge so much in the studies of healthy patients?

MEERA AGAR: I suppose our view is quality of life is so important. Often you have one chance to provide the right treatment without harms. The other challenge I think in people who are physiologically vulnerable is that if you do get a side effect it’s often very tricky to then reverse the new problem. So, my view is that people at the end of life deserve the best evidence to guide their care because you have often one chance to get it right and to do it really properly. And it has such huge effects on their lives and the lives of their loved one.

MIC CAVAZZINI: This is, for you this is an appropriate pace for the use of this drug that the patients that need or want to try it can get it?

MEERA AGAR: Yes, I think in people with advanced illness the current approaches allow us to access cannabinoids if we needed to do that. You know, there are always people that will be refractory to current available therapies where more novel off-label approaches may need to be considered. One of the approaches of palliative care is to develop that rapport with patients and be able to have, no conversation is out of bounds and I think it’s really important that patients and families feel able to raise the topic and to be able to be guided to sources of information that are relevant to their individual situation to help them make informed decisions.

MIC CAVAZZINI: Epilepsy affects 1 in 200 people at any one time, but since it can come and go, the lifetime incidence is four times higher. About a third of patients are resistant to first and second-line therapies. Specific references to cannabis as a treatment for seizures turn up in Arabic texts from the 10th century, but research of the last few decades has fallen short of proving the therapy conclusively.

Until May last year, that is, when a large, international RCT published in the New England Journal of Medicine showed that an oral cannabidiol solution reduced the frequency of seizures in children with Dravet syndrome. This is a rare and devastating form of epilepsy that stunts development during infancy and is usually resistant to treatment. Children with Dravet syndrome rarely live beyond ten years and almost half of deaths are sudden and unexplained.

I discussed the findings with neurologist Professor Sam Berkovic of the Epilepsy Research Centre at Austin Health and University of Melbourne. He co-heads the centre with one of the study authors, Professor Ingrid Scheffer. The pair have been awarded the Order of Australia and the Prime Minister’s Prize for Science for two decades of ground-breaking work.

In 1995, they were the first to identify a mutation associated with epilepsy, in a gene for an ion channel triggered by neurotransmitter. Ion channels control the excitability of every individual neuron—disturb this and very quickly the activity of entire brain networks gets out of control. Dravet syndrome is caused by a mutation in voltage-gated sodium channels, which have the biggest influence on neuronal excitability. Professor Berkovic says that cannabinoids are not a targeted treatment within this genetic understanding of epilepsy.

SAM BERKOVIC: So, there are now well over 50 genes implicated in epilepsy and many are ion channel proteins, others are proteins involved with the synapse so there are a small proportion of patients with epilepsy that have so-called single gene epilepsies and the majority there are probably a number of genes that contribute to the seizure susceptibility in any one person.

MIC CAVAZZINI: And to my knowledge there are no mutations to cannabinoid receptors in this picture so where do cannabinoids fit in with the molecular and biophysical picture?

SAM BERKOVIC: That’s correct. So, there’s no link at the moment between the pharmaceutical effects of cannabis and the known genetic architecture of epilepsy. Doesn’t mean there isn’t one but we don’t, we haven’t discovered it. Most of the current drugs appear to work on ion channels which are the final common pathway to excitability but they’re not targeted to specific genetic defects for the most part and they certainly weren’t discovered that way.

MIC CAVAZZINI: In the study led by your colleague Ingrid Scheffer and collaborators, the researchers measured seizure frequency in 120 children for four weeks and then gave them cannabidiol or placebo on top of their usual treatment regimen. the headline result of the trial was that five per cent of the children in the treatment group were seizure free whereas none were in the placebo group. And the median frequency of convulsive seizures was halved by cannabidiol. Is that dramatic in comparison to other available therapies?

SAM BERKOVIC: No, look it’s good but it’s not out of the park so to speak in terms of a drug trial. It doesn’t mark this as a drug of extra-ordinary effectiveness. It marks it as a drug that works and that’s great. We’d like to have a lot more than five per cent seizure free. But in that trial, it was just like any other new drug that works.

MIC CAVAZZINI: So, in your editorial in the NEJM you commented that it’s a valuable study but that cannabidiol is not a precision therapy for Dravet syndrome, and Professor Scheffer herself has said it’s no golden bullet.

SAM BERKOVIC: That’s right.

MIC CAVAZZINI: Will you be prescribing it to patients if they don’t respond to other therapies?

SAM BERKOVIC: The answer is yes. I mean we’re persuaded that it works in this disorder. It doesn’t work particularly well but it is a useful addition to the armamentarium.

MIC CAVAZZINI: The results from another large study have just been published in The Lancet looking at patients with Lennox-Gastaut epilepsy which affects both children and adults. In that study cannabidiol led to a 44 per cent reduction in frequency of seizures as compared to 22 per cent for placebo. Does this suggest cannabidiol has some generalised role that could be an add-on treatment?

SAM BERKOVIC: Look, we don’t know. We conducted a trial in adults with milder epilepsies and we did not see a significant effect, to our disappointment and surprise. So, a lot more trials need to be done. There’s a lot of argument as to what the right preparation is, whether you should use CBD, or CBD plus some THC or other compounds.

There’s issues about its mode of delivery, there’s issues about the dose and we know, experimentally that THC if anything is pro-epileptic so it’s still in a really early stage and unfortunately with all the hype there’s, you know, the enthusiasm from the government is good, but in many ways it sort of interferes with the science because that’s where the headlines are.

MIC CAVAZZINI: But it’s not the first time some natural therapy has been held up as a panacea. What makes medicinal cannabis such a hot button topic? Is it the illegality that makes people feel so hard done by?

SAM BERKOVIC: Yeah absolutely. You know, if you believe that a particular Chinese herb does something it’s pretty easy to get that Chinese herb. The medicinal cannabis is not regarded by patients’ families or even doctors as sort of like any other drug, you know. The fact that it’s from a plant, the fact that it in certain circumstances it’s illicit has put an aura around it that makes it extremely difficult to get hard data. And there are many miracle stories in the popular press about it, you know, there’s a very high expectation that it’s going to work and there’s a very very big placebo effect.

MIC CAVAZZINI: And you wrote something in your editorial in the New England Journal about the placebo in children is surprisingly big as well.

SAM BERKOVIC: Yes, so when this was first reported, you know, it wasn’t something that I intuitively thought was likely but there’s now very good evidence that there is in fact a greater placebo effect in drug studies in children than there is adults. And, you know, you can speculate on the mechanisms of that.

There was a very sort of insightful study done in the US where, as you may know, in Colorado marijuana was legalised very early and they showed that the rate of response of children who were brought to Colorado by their parents, in other words they uprooted themselves and moved from the east to Colorado or whatever, the rate of response in those children was three times greater than it was in native Coloradan children.

So, when you put a lot of energy into doing something you’ve got to see a good response, and you do. And, you know, we can argue about how much is physiological, how much is psychological. That’s still not resolved but there’s no doubt that there’s an enormous placebo effect in children and studies have to be very well-designed to avoid that to show a true pharmacological effect.

Coupled with this, the problem with epilepsy is that it fluctuates. People take new treatments often when they’re in a bad phase of the disease, and when you’re in the bad phase of a disease that normally fluctuates you are destined often to get better. So that can be then interpreted as an effect of the drug whereas in fact it’s just natural fluctuation.

MIC CAVAZZINI: Perhaps the most contentious area in the medicinal cannabis debate is chronic pain not associated with cancer. The drive for a simple treatment is strong, from both patients and the pharmaceutical industry. And the systematic reviews conclude that there are good quality studies showing that cannabis does have an analgesic effect.

But the effect size is small and the studies are restricted to neuropathic pain only. That's the dull, burning type of pain that comes from aggravation of nerve pathways as opposed to the sharp nociceptive pain that immediately follows injury.

The Faculty of Pain Medicine has already published a position statement trying to manage patient and clinician expectations. They say that cannabis won’t be a harmless fix for the 20% of the population reporting chronic non-cancer pain. Former board member Carolyn Arnold explains how only a fraction of these patients are likely to need or even respond to cannabis analgesia.

CAROLYN ARNOLD: So, my name’s Carolyn Arnold. I’m an Associate Professor in Anaesthesia and Perioperative medicine at Monash University. I’m the head of chronic pain services at Alfred Health Services, and I’ve been a representative on a Victorian Advisory Group about medicinal cannabis.

What we know, is that 20 per cent of the adult age population have chronic non-cancer pain. It’s such a big heterogeneous group so some would have no susceptive pain which is more associated with like joint disease. If we look at it, that’s one in five people but there is a lot of really good functional people who manage chronic non-cancer pain pretty effectively with minimal input from medical services. And it’s only probably about 25 per cent of those people who have poorly controlled pain who are disabled by it.

MIC CAVAZZINI: In the past, I’ve spoken to your colleague Michael Vagg and he said that the analgesic effect of THC products was comparable to codeine or tramadol. Should that be cause to raise or to lower expectations of this drug’s potential?

CAROLYN ARNOLD: Well I think perhaps it puts it in perspective. You know, people have the belief that it’s going to be really effective, they’re going to a hundred per cent relief of pain. And what we’re knowing is that it’s going to reduce the severity of the pain by, you know, 10, 20, 30 per cent and that is often not sufficient to improve function and so, you know, really if you’re going to use analgesic drugs it should be part of a package, it’s not a complete answer.

But a lot of the studies are short-term and we don’t know, whether those benefits are retained or whether over time they need to have an increased dose to get the same effects. And they haven’t addressed quality of life in terms of working, social relationships, participation in normal roles because these wellbeing things are important.

But we need to try and understand whether it’s as a result of an analgesic effect as in a pain reduction effect or whether it’s some affective change on mood and whether that’s really what we’re getting with those drugs. I think that would be important to understand that better.

MIC CAVAZZINI: Talking about effects on mood and motivation can you explain why, in the context of modern behavioural approaches to therapy why this is important?

CAROLYN ARNOLD: I’m very much in favour of behavioural approaches addressing the comorbid depression, anxiety, reactivating people who’ve become very sedentary because of pain. And cannabis has an endogenous cannabinoid system with receptors and it has a lot of function. So we know, that for example with opioids that we do have in our body an endogenous opioid system and people who take chronic opioids that system is supressed, and the normal way that we activate our own natural endorphins in our body is through things like laughter, social interaction. It has a big role in bonding within families and socially. And also exercise releases endorphins so that’s all kind of put out of action by some of these medications and really what we want to do is get people having their own natural analgesic systems working better in the way that they normally do when people are functioning well.

MIC CAVAZZINI: The Faculty of Pain Medicine presents opioids as an example of rushed registration that resulted in great harm, and your colleague Chris Hayes is on the record as saying, “Ten years ago we told our patients to get on opioids and stay on them, now we’re questioning if we should issue a sorry statement over our over-enthusiastic extrapolation of the evidence.”

CAROLYN ARNOLD: Yeah well, that’s a really good point and he’s really emphasising that, that’s a really good way of emphasising how concerned we are about a public health problem that’s been created. You know, we’ve really been burnt with the opioids now and we’ve seen lots of people on high dose medication who haven’t got any benefit and gain and it’s another restraining factor on rushing in to the medical cannabis.

MIC CAVAZZINI: And there’s obviously epidemiological evidence for the addictive potential of cannabis in recreational users.

CAROLYN ARNOLD: That’s right.

MIC CAVAZZINI: The latest TGA guidelines summarise the findings like this. They say that using cannabis for pain relief the number needed to treat is 22. Meanwhile the number needed to harm enough to stop treatment or to seek help was six. So where do we proceed from these kind of findings?

CAROLYN ARNOLD: Right well I think that’s important for people to understand that because it’s not as great as we would like really so that means you’re going to have to treat 22 patients and one will have a 30 per cent reduction of pain. That’s a lot of patients to treat with not much impact. And I think harms are interesting because some people say the harms aren’t too bad but these, again they’re short-term studies. It’s complicated, it’s not a straight forward drug.

MIC CAVAZZINI: Every strain of the cannabis plant has a unique concentration of THC, CBD and the many other cannabinoids present may have positive or negative effects too. There is concern that a poorly regulated industry of cottage suppliers would result in a broad range of unpredictable cannabis products. 

There are international suppliers who are growing specific strains with known and replicable drug concentrations for medicinal use. The Australian government is importing bulk quantities of these products, and has granted licences to a few growers across the country to start producing pharmaceutical grade cannabis locally.

In New Zealand, doctors and pharmacies are now permitted to import cannabidiol products, but not if they contain more than 2% THC or other uncharacterised cannabinoids. And these can be prescribed by physicians and GPs without getting special approval from the Ministry of Health, but there’s a limit to scripts of three months only.

Cannabis regulation in Australia is more confusing, as it needs to meet both federal and state legislation. About 30 doctors in Australia have been granted so-called ‘authorised prescriber’ status for cannabis. These would be experts in a particular application of cannabis to a specific condition, and come under the same scrutiny that prescribers of methadone do when treating someone with addiction.

By contrast, the Special Access Scheme, allows any specialist to make an application on a patient by patient basis. Most states then permit GPs to manage ongoing treatment, while Victoria and Queensland also allow GPs to submit a new application themselves.

Professor Jennifer Martin explains how a clinician goes through the SAS process. She’s a clinical pharmacologist with the Australian Centre for Cannabinoid Clinical and Research in Newcastle, and a physician at the John Hunter Hospital.

JENNY MARTIN: There are very clear statements around things like that other therapies, drugs and non-pharmacological therapies have to have been tried and documented. Like for example in palliative care for nausea you don’t necessarily need to have had all of them but you need to have gone through the guidelines and said my patient hasn’t had steroids because they previously had psychosis or they’re worried about bone fractures or something, or they’ve got diabetes so now there’s nothing else the patient can have.

But it’s very quick, I mean it’s less than 48 hours for the TGA approval and you put the one into, for example New South Wales Health at the same time. It’s a one week turnaround and because the product is already here, that afternoon it can be shipped to the patient’s pharmacy so it’s very quick.

But for some reason there’s a misperception in the community that the SAS B takes months and months and there were a couple that took a long time at the beginning and that’s because a doctor didn’t fill all the information in or they weren’t working with a specialist. It has to be a GP working with a specialist and the reason they do that is so we can monitor it very easily but it will be like a lot of other medications, for example the hepatitis C medicines, that was initially specialist only and then we got experienced and knew how to use it and then it very quickly became open for GPs. So I’m very hopeful that it will happen in time once we get more knowledge about it.

MIC CAVAZZINI: There’s about 150-odd patients that have been granted medicinal cannabis under the Special Access Scheme and these are typically on compassionate grounds for extremely ill patients. Apart from these terminal patients what are the scenarios that have met SAS requirements to this date?

JENNY MARTIN: There’s a variety I guess so an adult with epilepsy, a couple of patients with chronic pain, dementia with difficult to manage symptoms. Certainly there’s some evidence to suggest some of those patients might benefit from at least a trial, and that’s probably about the majority of it. You’re right, most of them are palliative care and that would be fast-tracked if someone was already in hospital so if it’s an urgent case.

MIC CAVAZZINI: Now you’ve explained the logic of the application process to prescribe cannabis but there was a lot of clamour in the press and in the parliament about making it even more widely accessible, and this would require fast-tracking cannabis through the assessment process of the Therapeutic Goods Administration. How unusual would this be? Is there any precedent to this?

JENNY MARTIN: There’s no precedent to my knowledge. Before we provide medications to patients they usually go through a highly rigorous set of testing with animal and human studies and if the data shows that the drug is safe, and that it might be effective also, that drug is then registered by the Therapeutic Goods Administration which means we get, it’s a badge of quality and safety that goes with each product. And that’s because of a lot of issues that we had early on with new medicines such as thalidomide and I think that really does affect your tolerance for practicing outside the evidence.

You can make people sick by using the wrong drugs at the wrong time and there’s quite a few stories out there, so-called natural products for weight loss and that sort of thing that have actually caused liver failure and liver transplant or death. Some of them have even been sold through pharmacy but haven’t been registered products. Now we’ve seen that with black cohosh and some of the plant materials that have been used to relieve menopausal symptoms. But the problem is the plant doesn’t just have that oestrogen like activity molecule, it has a whole lot of other chemicals, alkaloids and other things some of which are present in the cannabis plant.

And also you couldn’t really predict who got sick. So we looked back and said, “Is it just obese people or is it just Caucasians?” There wasn’t any rhyme or reason so it made it difficult for us to say, “Oh okay, you can take this as long as you’re not X Y and Z.” And I guess that’s what we’re probably finding with the cannabis as well, that we know, that when people take it recreationally some people get very significant amount of psychotic activity and other people are completely fine, and we don’t really know, at the moment how to predict who’s going to get side effects.

MIC CAVAZZINI: Regular recreational use of cannabis is associated with increased onset of psychotic symptoms like paranoia and hallucinations, and other side effects include loss of memory, concentration and balance. But widely respected physician Alex Wodak argues in The Conversation that the side effects in medical practice are much milder than they are for recreational users. Is that a fair assessment?

JENNY MARTIN: No I think he’s right in the sense that from the studies that we have out there but the problem is that we do know, in general that side effects reported in clinical trials are less than what happens in the real world mainly because we only select healthy-ish people, we don’t select people at the end of life or with other comorbidities or that sort of thing that are out there. And they’re usually not taking a whole lot of other medicines and I suppose the problem is in general medicine we have people taking 15 or so tablets and then we’re having cannabis in there too so it might be a bit more complicated.

MIC CAVAZZINI: Psychopharmacologist Iain McGregor of the University of Sydney told The Age that 100,000 Australians are already self-medicating with cannabis, and some of the arguments that Ian McGregor or Alex Wodak make are compelling but would it be more appropriate, more rigorous to discuss this in the framework of harm minimisation rather than trying to shoehorn cannabis into the register of therapeutic goods before the evidence is in?

JENNY MARTIN: I think you’re right and I think that’s exactly the issue. That legalisation debate, that other debate, that still is going to go on out in the community anyway and there may or may not be legalisation. But whatever happens, regardless of that, we need to look at medicinal cannabis as a therapeutic good to see whether a doctor should write a script for it and I think it’s kind of important that we distinguish those two arguments.

So although it might be hard for patients to accept this, this request to get better evidence, push the research along is actually going to benefit patients long-term, because without evidence there’s no way we can get these drugs funded.

MIC CAVAZZINI: And the problem with saying, “No we can waive the registration process on this,” but it’s still being talked about as a medicinal product—then doctors are being forced to use an ethical judgement when they’re looking the patient in the eye rather than any real clinical judgement.

JENNY MARTIN: Yes, you’re right. I think that whole ethical thing of doing the right thing as a practicing doctor. I mean this is very very important, this autonomy stuff to come up and I think as a profession we do need to grapple with it but we—I think a lot of that it’s able to be sorted out often in discussion with patients by separating out those issues but I don’t think it’s able to be sorted out in the media. And that’s the problem, we have sort of trial by media and it’s all political but at the end of the day as physicians we’re left here with patients that we need to look after and do the best for them.

MIC CAVAZZINI: That was Jennifer Martin closing this episode of Pomegranate Health. Thanks also to Peter Grimison, Meera Agar, Sam Berkovic and Carolyn Arnold for their time and expertise. The views expressed are their own, and may not represent those of the Royal Australasian College of Physicians.

Sources of funding and other declarations of interest are listed at our website racp.edu.au/pomcast. If you missed anything, you’ll also find a transcript of this episodes, and links to plenty of relevant literature. There are also guides for how to prescribe cannabis in New Zealand and Australia.

If you prefer to listen, one of our favourite podcasts, Pediacast CME have another hour of discussion on medicinal cannabis.

I’m Mic Cavazzini. I would love to hear your thoughts about the show in the website comments section, or by email. Please, get in touch.

Comments


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24 Jun 2018

Bruce Foggo

This discussion brings a dose of reality to the mixed messages being aired publicly and politically. The limited evidence for use of medicinal cannabinoids in a wide range of conditions. An NNT of 26 for a 50% pain reduction in patients with chronic pain against an NNH of 6 is not very persuasive. I suspect however that public pressure for what is seen by many as a panacea will carry the day with politicians. BF

01 Feb 2018

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