There is a growing research interest in using medical cannabis for various symptoms caused by medical conditions and therapies.
About one in two people who use cannabis for medical purposes report suffering from persisting pain.
Chronic pain is a complex condition that is influenced by a vast range of factors. From the way we think and talk about it, to our level of stress and anxiety, to the social environment we live in or our level of physical activity, it all matters.
Most cases of persisting pain don’t present an injury or disease severe enough to explain the level of pain the patient feels. Often, scans and examinations fail to find a cause. In many cases, pharmacological therapy alone, such as opioids and other strong painkillers, fall short.
While the current best evidence-based treatment for chronic pain is a multidisciplinary approach that accounts for the multifaceted nature of pain, an increasing percentage of patients who don’t respond to standard therapies are resorting to medical cannabis.
The vast majority of the evidence on the efficacy of medical cannabis in pain remains anecdotal, while researchers are trying to demonstrate rigorously the safety and efficacy of the drug.
But based on the available evidence, experts can’t find an agreement.
“Anecdotes are only useful for generating scientific hypotheses,” says Associate Professor Michael Vagg, dean at the faculty of pain medicine at the Australian and New Zealand College of Anaesthetists (ANZCA) and clinical director of Rehabilitation and Pain Services, Epworth Geelong.
“Anecdotes by themselves are interesting, but they’re not data because they happen in the real world, and people’s experiences and expectations heavily influence them. That’s why we do proper studies,” he tells The Medical Republic.
Last March, the faculty of pain medicine at ANZCA published guidance for health practitioners, recommending them to not prescribe currently available medicinal cannabis products to treat chronic non-cancer pain unless they are part of a registered clinical trial.
The International Association for the Study of Pain presidential taskforce for the use of cannabis in pain management has gathered 20 international expert pain researchers to analyse the existing literature meticulously. They looked at pre-clinical and clinical studies and found that, overall, numerous knowledge gaps exist. Most importantly, they noted that the quality of the research is flawed.
“The cannabinoid studies are generally very small. Manufacturers generally pay them, so there’s a high risk of bias. And many of them have quite a poor methodology,” Professor Vagg says.
The majority of the evidence that cannabinoids have an analgesic effect comes from animal studies.
“Cannabinoids certainly have biological plausibility,” Professor Vagg says. “Everybody knows they work great if you’re a mouse or a rat.”
That is because mice and rats have extremely simple nervous systems. In pain research, it is fairly common for a treatment to work well in animals but fail in humans completely, he says. “That’s not surprising because humans have a far more complicated nervous system than a mouse or a rat.”
Professor Vagg says studies on the pharmacokinetics and pharmacodynamics of medical cannabis products have not been done, and much remains unknown on the mechanism of action of cannabinoids and their potential interaction with other medications.
“These studies are really important to enable you to make predictions about which patients could use it safely. Those studies have not been done. For any type of medicinal cannabinoid, we literally have no data on them,” he says.
“We would actually expect to see these things done before we start using [medical cannabis] widely because the days of just rushing new treatments on to the market without having properly evaluated them are hopefully long gone.”
There are 190 different medical cannabis products in Australia – capsules, oils, nasal and oral sprays – that doctors can prescribe. Some of these are plant derived. Others are synthetically produced. While only two products are TGA-approved (Sativex and Epidyolex), doctors can request access to non-approved products through the TGA Special Access Scheme or as an Authorised Prescriber.
Medical cannabis products contain either THC (delta-9-tetrahydrocannabinol) or CBD (cannabidiol) or a combination of the two. While there is no difference between plant-derived or synthetic THC and CBD molecules, plant extracts typically contain a variable amount of THC and CBD, a series of other terpenes, and a formulation matrix, generally oil or triglycerides.
“Obviously, a mixture behaves differently compared with the pure substance alone,” says Dr Samuel Banister, a researcher and expert in using natural product scaffolds for the development of new drugs at the Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney.
THC is an agonist of two cannabinoid receptors, CB1 and CB2. These G-protein coupled receptors are found throughout the brain and are involved in things such as cognition, memory, appetites and pain. “THC-containing products are presumably activating CB1 and CB2 receptors, and this is how they’re having some of their anti-nociceptive and other analgesic properties,” says Dr Banister.
CBD is a little different. There is some evidence that CBD also interacts with CB1 and CB2 in animals, but the mechanism is not yet understood, says Dr Banister. He says CBD is thought to activate a whole host of other non-cannabinoid sites, “it is presumably a multimodal drug with quite a complex pharmacology”.
High doses of THC are known to cause judgement impairment with an intoxication window that can vary from three to 10 hours, depending on administration method and dose. The use of THC can affect people’s ability to drive or operate machinery.
“Acute use of THC-containing product can cause cognitive impairment,” says Dr Banister. “But in terms of acute toxicity, cannabis is one of the safest medicines around.”
Dr Banister says most of the issues with dependency due to longer-term use are linked to misuse and self-medication rather than prescribed medical cannabis.
CBD is safer, with some non-severe side effects, such as diarrhoea and tiredness, at high doses. It is also non-addictive and has no withdrawal.
However, drug-to-drug interactions are a concern. Medical cannabis can interact with lipophilic medicines that need to be broken down in the liver, including cardiac medications, antifungal therapies, epilepsy medicines such as benzodiazepines, antidepressant therapies, and pain medicines such as opioids. Cannabinoids can slow down or stop the breakdown of these products, making their levels in the blood dangerously high.
“These products are being explored in a huge number of indications,” Dr Banister says. “But the big problem with cannabis is that the evidence is not very strong, and that’s largely because not a lot of studies have been done.
“Despite the low evidence base, [pain] is one of the more interesting areas where medicinal cannabis may find some use, especially for refractory pain.”
According to a report from the Australian Institute of Health and Welfare, about 2.5 million Australians used cannabis in 2019. Of these, about 600,000 people used it for medical purposes, either always or sometimes, with only 3.9% of them obtaining the drug by prescription.
More than half of people using cannabis for medical purposes reported using it to manage chronic pain.
“This stands at odds with the argument that there’s really no evidence on efficacy,” Dr Banister says. “The evidence base may be low, but we know that people are seeking it for pain and having some success with it.”
Professor Iain McGregor, head of the Lambert Initiative, says there are “hundreds of thousands of Australians who are self-medicating with cannabis for chronic pain”.
“The phenomenon exists regardless of what the medical professionals or the specialist colleges think about it,” he tells TMR. “And pain is overwhelmingly the number one medical use of cannabis.
“We’ve got a massive, uncontrolled experiment where millions of people around the world self-medicate with cannabis products for pain. And I presume that’s because it works. But we don’t have the scientific evidence to prove it.
“That is a real shame because clinical trials give doctors the confidence to prescribe it.”
Professor McGregor is involved in a series of clinical trials with the Lambert Initiative, including a placebo-controlled trial of CBD in spinal cord injury patients and one of topical CBD use in osteoarthritis.
He says doctors don’t know enough about medical cannabis to prescribe it.
Besides the vast array of products GPs can choose from, every pain syndrome, be it arthritis, fibromyalgia, cancer pain, IBD cramps or back pain, might respond differently to different THC and CBD doses and combinations.
Much of the information around dosage and method of administration for each pathology still lacks robust scientific evidence.
Health professionals can access the NSW Cannabis Medicines Advisory Service set up by the University of Newcastle and funded by NSW Health. The service gives doctors advice that is tailored for the specific patient.
The Australian Centre for Cannabinoid Clinical and Research Excellence has developed a suite of six prescribing guidance documents to assist medical practitioners. The TGA has published guidance documents on the use of medical cannabis based on current evidence.
“There are more educational events and resources available to doctors. But it’s still a bit scattered,” says Professor McGregor.
Professor Vagg says GPs are the cornerstone of chronic pain management in Australia.
“Far more people will see a GP than a pain-management specialist,” he says. “But GPs don’t appreciate the nuances of interpreting the literature unless they’ve had time to sit down and go through it in a lot of detail.
“Pain-management services exist to back up GPs. When primary care management fails, patients need evidence-based effective treatment.
“If we’ve learnt anything from what happened with opioids in the early 2000s, then we’ve learnt that it’s very unwise to embark on large-scale use of pain treatments when we don’t have adequate data.
“The real risk of the whole medicinal cannabis debate is that it deflects the public discussion away from what is the real issue in pain management. That is, funding treatments we already know to be effective: multidisciplinary pain clinics, physical and psychological strategies and procedures that are now widely available and cost-effective.
“We already spend a lot of time trying to persuade people that they don’t need to try any more medications. If we just had the funding to apply what we know is best-practice pain management, then nobody would care about medicinal cannabis because we would be doing so much better than we are now.”
Cannabis in cancer
In the past decade, cancer therapies have become more effective, increasing the chance of survival and longevity. But many patients face years of treatments, which often cause a series of undesired symptoms, including chronic pain.
Increasingly, cancer patients are asking for medical cannabis to manage conditions induced by cancer and cancer therapies, especially those with advanced disease who respond poorly to conventional relief options.
The TGA says there is little evidence of benefit to advanced cancer patients with chronic pain.
“The results so far are really underwhelming,” says Dr Tim Hucker, a cancer pain specialist at the Peter MacCallum Cancer Centre, Melbourne. “[Medicinal cannabis] has been heavily investigated, and the systematic reviews are disappointing.
“We were hoping for it to be more efficacious than it is, as there are cannabinoid receptors throughout the physiological pathways of pain, but it doesn’t seem to be showing the effects we were hoping for.”
Dr Hucker adds that costs and driving restrictions make the use of medical cannabis impractical for many patients.
“The studies until today have not been robust enough for us to say [medical cannabis] is as effective as, or more effective than, opioids,” says Associate Professor Judith Lacey, head of Supportive Care and Integrative Oncology at Chris O’Brien Lifehouse.
“Some of the evidence is still anecdotal, but increasingly, it’s observational evidence to suggest it helps.”
Professor Lacey, also a clinical researcher at the University of Sydney and Western Sydney University, is involved in clinical trials that aim to assess the safety and efficacy of cannabis in cancer patients.
People with cancer pain often present various other symptoms, such as sleep disturbance, nausea and loss of appetite, that interconnect with pain. “We find that cannabis makes people feel more relaxed. They can sleep better, so even if their pain is the same, their quality of life is improved,” Dr Lacey says.
But the scientific evidence so far is conflicting.
Some studies on nabiximols – a spray that contains a combination of THC and CBD – suggest that it might have a positive effect on cancer chronic pain and quality of life. Other studies concluded that improvement of pain, sleep and quality of life was not significant compared with placebo.
“For some people who do respond, they get significant relief,” says Dr Lacey.
She says cannabis alone has the potential to manage a range of symptoms. “We can possibly reduce polypharmacy – using a drug for every symptom – with one pretty safe drug.”
Some initial studies, including a phase 2 trial in patients with glioblastoma multiforme Dr Lacey has co-authored, suggest that medical cannabis is safe and well tolerated. However, more research is still needed to fully understand safety and potential risks.
One of these risks is judgment impairment, which can affect driving or completing dangerous tasks. Another risk is dependency.
A recent literature review found a clear difference between medical and recreational cannabis use in terms of dependency. But too many gaps are yet to be filled with scientific research, the authors of the review write.
“[Medicinal cannabis] is far safer than opioids and has a reduced dependence risk,” says Dr Lacey. “If somebody is going to live longer, I would not want them to be on long-term opioids and benzodiazepines. Perhaps cannabis would be the drug of choice for some of them.”
Unlike opioids, medical cannabis has no risk of overdose, says Dr Lacey. “It is pretty hard to kill somebody with cannabis. It’s much easier for people to die from opioid overdose.
“People now live with cancer as a chronic illness and are often stuck with opioids. Cannabis has a really interesting role in that space. It’s a growing, interesting space to be watching.”
Cannabis in rheumatology
The best evidence available today that CBD (cannabidiol) has some anti-inflammatory effect comes from animal studies. “But in humans, we don’t know whether [CBD] is better than the anti-inflammatories we’ve currently got,” says Professor Jennifer Martin, chair of clinical pharmacology at the University of Newcastle.
“There is a paucity of evidence,” she says. “There still haven’t been good quality clinical trials of the type that we would expect to see in a rheumatoid population.”
But research interest around the treatment of some of the symptoms of rheumatoid disease is growing, she says.
Professor Martin says that most rheumatology patients who use medicinal cannabis use it to manage symptoms such as chronic pain rather than as a disease-modifying medicine.
In a position statement, the Australian Rheumatology Association (ARA) says the evidence for the use of medical cannabis in chronic pain and musculoskeletal conditions is limited.
“Several systematic reviews of the use of cannabinoids in chronic non-cancer pain (including fibromyalgia, rheumatoid arthritis and neuropathic pain) indicate at best modest efficacy with significant adverse effects including alteration of perception, motor and cognitive function which may outweigh any benefits,” the ARA writes.
The statement concludes that well-conducted, long-term trials are still needed. In the meanwhile, ARA recommends practitioners prefer a biopsychosocial model for chronic musculoskeletal pain management.
“Overall, the evidence is not all that good for pain. And we’ve got other evidence-based therapies that we know are more beneficial for some patients,” says Professor Martin. “But when you talk to some patients, they say they feel a lot better with cannabinoids.”
She says patients often report an improvement in quality of life that helps them control their pain.
Until quite recently, running clinical trials on cannabis products had been a genuine challenge. In Australia, cannabis products were legalised only in 2016 – “there was so much red tape to be able to study it”, says Professor Martin.
Cannabis products were difficult to source and often contained unknown pesticides and heavy metals that made them unsafe to give to humans.
It was also challenging to get consistency because where and how the plant is grown changes its pharmacological properties.
“A lot of those issues make it difficult for researchers to do the work,” she says. “And there was certainly a big community feeling that we didn’t need to do quality research; that we could just get access to the recreational products.
“But this is not about younger people getting a high. This is about quite vulnerable people with a lot of medical problems.
“But I think things have come around a bit.”
Professor Martin says patients are increasingly aware of the benefit of taking part in clinical trials rather than self-medicating using recreational cannabis.
“Patients realise that it’s quite nice to be able to access safe, standardised products, rather than just being at the mercy of whoever is selling you the products.”
Note: This has been corrected to include the products that are TGA-approved.