PAIN MANAGEMENT

Pharmafile speaks to Sapphire Clinics

Simon Erridge: I think there’s been a real emphasis to move away from many of the habits of prescribing we’ve seen in the earlier part of the last 10 years. That period saw a sharp increase in the number of patients who were prescribed opiate medications. Over the past few years, most recently with some of the NICE guidance around primary chronic pain, we’ve seen a move away from using opiates in the setting of chronic pain, and more of a focus on other medications, such as antidepressants. Even with gabapentinoids, which the medical community has been using with increasing frequency – there’s been a little bit of hesitancy around guideline makers recommending those, due to potential harms and the lack of evidence of benefit in chronic pain.

The main shift has been towards firstly working with patients to acknowledge that with the medications and other treatments that we use in chronic pain, things may get better, but there’s no certainty or guarantee that whatever we use will resolve that chronic pain. Psychological therapies such as CBT (cognitive behavioural therapy), in combination with physiotherapy, are all first line measures to try and get on top of those aspects of chronic pain.

I think the real unmet need is with respect to pharmacological management. For lots of patients that I’ve seen and have referred on to physiotherapists, often I’ll get a report back that will say ‘this patient is in too much pain to even engage in physical therapy’. Although we recognise the benefits of having a medication that enables people to engage in physiotherapy and psychological therapies, that is not a one stop fix, and takes time. Giving them options, so that they can carry on their day-to-day activities, so that they can sleep well, they can go to work, all these are really important. The real unmet need is identifying pharmacological management methods that can be used.

We have seen some work on more interventional treatments around chronic pain, and that really depends on the individual condition, and the sites, such as joint injections. We need more research into the more interventional measures.

Taking something like chronic pain, which in and of itself is a really heterogenous group of conditions, and affects a wide variety of people, what would probably benefit all patients the most is more identification of novel therapeutics for them to use.

We’ve seen a real increase in the amount of evidence surrounding medical cannabis and chronic non-cancer pain, but also in chronic pain related to cancer, whether that’s the cancer in and of itself, or the side effects of cancer treatment.

There was a recent, rapid recommendation based off a systematic review and metaanalysis published in the BMJ last year, which suggested that patients who have failed first line therapeutics for chronic pain could trial non-inhaled medical cannabis agents. That’s either oils, capsules, or lozenges, as they recognise that there was a small but significant benefit in respect to pain specific outcomes, but also looking at things such as sleep and general health-related quality of life.

In addition, at Sapphire Medical Clinics, we have generated evidence through the UK Medical Cannabis Registry. We published some data this year, looking at patients prescribed medical cannabis, including oils, and dried flower. In those prescribed for chronic pain, including those with cancer pain and non-cancer pain, we saw that there were statistically significant improvements in their scores for interference with the pain in dayto-day quality of life, and also with respect to anxiety symptoms, and their self-reported sleep quality.

There’s an increasing body of evidence to support the use of medical cannabis. The BMJ article, Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials,makes recommendations towards utilising medical cannabis for those patients where first line therapies haven’t been effective. 1

In other aspects of palliative care, such as psychological components of end-of-life care, whether that’s anxiety and low mood, there’s very limited evidence directly from the palliative care population. Looking at anxiety disorders as a whole, there’s really promising preclinical evidence, and now increasing levels of clinical evidence around its utilisation in anxiety disorders. There have only been a few randomised control trials, and they’ve mainly looked at social anxiety disorder, rather than generalised anxiety disorder, or PTSD, or anxiety related to health conditions. They’ve been largely positive, and again, we’ve looked at patients prescribed medical cannabis for anxiety in the UK through the UK Medical Cannabis Registry. That select cohort of patients in the UK who were prescribed medical cannabis for that indication, we’ve seen significant improvements in their anxiety, general health related quality-of-life, and sleep.

The main difference in how it’s used is largely in response to whatever symptoms you’re trying to treat. In fact, the way medical cannabis is prescribed for cancer and non-cancer pain largely is very similar. You would ideally start out with a higher dose of cannabidiol, and maybe either have no THC, or a very low dose of THC. As people start to tolerate the effects of both of those medications, you’d slowly titrate them up, until they would be receiving the maximum amount of benefits, with the lowest risk of them developing any adverse events from the medications.

With respect to some other symptoms around palliative care, for instance – if they’re having difficulty sleeping, or with anxiety and they need something that’s more shortacting, in order to manage symptoms quickly, rather than slowly titrating up with an oil, they might be better off taking their medication in the form of dried flower.

That dried flower is vaporised to a lower temperature than it would be for people who would smoke it, and we specifically counsel patients not to smoke medical cannabis because of the associated carcinogenic risk.

However, when it’s taken at lower temperatures through inhalation, the onset of action is much quicker, and then drops off much quicker as well. Normally, these would contain a slightly higher dose of THC compared to if they were titrated up solely through oil, so these patients get a quick relief of their symptoms, and then the effects of the medication quickly taper off.

At the moment, there are quite a few barriers to medical cannabis in the UK. One is knowledge – the general public really are quite unaware as to some of the legislation changes, even though we’re two and a half years down the line from when some legislation changes came into effect.2

We did a YouGov survey last year which showed that only approximately 50% of people that were surveyed were aware of the legislation changes. That’s obviously a big barrier for those people who it may otherwise be appropriate treatment for, with these people not understanding that medical cannabis is even a possibility for them. To some degree, that problem exists amongst clinicians as well. It’s to a lesser extent; lots of clinicians are aware of its legal status – but for many, when they were coming through medical school and their training, medical cannabis wasn’t on the curriculum. Because of this, they have less of an understanding of what it is, what it does, how to prescribe it effectively and safely. Therefore, they’re more reticent to either recommend or prescribe it themselves.

Knowledge and education is a big barrier. Another major barrier is stigma. A lot of patients say to us, they wouldn’t be willing to even disclose that they’re taking medical cannabis, even though whatever they’re doing is completely legal. They find it really difficult to share that, whether that be with members of the criminal justice system, police courts, the other health care providers, or family and friends. Some people really find that quite difficult, because of the stigma that’s still associated between recreational cannabis use and those being prescribed it for medicinal reasons.

Finally, cost is a barrier: it’s not available on the NHS. Apart from a very small number of patients – I believe only three to date – have managed to get medical cannabis prescription through the NHS. But how do I think it’s going to change from that point? Things will slowly change in terms of education, and this will help address stigma. The key to unlocking all of this is more research, as we do more research, and more specifically, do randomised control trials that compare medical cannabis against first line therapies for some of the conditions in which it’s being prescribed. We can more clearly find out where this sits in our treatment arsenal for any specific condition, because at the moment, you need to have tried first-line licenced therapies before you can even be considered to start medical cannabis treatments. Once we have that extra data, we can perhaps say that actually for chronic pain, it might be a first line treatment, or that for some of the other conditions that it’s been prescribed for currently, there are better things out there, and we probably shouldn’t be using it. I think that’s how things are going to change: we’ll see medical cannabis being more widely used in individual conditions, hopefully within the NHS if they can demonstrate cost effectiveness as well as through health economic analyses. But alongside this, in some conditions, we may in fact see medical cannabis’s use being far less.

When you look at the cannabis plant, and how it gets distilled down to what causes its effects, you have what’s thought to be over 400 potential active pharmaceutical ingredients in the plants. The two main ones that we understand are THC and CBD. This is what the prescription is made up of. But there are over 100 potential cannabinoids, and then many more terpenes and flavonoids, which are all purported to have individual effects on many receptors across the body. We understand that those three compounds are actually quite low potency, in that they don’t elicit really strong effects in receptors across the body.

With respect to chronic pain, we have evidence that the major compounds in cannabis-based products dampen down the response at peripheral pain receptors. Chronic pain is really complex, and a lot of the experience and severity of pain can also be modulated by your own central nervous system. For instance, we all understand that if you’re laughing, you’re really enjoying yourself, and you don’t feel the effects of chronic pain as much as you would do if you’re stuck inside on a grey rainy day. We understand that the cannabinoid receptors in the brain have lots of particular roles in terms of modulating anxiety, and other emotions, and this has a really clear role in heightening or dampening down the effects of your interpretation of chronic pain. If we look at those people who have high levels of anxiety with their chronic pain, those people can have an even greater response than those where anxiety doesn’t do much of a role in their experience of chronic pain. That’s one of the main points: you have so many compounds, and so many different receptors that can potentially be acted upon.

If you can find the right formulation for the right patient, then there’s a multitude of possibilities, but obviously it goes without saying that medical cannabis may not be the right thing for them at all.