ALTERNATIVE TREATMENTSEmbracing transdermal technologiesA number of challenges exist within the delivery of quick, effective pain management which doesn’t deliver significant side-effects. Pharmafile spoke to Ken James of Futura for insights into the effective delivery of drugs to relieve pain, and alternative technologies Pharmafile: What are the therapeutic benefits of transdermal delivery in pain management? Ken James: The benefits are there, but it’s worth highlighting that there are certain drawbacks and potential limitations as well. The obvious benefit is that higher systemic exposure of drugs is avoided when a patient takes drugs orally. It’s not a particularly selective mechanism; an oral drug has to be dissolved, it enters the systemic circulation (it can go anywhere in the systemic circulation) and interacts with various parts of the body. Then, it takes a tortuous route, and eventually gets to the site of the pain. In that tortuous journey, systemic side effects can occur, such as, with oral non-steroidal anti-inflammatories, gastric upsets.There’s additionally been a lot of work done recently to show that there are potential cardiovascular side effects that can occur with orally administered, anti-inflammatory drugs: it’s not a very selective way of administering the drug. The benefit of an effective transdermal system is that this tortuous, circuitous route just to get the drug to the side of pain is avoided – it gets there through a more direct route. In other words, you apply the drug directly to the skin. If you formulate it properly, you can get the drug directly to the site of pain, minimise the amount of drug in the systemic circulation, and avoid the stomach, and so on and so forth.The drawback is that the art of delivering drugs locally or topically isn’t as well developed as the oral route. Therefore, there’s a lot of skill that is now being devoted towards the effective delivery of drugs topically.What difference does it make for antiinflammatories to be non-steroidal? Steroids are very potent drugs – they’re all chemically related to hormones in the body – and they can lead to quite significant side effects. If you take them orally, you can get this ‘moon face’. You can get skin thinning, if you apply them locally. You can get a worsening of the condition over time, if you use steroidal injections for arthritis. They’re highly effective, but they do have quite significant side effects, particularly if you use them over long periods of time.The non-steroidal anti-inflammatory drugs are quite effective if they’re delivered effectively, but a lot of them aren’t. If you can deliver them effectively, the side effect profile is much better, particularly for topical delivery as opposed to oral delivery. There are some local side effects that can occur: you can get some irritation, either as a result of using excessive amounts of drug, or harsh penetration enhancers. They’re not devoid of side effects, but, in comparison with steroidal anti-inflammatories, the side effect profile is much better.What are the challenges of transdermal technology being utilised for pain management? Two main challenges exist. First off, the skin is meant to be a barrier to the elements – it’s there for a purpose: to stop things attacking the body. The two challenges that exist with transdermal delivery are, firstly, breaking through the skin barrier – that is, getting the drug through the epidermis. That penetration relies on having a good partition between the vehicle that the drug is in, and the skin layer, so you effectively want to make the drug want to get into the skin, as opposed to remain in the cream. You do that through partitioning. For example, the skin surface has a number of lipid layers, so an environment that is conducive to partitioning more into that lipid layer needs to be created.The second difficulty is, once you’ve got it through the epidermis, that’s still not where the site of the pain is for many pain conditions, such as soft tissue rheumatism, arthritis, or sports injuries. The drug must be enabled to diffuse through the dermis to get to the sites of the pain. Therefore, it must be formulated with that second objective in mind. To get to the actual sites of pain, a combination of a partitioning to get it through the outer layers of the skin, and then diffusion into the lower layers, is needed. Those are the challenges, and it is quite a skill to balance those two factors and to come up with effective formulations that work.How do CBD products differ from other pain relief products? Not everything is known about CBD, but it does seem to work through a different mechanism. It seems to work through binding to cannabinoid receptors and other receptors in the body to block neurotransmission – so effectively blocking nerves that transmit the pain. That’s a different mechanism to non-steroidal anti-inflammatories, which block an enzyme called cyclooxygenase, which is responsible for producing prostaglandins. It’s prostaglandins that cause the pain and the inflammation, so this is an entirely different mechanism.Since with CBD products, you are binding to the body’s cannabinoid receptors – which are natural receptors in the body. It could be argued that this is a more natural mechanism to treating pain, rather than a “chemical” mechanism which some would regard as undesirable. The naturalness of blocking neurotransmitters, is what I think is attracting people more towards the products that contain CBD.It’s derived from hemp, but it doesn’t cause any high – you don’t get any CNS effects. CBD itself does not cause this, particularly if you can control the level of THC in the formulation. The natural benefits of the cannabinoids are delivered without the high that is normally associated with hempor cannabis-derived products.What are some of CBD’s grey areas at the moment, and what is still unknown? Our understanding is increasing, but the science is really only just emerging at the moment. I think it’s because of popular opinion – anecdotal evidence of these products suggest they work in a variety of conditions. What is lacking is large-scale clinical studies, and, in fact, some of the basic safety work that you would normally carry out in a drug development programme. This is what I think is holding things back at the moment, because, as things currently stand, the regulations do not allow for any medicinal claims for CBD creams to be made. Whilst the products can be sold, any medicinal claims would make them illegal. There’s also been a number of enforcement actions that have been undertaken in Europe, the UK, and in the US, against companies who try to make medicinal claims for products that, at the moment, are classified as cosmetics. They’re classified as cosmetics because the basic science to underpin all this kind of anecdotal evidence just frankly hasn’t been done. You won’t find any big Phase III clinical studies, for example, studying the pain-relieving effects of CBD, and therein lies a big opportunity. If a company were to garner the resources and actually conduct all this work, that’s a winning proposition because there is a weight of anecdotal evidence – people believe that it really works.The science needs to catch up a bit, and then if companies go through the drug registration route, I think it puts it on a much better ethical footing. I would say, from our studies, that the plethora of cannabidiol creams, gels, and so on that are on the market, in general, are very poorly formulated from a pharmaceutical perspective. This comes back to what I was saying: just taking an ingredient and shoving it into a cream or a gel isn’t really going to cut it. That won’t get it through the outer layers of the skin, the epidermis, and won’t achieve the diffusion that’s necessary to get it to the lower layers and, therefore, effectively treat conditions such as pain and other topical conditions such as pruritus (itchy skin).There’s a lot that can be done, and this is work that we’ve been researching. It is possible to formulate the products more appropriately, and, therefore, make them more effective. The other thing to note is that, as we’ve studied the many products on the market, there are clearly problems of instability with the CBD in the formulations: they discolour over time, they go brown; when you measure the level of chemical present, often it drops below the declared level on the tin. As it’s a fairly labile chemical, you have to formulate it properly to get a stable formulation. There’s a lot of scope for developing superior CBD formulations – they’ll work better, and they’ll be more stable through the course of their shelf life.What work needs to be done to improve the quality of life for those suffering local pain? There are various ways of treating local pain; I could write an encyclopaedia to answer that question. But it’s all about offering people greater choices. Coming back to the question of more natural therapies like CBD, there are great advantages if you can formulate the ingredient properly, using a product such as this, because it’s a more natural action working with the body, rather than using heavy-duty steroids, or some of the side effects that you get from the non-steroidal anti-inflammatories.Offering people greater choice is how we can improve things. The next step would be to do some proper clinical research on it to prove that the formulation really does deliver CBD to the deep tissue, where you want it to work. We can put the icing on the cake by conducting proper clinical research on that, but these are the greater choices we can offer people to improve their quality of life.You speak a lot about how the weight of evidence in favour of CBD is real-world data, and evidence that’s not clinical trial based. What is needed to launch CBD in clinical trial settings? You should really go through a systematic drug development programme. There’s a reasonable understanding as to how CBD actually works. Therefore, what you need to do next is conduct proper Phase I, then Phase II, and Phase III clinical studies. Typically, Phase I would look at the pharmacokinetics: how much gets where. Phase II would try to optimise the dose. At the moment, you go into the marketplace and can find any number of doses. But what’s the proper dose to be delivered? People don’t know that yet, to treat the various pain conditions. Phase II studies, which are typically dose ranging, look at a range of doses against a suitable pain model. Phase III studies have established a dose and go into multi-centre, possibly multi-country studies, using hundreds or thousands of patients, and a placebo control, to prove ultimately that the product works. That’s really what regulators expect out of Phase I, Phase II, and Phase III trials.Then, in the course of that, you really do need to show that the products are safe, particularly in a drug delivery system that treatments haven’t been delivered in before. In the case of CBD, it’s a drug delivery system delivering much higher concentrations. It needs to be proven to be safe – and just because something is natural, it doesn’t mean that it’s safe, which is a common fallacy. There are many toxins and poisons which are natural, but people ultimately jump to the false conclusion that natural means safe. No, it doesn’t. What is needed is to support good clinical evidence with good safety data as well.Finally, I’d like to express my enthusiasm for CBD pain therapies. It’s nice to see an emerging area, something that’s got a completely new mechanism, and it’s exciting having the opportunity to explore and research it, and underpin it with some good clinical research. Some companies do have a winning proposition in my view, because CBD has obvious theoretical benefits over steroids and non-steroidal anti-inflammatories. It’s great to see a new field opening up. Over the next few years, we’re going to see some real breakthroughs in this area, as the science catches up.Ken James is the Head of R&D at Futura Medical. He oversees the development, regulatory and manufacturing strategies for the Group’s existing pipeline and the evaluation of early-stage pipeline, opportunities with over 40 years of experience in the research, development, and commercialisation of consumer health care products. Ken is an experienced global R&D leader, and Non-Executive Board Director in multi-category Consumer Healthcare and Pharmaceutical Technology industries. He has a strong track record of innovation delivery, and senior executive and non-executive leadership.