The Use of Cannabinoids to Treat Pain

So yes, today I’ll talk a bit about the use of cannabinoids to treat pain, And I have no financial disclosures that relate to this And before I get into the scientific background of how we actually use cannabinoids to treat pain. I think we just need to acknowledge what a mess this situation is so. We have fairly few states with legal medical cannabis. This slide as of a couple days ago, is outdated because Illinois just passed adult use recreational law, so we now have 11 states with adult use cannabis, And this is despite it being schedule one. So under the Controlled Substances Act it has no accepted medical use and a high potential for abuse. So this has created such a mismatch for so many clinicians who want to know how to adjust the use of cannabis in their patients and how to do this. In a safe and effective way, And so to this point a little bit –, we just published a paper little while ago, we see the conditions for which people are actually using cannabis Far and away the most prevalent qualifying condition for your cannabis license is chronic pain,

It’s about two-thirds of the total number of qualifying conditions and about 80 % of the total patients. So what does this look like? Then? In Michigan We’re one of the biggest states in terms of the number of medical cannabis patients, We have about 270,000 patients as of 2017 And we’ve had medical cannabis, –, a medical cannabis law since 2008.

But because of this mismatch, we have a lot of uncertainty about how to actually interface with patients. A lot of physicians are uncomfortable regarding certifications for their patients, They’re not actually saying “. This is the prescription, and this is how you should go: use cannabis .”. Instead, what they’re doing when they sign an application for your medical cannabis license is they’re, saying “? Yes, you have a condition that qualifies you under the state law to possess cannabis up to two and a half ounces and 12 plants, and go and figure it out for yourself, .” And so because so many physicians are uncomfortable. With this there’s also a lot of clinics that have popped up where all they do is medical cannabis, certifications,

You can go in get a five-minute appointment, pay, 100 bucks or something and voila you have a license, but still no idea of what necessarily to do So. We have that mess on that side And then, of course, as everybody’s been talking about today, we’re in the midst of an opioid crisis And there’s a lot of interest in using cannabis or cannabinoids. The active compounds in the cannabis plant to treat both opioid addiction. But then some of the undergoing chronic pain that has driven this opioid crisis And there is some support of this being plausible. So we know from a lot of preclinical studies as well as like. There are some clinical trial that there does seem to be some synergism between THC one of the compounds in cannabis and opioids

So in this recent clinical trial they gave people Oxycodone as well as [, inaudible, ] cannabis, And they found with sub-threshold dose of the cannabis and Oxycodone together they got the same pain relief with –, as they saw with a higher dose of the opioid. So there’s some interest there and might be a way that people are able to reduce their opioid consumption when they start using cannabis. But then we also see statewide analyses where people have shown that states with medical cannabis legislation have lower rates of opioid overdose. Lower opioid prescribing than the states without And having active operating dispensaries is really important for these effects. We then also see numerous — dozens of studies at this point in the US in Israel, in Canada, where people say “. Yes, I’ve substituted cannabis for opioids, and I do so for better symptom management, and I do so because there’s fewer adverse side effects .”. So again schedule one substance, not much clinical guidance, widespread availability,

You can see why we’re in quite a mess, So I think that what we need to do next is then figure out where the evidence lies for chronic pain, how we can use this in a safe of a way as possible and how to conceptualize cannabis in The correct way, which at least in my view, is rather than thinking of it as a panacea or a poison which are really the extended –, the dichotomist use that are really out there at this point and think of it “ Well. This is potentially one pain. Medication that people could use – and this is the way in which they could do so .”, So with that, let’s drum into some of the science. So in terms of definition and background, then I’ll go into some of the risks that are known about cannabinoids their role. In pain management looking at some of the clinical trials and then some practical tips and guidelines on how of use these compounds So and much of this comes from the National Academies of Sciences 27 through — report on the health effects of cannabis and cannabinoids

There is some stuff – that’s been updated since this time, but this is a really good place to start It’s available to anybody online, so I would suggest looking into it if you would like In terms of definitions, so I’m going to use “ cannabis” instead of “ Marijuana”, just because “ cannabis” is the botanical name and “ marijuana” has you know [, inaudible, ], xenophobic history to the word so I’ll just avoid using that for now

And so there’s subspecies [, inaudible ], And then we also have cannabinoids, which is active compounds both in the cannabis plant, but also we –. Our body makes its own endo or endogenous cannabinoids And then there’s also synthetic cannabinoids which either are replicas of the Phyto cannabinoids. That are synthesized in the labs or novel cannabinoid compounds that we think of as having potential therapeutic uses. These compounds all interface with the endogenous or endocannabinoid system, which is the set of receptors from your naturally recurring ligands and enzymes regulating control, And this system is so ancient, so widespread and involved in so many functions, including memory. Analgesia stress appetite sleep that there’s a lot of excitement about targeting it for clinical applications. I guess I can’t tell if it shows up nicely The two most common receptors in this system. The ones that are the most widely studied are cannabinoid receptors. One and two CB1 is one of the most common receptors in the central nervous system And it is — when it’s activated it tends to be more involved in the sleep memory. Analgesia appetite those responses.

By contrast, CBQ is found more in the immune system And when it’s activated it doesn’t seem to have any kind of psychoactive effects in the same way as the CB1 receptor. So there’s a lot of interest in targeting that immune system-related conditions. So next, let’s go into some of these cannabinoids and what we know about them At this point, I’m just going to touch on two, even though there’s over 100, which have been discovered But the most commonly studied, is THC or tetrahydrocannabinol. It’s analgesic it’s mood-altering and appetite-stimulating, and it partially binds to both CB1 and CB2

I will note that, even though there’s a lot of concern about the psychoactive effects and all of that of THC when in smoked cannabis, that synthetic THC as dronabinol has been legal for decades for treating chemotherapy induced nausea and vomiting and AIDS-related anorexia. So there is a known therapeutic use. It’s FDA-approved, It’s a schedule-free substance, while herbal cannabis is schedule, one further muddying confusion in the waters about what’s going on with this Hot on the scene is CBD or cannabidiol. We’ve known about this compound. As long as we’ve known about THC, but there’s so much more excitement about it at this point because it is non-intoxicating, It seems to protect against some of the psychoactive effects of THC And then in a lot of preclinical studies. It has anti-inflammatory effects. It has effects on pain and most excitedly is a very potent anticonvulsant. In fact, the FDA just approved a CBD-based drug last –. I think it was last June in 2018 called “ Epidiolex” for childhood epileptic disorders And it is schedule five, so very low abuse potential.

I would be remiss if I didn’t mention the other cannabinoids, I’m not going to go into them much, except to say that there’s over 100 of them And there’s a big dispute in the medical and scientific community at this point about how to account for them. Because classically pharmaceuticals will try to find the active ingredient and synthesize that and give that in isolation and say “: Okay, that’s a good –! That’s the effect that we want .”, But because there are so many terpenes responsible for aroma and taste, et cetera as well as these other cannabinoids and herbal [, inaudible ] people want to know “. Should we use a full spectrum product or should we use an isolate ?”? So I’m not going to go anymore into that, but just to say that it’s out there In terms of photos, you can see that there — it’s a close-up of a cannabis bud and then a cannabis oil, [, inaudible ] And you can — now that CBD Is so exciting and hot on the scene, you can buy it anywhere.

You can buy it on Amazon, you can buy it at gas stations, you can, but it at CVS And to the frustration of scientists who want to actually do studies on this stuff. But you have to get a scheduling license to do so. You can buy it for your dog [, laughter ] in case your buddy has anxiety or joint pain, or something like that. You can get this in BarkBox delivered to your house.

[ Laughter ], So we also see that this situation is evolving quite quickly, So in 2018 — at the end of 2018, President Trump signed the 2018 Farm Bill that legalized industrial hemp and thus opened the door for the availability for many hemp derived CBD products. So they have less than .3 % THC in them, But there’s not a lot of uncertainty about how the FDA is going to regulate that. So there are concerns about products that have heavy metals, because hemp is a bioaccumulator There’s also a lot of shady. You know companies out there who don’t have good processes in place that remove the solvents that are used to extract these compounds or they use a lot of pesticides and then don’t do anything about that when they’re actually doing the extraction.

So it’s really important to go to –, ideally to go to a place that has third-party independent testing for metals, for solvents, for pesticides and then also so, you’ll actually know what is in the product that your patients might be using One such place. There’s a nonprofit called [, inaudible ] that has collaborated with places like Johns, Hopkins University And they’ve done much of this safety and potency testing and have a list of product that they verify as being safe and actually accurately labeled And then. Lastly, in this definitions and background section, I just want to talk about how these compounds work a little bit in the body, because this will come in later when we’re talking about how to use them and the effectiveness

 

So pharmacokinetically you can see from this slide the way that THC shows up in the blood administration groups. If anybody knows of anybody who’s injected cannabinoids, please let me know so that one that injection one it looks almost the same as smoking. So you can just go with that, But if you [ laughter, ], actually ingest the compounds orally, you have less of a spike of THC in the bloodstream and less of a fast taper and instead you have an extended –. It takes a while to hit and then an extended taper, So you can think about slow and fast release administration groups for using these compounds, especially knowing that the feeling of high maps onto those pharmakinetics really nicely And then, lastly, about how these interact in the body. We do seem to see a u-shaped curve for cannabis and cannabinoid effects. So with that in mind, what this means is there’s a kind of sweet spot above which, if you go above a certain point, you can end up overshooting your medical dose and then just get higher, in fact, maybe even get worse pain.

So if you look at the Y axis, you see a green plus and a red minus The curve shows where somebody’s pain relief is So maybe you have a low dose and you get a little bit of pain, relief, you’d find that sweet spot up at the Top of that curve, But if you go past that people could have increased anxiety, they could have increased pain So trying to figure out how to do that safely is something that’s really important when using these compounds All right. So next, let’s move into cannabinoid risks. I feel like this is really important to go into because there’s so much concern about this. Just given that cannabis is still a schedule, one drug – And actually this is where the bulk of the research funding from the National Institutes of Health has gone in the past. And we don’t have that much info on the medical risks of cannabis and cannabinoids. Because these studies have typically looked at recreational users, But because many of these folks who are using it recreationally would be considered the chronic heavy users they’re smoking a lot daily and tend to be younger. We can say “ Well, these are probably –. This is the worst case scenario of what this might look like, at least as a surrogate right now .”. We know that smoking not really good.

So the respiratory effects of that those are some of most widely known risks of cannabinoids, but there’s also risk of dependence and addiction About nine percent of people who use cannabis, develop some kind of dependency issue. There’s also increased rates of psychotic illness developed by people, especially using cannabis under the age of 25. I also need to addend the point on dependence and addiction. People who use cannabis at a younger age have about a double of that risk of addiction. So important to note that as well And that’s a particularly vulnerable population, And we see some long-term effects on memory and brain structure in cannabis users as well. In terms of in the acute phase, we see dizziness somnolence euphoria, although some people might not say that that is a risk, lightheadedness anxiety and others Less commonly, but especially seen in people who take way too much in terms of an edible dose. You’ll see some vomiting paranoia occasionally seizures and hallucinations, although those are more associated with the synthetic cannabinoids like spice that people can buy on the street, not typically cannabis itself and then vehicle accidents, of course, and then. Lastly, as with the CBD products that you can buy on Amazon, there’s an uncertain quality of many of the herbal [ inaudible ] as well.

So in states that don’t have good regulatory statutes in place about testing for safety and potency, you can end up with things with bud mold on them. Like you see in that — in the upper picture And if somebody’s immunocompromised and smoking that it can be really serious and problematic if they get some kind of systemic fungal infection, So in terms of the risks of medical cannabinoid use, as I said, we have much Fewer data on this, The best study that I’ve seen came out of Canada on McGill called the “ COMPASS Study” and what they did was they followed folks using 12.5 % THC smokable cannabis for a year and what they — and compared to people who were not Using it in a chronic pain setting

And what they found is about a double direct increase in minor adverse effects in people who were using cannabis compared to those who were not, but also increases — or improvements in pain and quality of life, So definitely a mixed profile there, but in a place. Excuse me that needs a lot more work, especially given that you know there are so many people using cannabis medically and we just don’t really have a good sense of what that looks. Like risk wise, A couple studies that did come out of Israel where they have more regimented titration regimes have found that there’s a pretty low risk profile in elderly adults.

They would be looking in a population of mixed cancer patients and they found with this titration regimen that they saw very few adverse events. Okay, so going into the role of cannabinoids and pain management. We’ve talked a lot today about the mechanisms of pain. So I’m going to skip over this a little bit except to remind you that there’s the peripheral, neuropathic and centralized pain states and that people can have any of these in combination In terms of preclinical models of pain. We know that CB1 and CB2 agonists are quite effective in many of these types of pain, but people are really concerned about the CB1 acting compounds because of the off-target central nervous system activity, the types of effects that we’d associate with the cannabis high, While CB2 agonists There’s a lot of excitement about at this point because, as I said, they don’t really seem to produce that effect.

And there’s actually a company making a compound called [ inaudible ] that they’re testing in a lot of inflammatory disorders that doesn’t really appear to bind to CB1 And so there’s some potential there to. Maybe in the future, see some CB2-specific compounds on the market. In terms of clinical trials with chronic pain, the most recent meta-analysis that looked at all of the clinical trials noted as with all the other studies that have done this, that these are short-length studies. They have small sample size, they have unrepresentative dosing of what people actually use And they typically find a modest decrease in pain compared to placebo across pain states. But most of this effect size is driven by the data in neuropathic pain, using the combination of THC plus CBT — CBD. Excuse me called “ sativex”, which is a sublingual, It’s a one-to-one ratio of the two

It would be really nice if I could give you more data about how CBD alone is effective in different types of pain. But unfortunately, I’ve only seen one study that has looked at that in any kind of long-term setting and that has just been published as an abstract as opposed to a published paper. They did find decreases in pain and improvement in function, but mostly in men with knee osteoarthritis. I will say also that there’s a pretty clear mismatch between these clinical trials and the observational studies in which many people using cannabis, who have been followed over time. They say that they’ve great success they’ve been able to taper off opioids, whatever it might be, But that uncontrolled nature of their dosing makes it really unclear about how exactly they’re doing that and how to translate that into a more clinical setting. Because we’ve talked about — oops. Excuse me, because we’ve talked about surgical pain, a little bit as well I’ll. Just touch on that briefly.

There’s only been about seven studies that have been done in the acute or surgical pain setting and, unlike in the chronic pain space, there’s pretty much. No evidence that cannabinoids that have been tested thus far are effective in this setting, But similarly to the chronic pain studies fairly limited in length. Many of them actually use novel cannabinoid compounds that have CB1 intoxication psychoactive effects.

And none of these studies used CBD And given that there’s actually a CBD clinical trial that came out in the last week that there was a lot of excitement about it because it seemed to decrease –. What am I trying to say? It seemed to decrease, cravings and anxiety related to heroin addiction and recovery in people who were ex-heroin users, There’s a lot of excitement about using it, potentially as an opioid, sparing medication, potentially in a surgical space or as an opioid substitute again just CBD alone. Okay, So in summary, then we know that cannabinoids and chronic pain that they do, that plausibility for therapeutic value. We know that dosing is really important and we know that using them in the right people is also important. We need to consider how much to use, because we want to figure out that sweet spot on that u-shaped curve. So we don’t overshoot an effective dose

We want to know about cannabinoid content, THC versus CBD and then the administration groups as well, because smoking all day every day, probably is not an effective strategy. But it’s possible that you could think of using a long-acting form of a cannabis compound like an edible and then have — or a capsule and then having something for short-term great for pain relief. So actually I was just talking to Evan Latinas [ assumed spelling ]. My colleague at [, inaudible, ], Medicine and something that they do is they give people CBD alone for the daytime, and if people have issues with sleeping, they give them a little bit of THC with CBD at nighttime to help with that, as well as the CBD for your pain, starting at very low doses, so that people can avoid getting too high, incidentally, by taking a product that they don’t know what’s in it or one that has too much THC

So I guess along those lines, then some practical tips would then be to start low and go slow so again, those low doses, so you don’t overshoot using a verifiable source with credible third-party testing. So you know what you’re getting and you’re avoiding heavy metals pesticides et cetera, And then because we know that smoking is really not probably a good way to ingest medicine, if you can avoid it using other administration groups that are available, tinctures capsules vaporizing. If somebody absolutely feels that they have to inhale things of that nature,

And using a combination of CBD and THC, because using just THC alone seems to have a much lower toxic threshold for psychosis and potentially other adverse events than using that combination together And actually Dan. And I published a paper in “ Annals of Internal Medicine”. With a commentary of how we think people should be using these compounds from more of a harm reduction standpoint and on a safety standpoint And if anybody’s interested in that, I’m happy to send it your way. So with that, I know I’m at the end of my time, I’d be happy to take any questions “ And thanks so much for your kind attention.

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