The rationale for cannabinoids as a new class of analgesics

In a recent post on DrugMonkey, the DM suggested that I write a post on clinical trials for cannabinoids as analgesics. Due to some obligations I am quite sure that I am unable to talk about certain aspects of these trials; however, I can talk about about their rationale and why the public should know that cannabinoid analgesics need not have any association with cannabis smoking.

Let’s start this off with a little background on why cannabinoids are analgesic. Human’s have known that cannabis smoking can be analgesic for thousands of years but it is only recently that we learned why. Soon after the first cannabinoid receptor, CB1, was cloned, Andrea Hohmann and Miles Herkenham at NIH began a series of elegant studies examining the expression of cannabinoid receptors in the central nervous system (CNS) and how this expression pattern was relevant to pain. They found that CB1 receptors were expressed in the outer lamina of the spinal cord, suggesting that CB1 receptors might be involved in pain control (since this is where pain-sensing neurons first terminate in the CNS). Subsequently, it was shown that spinal injection of cannabinoids induced analgesia and that knockdown of CB1 receptor by antisense led to increased pain (hyperalgesia). These studies were done largely by Ken Hargreaves’ group. All of these findings suggested that an endogenous spinal cannabinoid system was involved in pain control. These were really the first studies to suggest a mechanism of action (MOA) for cannabinoid analgesia in the CNS.

Around the same time, two groups, Ian Meng in Howard Field’s lab and another led by the late (and far too soon I might add) J Michael Walker, demonstrated that cannabinoids could induce analgesia via another mechanism, this one also in the CNS. CB1 receptors are expressed in a particular area of the periaqueductal grey (PAG). The PAG is a major pain control center and is often considered to be the location of the brain where endogenous opioids mediate analgesia (think runner’s high). Walker’s work showed that PAG cannabinoid receptor containing neurons exerted control over neurons in the rostroventralmedial medulla (RVM). This is important because the RVM sends projections down to the spinal cord and these neurons are responsible for controlling synaptic output at the level of the outer lamina of the spinal cord. Essentially what happens is that cannabinoids activate CB1 receptors in the PAG. These neurons then modulate the output of the RVM such that the RVM exerts descending inhibition on the outer lamina of the spinal cord. All of this leads to analgesia. Hence, in the CNS, there are two major loci of cannabinoid action to cause analgesia, the outer lamina of the dorsal horn of the spinal cord and the PAG.

These CNS actions contribute strongly to the analgesic action of endogenous and exogenous cannabinoids but these findings were not particularly interesting in terms of pharmacotherapy for pain because a cannabinoid drug for pain control would have to cross into the CNS to give analgesia. This is potentially bad from a drug perspective because the psychotropic and abuse properties of CB1 agonists (think getting stoned and stoners) can not readily be avoided via this MOA. Luckily for those of us in the cannabinoid analgesia field, this was not the end of the story.

In the late 1990s, Ken Hargreave’s and Daniele Piomelli’s groups both demonstrated that there was another site of action for cannabinoid analgesia. Cannabinoids can also act in the periphery to exert pain control. In other words, a cannabinoid drug need not enter the CNS to achieve analgesia. This was a particularly exciting finding because it demonstrated that cannabinoids could achieve analgesia without having abuse potential or stimulating psychotropic effects. The papers from these two groups launched peripherally restricted cannabinoid programs at pharma industry labs throughout the world.

In the decade that has passed since these initial findings this area, peripheral cannabinoid analgesia, has been an area of intense scrutiny (and the body of work includes many of my papers and my dissertation). As far as I am concerned, the exact MOA of many of these compounds is still debatable. However, one thing is abundantly clear: peripherally restricted cannabinoid receptor agonists are analgesic and a number of these compounds have made it into clinical trials and you can expect to hear about the results of these trials soon. Moreover, a number of small, academic trials have been run and the results have been fairly positive. For instance, a variety of patch formulations have been utilized for the treatment of post-herpetic neuralgia pain. These trials have been particularly effective. Some trials have also been done for effectiveness in human pain models (a human pain model usually involves a normal volunteer who has a patch placed on their arm to deliver drug and then gets an injection of capsaicin at the same site. They then rate their pain levels and have some sensory testing done to quantify their thresholds for pain). These trials have also been met by a good deal of success.

So what should the taxpayer know? First of all, almost all of the work I discussed above was supported by NIH (in other words, by your tax dollars). Second, there is really no reason to believe that a peripherally restricted cannabinoid bears any real relation to cannabis or cannabis smoking. Sure, there are some similarities in pharmacology but the side effects will be completely different and there is EVERY reason to believe that a cannabinoid-based analgesic approved by the FDA will have little abuse potential and few psychotropic effects. Will these compounds be wonder drugs? Of course not, but there is a good chance that they can help a group of people that don’t get adequate pain relief from currently available analgesics. Will they be safe? This is the million dollar question right now. I honestly don’t have a good guess, but I can tell you that we will know more about this very soon.

To wrap up:
1) Hundreds of scientists have been involved in this effort throughout the years. If you’re reading this and I left you off, sorry!!
2) Cannabinoid analgesia is mediated largely via three sites: A) the PAG, B) the dorsal horn of the spinal cord and C) the periphery, outside the CNS. Peripherally restricted cannabinoids are the class of compounds that have the best shot at making it to the market. They act via mechanism C.
3) Don’t confuse cannabinoid analgesics with cannabis smoking. They are not the same things.
4) Know that the psychotropic and abuse properties of cannabis smoking can be avoided with cannabinoid analgesics.
5) Keep your eyes on the clinical lit for cannabinoid analgesics. We might be in for some interesting findings and, undoubtedly, some big surprises!

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8 responses to “The rationale for cannabinoids as a new class of analgesics

  1. I certainly hope you will follow up with a post on current understanding of the putative peripheral molecular targets of cannabinoids, including nociceptor TRP channels.

  2. Will I be getting academic credit for that one? :-P

    Seriously though, I’ll do it sometime soon.

  3. Pingback: Talking Tylenol… yes, more cannabinoid analgesia « JUNIORPROF

  4. You know, the first thing that pops into my head, is whether or not using cannabinoid analgesics would cause a positive for marijuana is a UA, I would assume that it does. In reality, I don’t see this as a problem, persay, but it would mean that people who, for whatever reason need to be “drug” free and prove it couldn’t take it.

    I really like the idea though. I would be interested in seeing how it compares to the analgesics that can contribute to heart disease. At thirty three I am starting to get concerned about my genetics and heart issues, especially as I find myself using naproxen sodium or ibuprofen more often than I used to. And I need to have pain relievers that don’t mess with my head too much. I rarely drive but I use power tools on a nearly daily basis. I would just find the irony delicious, if such a thing came from my rather old friend marijuana.

  5. great post! I’m not a neuroscientist, but found the post interesting because my parents have problems with arthritis, as many older folks do. Their treatment was substantially affected by the removal of Vioxx and the other COX-2 inhibitors from the market. Do you think that the cannabinoid analgesics would have therapeutic value for arthritis?

  6. DuWayne, The cannabinoid analgesics that I am talking about would NOT cause one to test positive for marijuana in a UA. These compounds that I know of in trials bear little resemblance to compounds in marijuana although they share some common pharmacology.

    On the safety issue, cardio-side-effects are always a major concern and this is one thing we will begin to learn about as these compounds are taken over longer time courses in humans. I am not able to make any sort of predictions, nor would I care to. On the other hand, the vioxx story has everyone spooked so they’ll be looking for them….

  7. BugDoc, Thanks!! The Vioxx deal had a very negative effect on thousands of RA patients. In preclinical tests cannabinoids are effective for arthritis type pain. This would be a potential market area for the drugs. The first tests for efficacy will likely not cover this area though (its too slow and too hard). The first efficacy trials will likely cover human pain models (capsaicin test) and third molar extractions (the really classical inflammatory pain test). I would predict that post-herpetic neuralgia would also get some coverage in efficacy trials because those previous trials were so positive.

    If I had to venture a guess, I would say that once these initial trials are run you can expect that RA will be high on the list. On the other hand, some of these cannabinoid compounds share pharmacology with COX inhibitors so it will be a big issue safety wise. We’ll have to see.

    One other note, at the APS meeting I blogged about there were many posters on making COX-2 selective compounds safer. Different companies are taking different routes to achieve this goal. At least one of them seemed to work well in a preclinical model that included cardiovascular risk. Since we know that the compounds have efficacy one battle is already won and the safety issue could fall into line quickly for COX-2 drugs. A really interesting side note is that for one of these formulations to improve COX-2 safety they got the added benefit that the compound was suddenly effective for neuropathic pain (something COX-2 inhibitors don’t normally do). My interest was certainly peaked by that finding…

  8. Pingback: Why are new classes of analgesics needed? « JUNIORPROF

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