Cannabis-inspired painkiller as strong as opioids

Treatment for severe pain still relies heavily on opioids - morphine-like agents. These are very effective in the short term, but they’re highly addictive, and potentially deadly in overdose or if otherwise misused. Led by the fact that many people find relief with cannabis, US researchers have now come up with a compound that mimics one of the molecules found in cannabis. But the clever twist is that, by making their molecule more water-loving, it can’t get into the brain to produce any mood-altering or addiction effects. Instead, it works purely by activating cannabinoid receptors in our peripheral tissues. The effect doesn’t wear off with repeated use, and, although they’ve tested it only on mice so far,  it does seem to be incredibly potent. Here’s Washington University’s Richard Slivicki and, first, Susruta Majumdar…

Susruta - The questions we were trying to answer is can we separate the psychoactivity or the mild altering properties of cannabinoids but retain its pain relieving properties to develop a non-opioid analgesic or pain reliever?

Chris - Because when we talk about cannabis that's actually a cocktail of compounds, different chemicals, isn't it? And so are you saying then that the ones that give you the mind-altering, mind-bending effects are not the same as the ones that cause pain-killing effects?

Susruta - Yes, so what we are using here is a single entity, we're not using phytocannabinoids like are present in medical marijuana for example, but we are tweaking the chemical structure in a way so you can separate the mind-altering properties from the pain-relieving properties.

Chris - And Rich, how are you actually doing that? How do you dissect apart those two effects?

Richard - One way we can do this is target cannabinoid receptors that are located outside of the brain and the central nervous system, targeting tissues that are feeding in those pain signals into the central nervous system.

Chris - So in other words the pain-killing effect is not necessarily achieved in the brain, it can be achieved outside the brain but the mind-bending effects are achieved inside the brain and if you go for the two different targets you can isolate those two effects?

Susruta - Absolutely, that is the point. So what we did was we just made subtle chemical changes into this molecule and make sure that it only targets the periphery. There's something called the blood-brain barrier that the body naturally has to prevent drugs and harmful chemicals from entering the brain and the blood-brain barrier needs oily compounds or greasy compounds. So what we did was with this synthetic cannabinoid we made it more water-soluble or less oil-like as a result of which it will not enter the brain and only target the peripheral nervous system or tissues outside of the brain and you're able to achieve the pain-relieving properties while you're able to separate the mind-altering properties.

Chris - How did you test it, Rich, to prove this was going to work?

Richard - So in order to evaluate this for just pain-relieving properties we use animal models of pain and so we use different models of migraine, neuropathic and inflammatory pain. Inflammatory pain is just like an acute injury due to like a burn or like an infection. Neuropathic pain is more of like a pain and so something due to like nerve damage. We then screen these molecules for not only their pain-relieving properties but also their potential for side effects in rodents and so we can evaluate those which might equate to the mind-altering effects of cannabis which is something again we wanted to avoid.

Chris - And do you get a suppression of pain responses in these animals which would suggest that this is working but without producing the psychoactive effects?

Richard - We find efficacy across all three animal models of pain and importantly we didn't see any analgesic tolerance. That is with repeated dosing the compound still retained pain-relieving effects which is really important because with opioids and even cannabis we see this tolerance-like effect. And more importantly too we found a great separation between the pain-relieving properties and the centrally mediated effects which indicates that this compound has a really wide therapeutic window which is really important for kind of a first-in-class analgesic.

Chris - And Sus, one of the things about the opioids that makes them very attractive is they are incredibly potent. We can achieve really powerful control of pain with them which under certain circumstances we really need. So are these drugs any good at rivalling the opioids for that?

Susruta - That was one of the surprises of this project that these turned out to be extremely extremely potent. And I've been working in the opiate field trying to develop drugs on that side of things also and you're absolutely right the potency has always been an issue with the other targets but these were as potent if not more potent than morphine which is the choice for treating pain or even fentanyl for that matter. And the beauty of the system is that unlike the opioids they do not produce respiratory paralysis or loss of breathing and the non-addictive properties because we are targeting the receptors outside of the brain. Sedation is a huge issue, stoning is a big issue with the cannabinoids or psychoactivity and mind-altering. There was a hundred-fold separation between the pain-relieving properties and the adverse side effects like sedation with this class of molecules.

Chris - Rich, have you unpicked how exactly you're doing this? Do you know why those pain nerve fibres have those receptors on them? Why should those pain systems have the ability to respond to this class of compounds at all?

Richard - The body has its own cannabinoid-like system called the endocannabinoid system so we actually synthesise molecules that bind to these receptors. The body has these receptors throughout itself and it has various different roles and different physiology. Stress-induced analgesia is a big one. There's a lot of like pain inhibition that goes on with these endocannabinoids endogenously.

Chris - So this is presumably quite a big step forward then because you've got something which appears to give opioids a run for their money in terms of how good it is at painkilling but doesn't seem to have any of the negative baggage. The thing is it's one thing to have a molecule in a test tube but a test tube into a needle in a patient's arm or even a pill going down their throat, that's a big hurdle yet isn't it? So you think it's surmountable though, it looks promising.

Susruta - Right, I think it's very promising. I think one of the challenges we have had in the pain field has been to identify targets which, as you pointed out initially, have the potency of the opioids but with the non-addictive potential or the respiratory depression potential. So we have identified a target, the target has been derisked, and the next step is to modify this molecule or a second generation molecule and convert it into a pill. This is definitely doable.