Endogenous opioids: the body's own painkillers

Hi, this is the Chronic Insights podcast, and today's episode should be really, really interesting to anyone who has chronic pain, because we're going to be looking at the body's own natural painkillers, called endogenous opioids, and how they relate to synthetic painkillers like codeine or morphine, why synthetic painkillers just aren't very good at dealing with chronic pain, and what the cutting edge science can tell us about what the future might have in store for better painkillers. So, it's something that I have quite a lot of experience of personally, having taken opioids for decades for my chronic pain, and I'll be explaining opioid tolerance, dependence, and why I eventually stopped taking them on a regular basis. So, lots of really interesting stuff – and just another part of the journey we're taking together to learn more about how our pain works, how the medications we take work, and becoming experts on our own bodies, which I think is a really powerful way to become more empowered over our chronic illness.

As always, there's a link to a transcript of the show in the show notes, along with links to references, articles and scientific papers for further reading.

My name's James Allen, and I have a chronic auto-immune disease causing inflammatory arthritis, chronic pain and fatigue, so if you have a chronic illness too – hi, welcome, I'm glad you stopped by, because – I love being with people who live in the same world that I do, who share the same challenges in life. It's like – camaraderie, it's like – we're brothers and sisters, or old friends, companions in chronic illness.

How are you doing? If you're not doing great today, just remember – that's okay. Just try not to be hard on yourself. Try to have – self compassion. Self-compassion is often misunderstood, I think. It's easy to dismiss it as some kind of, like, narcissistic, you know, thinking only about yourself. Selfishness. This is a misunderstanding, I think. Because when you have chronic illness, one of the most common problems that I see in – myself, and other people who live with chronic pain – is that we're really hard on ourselves. Because we're not lazy, we're not – using our illness as an excuse, but sometimes we can trick ourselves into thinking that – maybe we are. You know? Or maybe that's just me. Maybe it's just me. I do. Sometimes I think, man, James, you're so lazy – when I'm lying in bed because all my joints have been aching – maybe not a lot, like 3 or 4 out of 10, but they've been aching all day. And yesterday. And the day before. And I just don't have the energy to push through it all the time. So – I do the sensible, the only, thing I can do – and have a long, long rest in bed. And sometimes I think – I'm being lazy. What is that? Why do I think that! Well, I think it's just part of being human. Especially when we live in a society that covets work and progress above everything else, it seems, even – our own wellbeing, our own mental health. It's a flaw in our society. That's probably always been there and always will be to some extent, it's just – because we're human and we just have this natural drive to do more, expand, progress.

So, when we talk about self-compassion – we're not talking about narcissism. We're talking about – giving yourself just a little bit of room to breathe, to let go of, perhaps, unrealistic expectations of ourselves, and – recognise that, actually, we're doing an amazing job. We're doing our best with the hand that we're given. And just because it looks like, or feels like, when we're in bed resting, we're actually working – we're working on our fatigue, we're working on our energy levels, we're working on our mental health, we're giving ourselves the headspace we need to be able to live with this really, really hard problem of how to live with our chronic illness.

So, if you need it today, I hope that helps – give yourself a bit more self compassion. Give yourself a hug and a pat on the back, because – you probably need it, and you definitely deserve it.

Thought for the day. I like to start with a bit of a thought for the day, because we all need a bit of help, a bit of encouragement, and to be honest – I do too.

So, just a little app update. I had a review in the Play Store for my symptom diary app Chronic Insights, which wasn't great, it was 2 star – which hurts, I'm not gonna lie, it's like a dagger in my heart – haha, no, it's all good, but like, this app is like – my baby, so, a bad review does actually – it really bums me out, haha.

But the comment on the review at least was constructive. So, the reason they didn't like the app was because you can't add a note when you record a symptom reading. You can add notes, in a separate screen, but you can't add one as you record a reading, so like I suppose if you were recording a symptom like pain and it was particularly high, you couldn't at the same time write a little note to say why, you had to do that separately. So, I thought, yeah, that's a really good point, that would be a really nice feature. So this week, that's what I've been working on, and happy to announce that it's gone live today. So, now when you record a symptom, or a vital reading like, blood pressure for example, or a factor, like – I did some meditation, or your mood – there's now an extra screen to optionally attach a note. And the cool thing is that you can also see those notes in the separate notes screen, and it will show the reading you attached the note to. So if you have a feature you want to see in the app – just email me, and – I might be able to just add it to the app.

And there were a few bug fixes too – there was a little problem with the weather feature, so if you looked at the data table for the weather charts, you might have noticed duplicate values – I made a little mistake with the logic for how the app downloaded weather, so I fixed that – and there was a problem where if you made two readings really quickly, one after the other, and you had the backup feature turned on, it would sometimes just crash the app - because it was trying to backup again before the previous backup had finished, which it didn't like, so I fixed that too. And maybe a couple of other really minor changes which I can't remember right now, and that's it.

So, to today's topic.

And, I just need to start with a short disclaimer. I'm not a doctor, I'm not a pharmacist, I'm not medically trained, and when I'm talking about opioids, I'm not advocating for – using them, or not using them, I'm not intending to provide medical advice. I'm just a guy who lives with chronic pain and who has read a lot of scientific papers on PubMed and articles in publications like New Scientist and Scientific American, sources which I think are reliable and balanced and contain unbiased, scientific facts. And I want to share what I've learned. Because I think – more knowledge is always better than less.

So with that in mind, let's talk about opioids.

In previous episodes, we've talked about special nerve cells, or neurons, that are designed to receive stimulus from our body and from the environment, and to tell our brains about these things that are happening, by sending signals up to the brain. They're our sensory receptors, receptor from the old French and latin 'to hold or contain', or receive, they receive sensory input. And we saw how there are loads of different types of sensory receptor, so there's one for light touch, there's one to detect quick pressure changes and slippage, ones for detecting long touch, like holding something, there's one for vibrations, for stretching and rotating the body, one for heat, one for cold, all sorts. And, there's one for pain, for designed to detect damage to the body, and they're called nociceptors, from latin noci meaning 'hurt'.

And all these sensory neurons, they take all this information and send it up via the spinal cord, up to the thalamus in the brain and on to the cortex where we experience these as sensations, like the sensation of touch, the sensation of vibration, and the sensation of pain. And the route they take is called the ascending pathway, because it goes up, it ascends, to the brain.

But just like we saw last week when we talked about the sympathetic nervous system and the parasympathetic nervous system, which work as opposites, nature has again equipped us with an opposite to the ascending pathway - it's called, unsurprisingly, the descending pathway.

And this is a common theme we keep seeing in nature, and I think it's one of the amazing things about our bodies, it's how these opposite systems work to keep everything in balance, to keep everything homeostatic, homeo from the Greek for 'similar' and static 'to stand still', to keep our bodies in homeostatis. Like, temperature – the body is remarkably good at maintaining our core body temperature at about 37 degrees celcius, and usually only changes up or down by only a few degrees, which is amazing when you think about it – like, despite all the different temperatures we experience, when we go outside, when it's winter, when it's summer, all these changes, and the body somehow – detects these changes, and adjusts all sorts of things to keep things – homeostatic. It's really amazing.

So we've got this descending pathway, going in the opposite direction to the sensory signals going from our pain receptors up to the brain. And this is where we get to learn about another one of those things that, as someone who lives with chronic pain, I just find really fascinating.

There are chemicals which the brain produces, and which can be released in the descending pathway, which can actually reduce pain signals going up to the brain. And some of these chemicals are called opioids.

Amazing, right? The body actually creates opioids. I had no idea. I thought that was an amazing fact to learn. My body creates opioids? Doesn't feel like it!

They're called 'endogenous' opioids, 'endo' meaning 'from within', and 'genous' meaning 'growing', so opioids growing from within our bodies, these endogenous opioids are not the same kind of opioids that you find in painkillers like morphene or codeine. But we'll get onto that.

First, we need to know - what are opioids? An opioid is just a generic name for anything which activates a particular kind of receptor in the body, the opioid receptors. There are 4 main categories of opioid receptors, called 'mu', 'kappa', 'delta', named after letters in the Greek alphabet, and 'nociceptin', there's 'noci' again meaning 'hurt', and there are 4 categories of endogenous opioids which activate them, called endorphins, dynorphins, enkephalins, and nociceptin.

It's not important to remember these names or anything – I mean it's cool to know them – like, 'mu' receptors were named 'mu', or the letter 'M' in english, because Morphine was the first substance found to interact with it – which is interesting, well I find it intersting, but it's more important just to realise that – it's complex, and there isn't just one thing going on in the opioid system, it's a bunch of related but slightly different things going on.

So an opioid is anything which activates an opioid receptor.

What do we mean by activate a receptor? How does that work? I've mentioned this a few times in past episodes, chemicals like neurotransmitters 'activating' or stimulating neurons so that they fire. Well the receptor 'recognises' molecules which have a certain, shape essentially, a certain pattern of atoms in it's molecular structure. And when one of these molecules with a similar enough shape, it binds to the receptor – it fits like a key in a lock – which activates it.

So opioids are just molecules with particular shapes, which fit the locks of these mu, kappa and delta opioid receptors. And endogenous opioids are actually quite large, complex molecules called peptides – which is why they're also called opioid peptides. If you Google peptides and go to images, you'll see – probably a bunch of really large, complex molecular shapes. And if you can imagine bits of these really complex shapes are like a key – you can imagine it slotting into a lock.

So let's go back to that descending pathway in the brain. Just like pain signals go up to the brain, signals can come down the descending pathway from particular parts of the brain. There's a whole bunch of them which might be involved, like the periaqueductal grey matter, the amygdala, the hypothalamus, and they might cause something called the raphe nuclei to release serotonin (which is one of the many neurotransmitters) to send a signal down the spinal cord, where it joins to another neuron via a synapse (a junction between neurons), and this other neuron produces enkephalin, an endogenous opioid. And this neuron synapses with the pain neuron in the ascending pain pathway, and it might stop the pain signal, or at least reduce it. That's just one example of what might happen – the release of the opioid doesn't always happen in the spinal cord. I'm just giving an example to illustrate the general idea.

So if you listened to the episode where we talked about synapses – the whole nervous system is joined together with these synapses, these little junctions between two or more synapses, and we saw how they are essentially gaps between one end of a neuron and another, where normally the electrical impulse can't cross over. Except that there are molecules at the end of these neurons called neurotransmitters, which can jump into the gap and – stimulate the neuron on the other side, so that the signal can carry on. But I mentioned that some neurotransmitters make it more likely that a signal will carry on, but other neurotransmitters, like endogenous opioids (yes, endogenous opiods are also neurotransmitters), and they inhibit the synapse and make it less likely it will carry on, so they act to dampen down and stop signals like pain. Again, it's homeostasis – opposing systems which help to keep things in balance.

Pretty cool.

So this is why the largest and most powerful group of painkillers we have available today are opioids. When we take opioids, we're actually trying to do the same thing that endogenous opioids are doing, using these neurotransmitters to inhibit the passage of pain signals up to the brain.

Unfortunately, as anyone who has chronic pain probably knows, artificial opioid painkillers just don't work very well, at least long term.

At least, that's my experience. I used to take a lot of opioids for my pain. I started on codeine, which helped a bit, for a couple of years, but I had to keep taking more and more of them to have the same effect. So, went to the GP, and was prescribed tramadol. Same thing, worked for a while, then it didn't. And I just went up and up this opioid ladder until I got to MST, which is a type of slow release morphine, and eventually – I was just so screwed up from the side effects, the drowsiness, constipation, nausea – and it didn't even feel like it helped the pain anymore. I mean, a bit, but not enough to justify how bad the side effects had become over time. This was after, maybe, 10 years of taking opioids.

So, luckily my axial spondyloarthritis, I had a good spell when I started on a new medication called infliximab, and I decided to just stop taking them completely. Which was an awful, awful experience, dealing with side effects as I weaned myself off them over several months, and at the end when I stopped completely I think I went for 2 or 3 weeks where I barely slept at all because I was just so fidgety and on edge, and itchy I remember, it was just awful. But I eventually got through it, and now I just try to manage without painkillers, except during bad flareups.

So for me, they just aren't helpful, because my pain is always there, and it probably will always be there to some extent. So why are they so bad long term?

Well one of the probems is that, at least currently, synthetic opioids like tramadol are like sledgehammers. The natural endogenous system is like an artists brush, carefully releasing small quantities of opioids in just in specific places all around the body in this carefully balanced system that has evolved over millions of years. But we can't do that with a tablet. At least not today. Opioid tablets basically just flood the system with opioids which activate opioid receptors all over the body in large quantities. It's a sledgehammer. And so the effects are way stronger than endogenous.

And one of the side effects is that, the body sees this, and – it wants to restore the balance. So one thing that happens is tolerance, which is different from dependence, and dependence is different from addiction, but they're often confused or lumped together. Tolerance is when you need more and more opioid to have the same effect. The body is doing what it does really well – it's adapting to this sledgehammer that you're throwing at it, meaning it reacts less and less. And it can even start producing less of it's own endogenous opioids, because it thinks – well I don't need this anymore, there's tons of opioids here, why do I need to produce more? Which is really bad, because then when we stop, we can end up feeling more pain than we did in the first place – making it more likely we won't stop. That's called 'opioid induced hyperalgesia': so, 'algos' is from the Greek meaning 'pain', and 'algesia' meaning 'sensitivity to pain', and finally 'hyper' meaning 'more or higher', so hyperalgesia is increased sensitivity to pain.

Dependence is slightly different to tolerance. We haven't mentioned this yet, but the opiod system, opioid receptors – are not only related to pain, they actually do a whole bunch of other things aswell: the feeling of reward (which is why we can get addicted to opioids), stress, breathing, the heart, the gastrointestinal tract. So, taking opioids can affect all these things, not just pain, which is why there are so many side effects, like constipation for example. And the body will slowly adapt to these changes, so when you stop taking opioids, all these adaptions the body has made to oppose the effect of opioids – now have nothing to oppose, so they send everything off kilter, like a seesaw with noone on the other end. And this is what dependence is: when your body starts to react negatively to stopping, which is called withdrawl.

And that's not necessarily addiction – you can have physical dependence on opioids but not be addicted. I was lucky that I didn't get addicted, and I think there were a couple of reasons – I wasn't taking them recreationally, I was taking them because I was in a lot of pain, and they helped just restore me to slightly more – normal. So, I never really felt 'high', I just felt – a bit less pain. And I never really liked the feeling, it always made me feel slightly sick, slightly itchy, and it just felt a bit weird. So, I ended up with massive dependence after 10 years, and massive withdrawl when I tried to stop - but I wasn't psychologically addicted. I feel lucky, because – obviously dependence and addiction are super related, withdrawl just adds another reason not to stop taking them, and it's a really powerful one. But luckily, homeostasis does go both ways – eventually, the body will readapt, just like it adapted before, so withdrawal does eventually end. But if you're psychologically addicted? That must be really hard. I just can't imagine how hard that must be.

So, they're a bit rubbish, really, painkillers – at least long term. Short term they're very useful. But for chronic pain – not so much, in my opinion.

But – there is hope. Let's end on a positive note. It's actually kind of crazy that we don't have a better solution, isn't it? That opioids are our best medicaton for pain, and yet – they have all these massive problems. One of the reasons for that is – the opioid system, and the whole nervous system, is so unbelievably complex. And we don't fully understand how it all works yet. For example, those opioid receptors, the lock and key – the shapes that opioid receptors latch onto – those shapes, are very complex, and we don't undertstand them fully yet, or what other molecules, other drugs, might be useful in stimulating them, so there's a lot left to be discovered.

An example is this idea that maybe we can find new drugs which just activate the pain suppression part of the opioiod system, and not the other parts connected to, for example, the reward mechanism or breathing, so maybe we can develop a drug which has the benefits but not the side effects like addiction.

And they're exploring these possibilities using computer modelling – by testing on a computer what molecular shapes might fit into those opioid receptors. And that's an area which, it turns out, AI is really really good at, and it might really turbocharge the number of new drugs that can be discovered in a shorter amount of time.

And there's even research into completely different things like bacterial toxins – yeah, sounds – a bit funky, right? But apparently certain bacteria can activate and suppress nociceptors. And so there was a study in 2022 into Bacillus anthracis, which is the bacteria which causes – anthrax – so yeah, sounds really scary, but – that's nature, you find solutions and medicines in the most unlikely places sometimes, and this study showed that it can indeed block pain signals. So, maybe in the future we'll develop a new medicine derived from microbes.

There's also research into the genetics of pain. There's already a couple of genes been identified which play a role in transmitting pain signals, which might in the future lead to some kind of gene therapy – I mean, there are people who physically can't feel pain, so geneticists are trying to figure out – why, and can we use that?

Runner's high: the phenomenon that marathon runners sometimes experience: that seems to be caused by the release of certain neurotransmitters after long periods of physical exertion. We used to think it was endorphins (which was one of the endogenous opiods we've been talking about), but more lately we think it's actually more likely to be Endocannabinoids – which are neurotransmitters which stimulate the cannabinoid receptors, the ones which are affected by cannabis.

And cannabis itself, is increasingly becoming more accepted as a possible alternative for some people for long term pain relief.

Norepinephrine, serotonin, those are other parts of the nervous system we haven't even mentioned which also play a role in pain.

So there are loads of different areas of research, and parts of the nervous system, which might end up being the key to solving the holy grail of – a good painkiller which has fewer side effects.

And as we've touched on briefly in other episodes, there's a lot more to pain than just the pain pathway from the body to the brain – the brain itself, our psychology, how we think about pain, our memories of pain, being educated about pain, learning how it works, we know that all these things can affect how we perceive pain and how well we cope with living with it, so painkillers are just one part of the solution, education, meditation, CBT – cognitive behavioural therapy – these are all other parts of the solution, and it's about finding the best combination which helps us, as individuals. Because we're all different, and what helps one person might not help you or me. Which is why I think it's really important that we educate ourselves as much as possible so we can help assemble the most complete toolkit we can to help ourselves.

So, there's hope. There's a lot of hope, I think. A lot of these hopeful topics I'm planning on doing episodes on in the future, because I think they'e really interesting.

And I hope you've found this interesting too. Let me know – feel free to drop me an email, james@chronicinsights.com. That's it for today, remember to check out my symptom diary app, you can find it on the app store, just search for Chronic Insights. I'm off for a rest, look after yourself and remember – self compassion is the key. See you next time spoonies. I love you. Bye.