- It didn’t work for me.
- It didn’t harm me.
- It cost me $368 CAD for four months to find out.
Read on for the full story...
I’ve been studying a drug that has been touted for relieving various pains, especially neuropathic pain. It is called palimitoylethanolamide (PEA). PEA (let us now dispense with biochemical names for our own sanity) is not a drug exactly but is a substance made by our bodies. Technically it is a fatty acid. No, it won’t make you fat or give you heartburn if you eat it. It is related to the cannabinoids — those things found in cannabis and made by our bodies — and is important in cell to cell communication.
So the deal with chronic pain these days is that we know the immune system is much more involved than we previously thought. There are two immune cell types that are thought to be invovled — glial cells and mast cells. What are glial cells? They are the most abundant type of cell in the central nervous system by at least 3:1 and maybe as much as 10:1 compared to neurons. If the actual neurons are the aristocracy, the glial cells are the commoners. The neurons get all the fame and attention and go to the coolest parties, but the glial cells really hold all the power and make it possible for the neurons to be so rich in the first place (read The Hunger Games). For example, if you get a tumor in your brain or spinal cord, a glial cell probably went rogue and started it. If your glial cells decided to stop working, all the aristocratic neurons would likely die of starvation. And if you have chronic pain, chances are glial cells are quietly organizing the revolution.
Just like commoners, the glial cells have different functions. The oligodendrocytes are chemical carpenters that wrap certain neurons with a fatty sheath called myelin which is like a slick skin suit on a swimmer — you go faster. Others have sophisticated jobs like the astrocytes which maintain a proper physical and chemical environment for good function and communication of the neurons. At the bottom of this feudal system are the microglia. Some people don’t even consider them to be true glial cells at all, instead giving them the lowly title of macrophage. Basically, garbage men. Microglial cells are resident macrophages in the nervous system. They clean up the garbage that our rich, energy hungry, neurons throw out and also “eat” up dead neurons (cannibalism, gross). An important function indeed, but they don’t like just being slaves to the “rich and fabulous” neurons, so they get up to antics. Sometimes they spike the punch at neurons’ parties by tossing around inflammatory chemicals that get the neurons all wound up and into mischief like chronic pain.
The other cells are mast cells. These are non-resident immune cells that roam around the body like mercenaries for hire and start bossing everyone around when they get excited by an infiltration of filthy invaders, like those barbarians from the North, the bacteria. Like all mercenaries, they have their good and bad sides. They show up and marshall the troops when your skin is cut so the hordes of bacteria waiting to get you can be defeated. But they also get bored when there is nothing going on and get up to hijinks. They show up when pollen gets in your nose and start releasing histamine and other chemicals that make your nose and eyes get juicy and your lungs get tight and wheezy, all, apparantly, in the name of self defence. Even though pollen is harmless. Like adolescents, they seem to like watching us grownups suffer.
When neurons themselves get injured, or when danger signals have been continually bombarding the central nervous system from some other tissue injury, then guess what? Mast cells show up and join their microglial cousins and make the already bad situation worse.
“Well, well boys! Looky what we have here. A bit of a breakdown in the power of the neurons. What say we have a bit of fun?!”
Then they sashay about the place in their barbaric military garb throwing around their devilish chemicals and rusty spears while the toga clad neurons run about the place in confusion and fear muttering, "WTF? Damn working class!” The result is we suffer because the neurons get wound up and hammer even more danger signals to the brain as if there was a lot more tissue damage than there actually is, so we feel even more pain.
Enter PEA. Remember that PEA is a signalling molecule made by neurons and immune cells. PEA naturally inhibits the release of pro-inflammatory chemicals from jacked up mast cells. So when your army of testosterone fuelled mast cells smells blood, or gets bored, and starts rampaging around spiking drinks and getting everyone amped up, PEA comes along like a chill pill and says, “Relax, Dude. You’re so tense. Why don’t you have a soak?”
A lot of our body systems are like this, one part to crank things up, one part to crank things down, always finding the right balance for the given situation. The immune system is supposed to get involved to clean things up, but at the same time be controlled and not run away with itself. Why these natural processes evolved to cause us seemingly unnecessary pain is not well understood. I think of our evolution as a work in progress and chronic pain as an unfortunate side effect of that progress. Hopefully we will evolve ourselves out of it.
If the neurons send more danger signals to the brain because the glial cells and mast cells told them to, then anything that shuts down the microglia and mast cells should do the opposite and relieve pain, right? That’s the theory, or one theory. Taking extra PEA, beyond what your body already makes, might be like calling the cops to come and bust up the party that got out of control.
Because PEA is targeting the root of the pain problem, the very immune cells that make the neurons hyper-excitable in the first place, PEA acts more as a disease modifying agent rather than a symptom modifying agent. That’s if you want to call chronic pain a “disease”.
PEA is not some nutraceutical dreamed up by the holistic health movement that we are to take on faith alone — like shark cartilage, or Cat’s Claw. It has actually been studied in clinical conditions and the results show some promise. One study involved 600 people with sciatica. For three weeks, randomized and blinded, 200 people took placebo, 200 people took 300 mg PEA/day, and 200 took 600 mg PEA/day. There was a significant dose dependent response in the PEA group. The 300 mg/day group showed more reduction in pain than the placebo group, and the 600 mg/day group showed more pain reduction than the 300 mg/day group.
The response was very good as the number needed to treat (NNT) for 50% pain relief in the 600 mg/day group was only 1.5. In other words you only need to treat, on average, 1.5 people with sciatica with 600 mg PEA/day for 1 person to get 50% pain relief. That’s unheard of in the pain world! The best we have otherwise is amitriptyline with NNT of between 2 and 3 for neuropathic pain.
I’m a little skeptical when I see results like this since it is only one such study. Most treatments have a decline in the size of the effect as more and more studies are added and I expect PEA will be no different. It doesn’t mean it will work for everything and it may never work this well again in other studies in same groups of people.
In another study of 600 people with various types of pain (sciatica, arthritis, shingles, cancer, diabetic neuropathy) PEA treatment of 1200 mg/day for three weeks followed by 600 mg/day for four weeks showed the average pain score across all groups decreased from 6.4/10 before treatment to 2.5/10 after treatment! That is a remarkable reduction of 60% and again is unheard of in the pain world so I remain skeptical of the result until it is repeated by different research groups. This was an observational study so there was no blinding. People knew there were taking PEA and there was no control group. Observational studies like this commonly show a greater effect size than randomized and blinded studies with control groups.
It also didn’t matter which pain condition was being treated — they all benefited. That could be another reason to be skeptical, as it is rarely the case that a pain treatment works on every kind of condition. Alternatively, it could be that the way PEA works is far enough upstream in the danger system physiology that it is common to most chronic pain conditions.
A trial of 1...
All of my reading gave me enough evidence to give it a try for my own neuropathic pain. I ordered enough from RS4 Supplements in Europe for four months. It came directly to my house by Fedex. No customs or Health Canada issues to deal with. For the first two months I took one 400 mg capsule three times a day (1200 mg/day). I kept track of my pain scores on a pain tracking app on my phone. I kept track of the medication I normally use (gabapentin, baclofen and sometimes ibuprofen) also on the app. I kept track of any side effects in a journal.
Over two months basically nothing happened. My neuropathic pain, which is quite variable day to day, essentially stayed the same. I used the same amount of medication, and I didn’t feel any side effects at all.
I increased the dose to 2000 mg/day for another six weeks. Unfortunately, nothing happened. So I’ve stopped it. My pain did not get worse after I stopped it.
Does that mean PEA doesn’t work? No. It just doesn’t work in me. I was disappointed because I wanted it to work. Of course this is why a single story like mine, called anecdotal evidence, can be very misleading. Bias creeps in because we want or don’t want something to work. Maybe we have fears, or heard somebody else say something about it, and all of that can influence how we report our pain symptoms. So take my story with a grain of salt.
Another possibility is that the mechanisms generating the danger signals going to my brain could be different. I have a spinal cord injury. It’s not that commonly studied in big pain trials. The patients in these trials had sciatica, diabetic neuropathy, and shingles, among other things. They likely have different mechanisms than central nervous system injury.
Maybe it has something to do with genetics? Maybe it has something to do with the fact I was injured 20 years ago? Maybe this kind of therapy works better early in acute pain that is evolving into chronic pain? We don’t know the answers.
I will continue to monitor the research and continue to discuss the consideration of a trial with my patients. I think there is some merit to consider it for neuropathic pain. From what I can see the downsides of a trial are that it will cost about $200 for two months of time for a trial. There may be unknown side effects or drug interactions but so far that has not shown up in the research. If you do consider a trial please discuss it with your health care professional first.
We need to keep finding ways to control the negative effects of immune system stimulation! If you’ve tried PEA, let me know your experience in the comments. If you have questions, please ask.