Your brain can amplify your pain. Here’s how to stop it.

This article is used with permission from the new book, PAIN RELIEF in 4 Simple Steps by Jacob Teitelbaum, MD. If you’re interested in this topic and would like to see all the articles published so far, visit Healing from Chronic Pain, a Multipart Series.

A Key Player in 70% of Chronic Pain and a Major Reason You Are Still in Pain

Central sensitization (brain pain), is a key contributor to chronic pain.

It helps to remember that pain is our body’s way of saying that something needs attention—like the oil light on our car’s dashboard. After a while, if the problem is not taken care of, changes in the brain occur that amplify the pain.

Two key players in this problem are microglial cell and NMDA receptor activation.

Microglial Activation

Microglial activation is a major driver of this brain pain. Microglial cells are like mild-mannered gardeners that fertilize and tend to their garden of brain cells. But just like a gardener, they may start to go wild if they see dangerous pests or weeds. Similarly, microglial cells activate in the presence of certain infections, stresses, injuries, or chronic pain.

This microglial cell activation triggers inflammation in the brain that increases pain sensitivity and amplifies pain. It can even cause a light touch on the skin to hurt (called allodynia). Unless treated, this creates a vicious cycle that both worsens the chronic pain and makes it hard for the pain to go away.
In the beginning, microglial activation can help to eliminate infections and other problems. But with chronic pain, it’s just—well—a pain.

Microglial activation can also cause problems with a key control center in the brain called the hypothalamus. This “circuit” controls sleep, hormones, and a key part of our nervous system called autonomic function.

When this occurs, people may also find that they have a condition called “fibromyalgia with associated POTS.” As this problem progresses, if it gets very severe it can trigger severe sensitivities to both foods and even the environment. This is called mast cell activation syndrome (MCAS).

So, in addition to amplifying the pain, microglial activation can also cause:

• mood problems, such as irritability, depression, and anxiety
• sleep problems, such as fatigue and unrefreshing rest
• cognitive issues
• fatigue
• POTS
• increased allergies and sensitivities
• increased appetite and weight gain (from leptin suppression and hormonal issues)

The good news? We now have several easy ways to help settle down this microglial activation!

PEA: A Superhero Molecule

Just as we have a system that increases microglial activation and inflammation, the body also has a balancing mechanism for settling it down. It does this through a special molecule called PEA (Palmitoylethanolamide).

Both the microglial and mast cells are two key cells that produce PEA. The problem occurs when this molecule gets depleted. That’s when these cells go haywire, triggering chronic pain, and sometimes the other symptoms above, along with hypothalamic control center problems.

What to Do?

It takes about 2–3 months but supplying PEA by mouth can often settle down these cells, along with the pain, sensitivities, discomfort, and fatigue. Improvements then continue to increase over time.

Hundreds of studies are now showing why PEA is helping people feel so much better. It is giving many people back their lives!

The problem? PEA is very difficult for the body to absorb. Fortunately, a new natural compound called Gammasorb may dramatically help absorption, making the PEA even more effective. This enhanced absorption form, which is combined with serratiopeptidase, is what I use in my practice. It is called PEA Healthy Inflammation Response.

This large body of research shows the powerful effectiveness of PEA for virtually all kinds of chronic pain, as well as the other associated issues (e.g., MCAS). The most common dose is 300 mg twice a day on an empty stomach.

In yet another study, and an accompanying three-minute video by the prominent Netherlands pain specialist Prof Jan Keppel Hesselink (which I recommend you watch), he shares his experience using PEA in many thousands of people with severe chronic pain.

His research shows dramatic drops in pain of 60–70%, (on a 10-point scale, pain scores dropped from 7.1 to 2.2!). A 30% drop is considered clinically quite significant.

Since then, he has explored PEA dosing to fine-tune these results. He notes that, in his experience, higher doses often lead to faster or more pronounced responses.

Here is the higher PEA dosing Prof Jan Keppel Hesselink recommends:

1. Start with PEA, 600 mg twice a day. Give it a month, and then increase to 1,200 mg twice a day for 2 months as a fair therapeutic trial. Most often, he sees pain relief beginning at 3 weeks using this higher dosing
2. After 3 months, the dose can be lowered to what’s needed to maintain pain relief.

Many, if not most, PEA products note a 600 mg dose on the bottle. But be aware that it usually takes 2 capsules in most products to get that 600 mg dose.

In a small percentage of people, taking the PEA at night can initially disrupt sleep. If that happens, I give it in the morning and early afternoon. Overall, the PEA usually improves sleep considerably over time, even taken at bedtime.

As symptoms stay settled for 3 months, dosing can often be lowered to 300 mg 1–2 times a day and still maintain the benefits.

This is very exciting new stuff. Please email me at FatigueDoc@gmail.com and let me know your experience with PEA.

Low-Dose Naltrexone (LDN) for Microglial Activation

There is a second treatment that has shown promise for calming microglial activation and supporting immune balance in many autoimmune-related conditions.

Naltrexone is an old prescription medication that has traditionally been used to block the effect of opiates. If somebody comes into the emergency room who has stopped breathing from heroin overdose, doctors give these medications and they typically wake right up.

They also give this medication to heroin addicts to block the high so they won’t take the narcotics. The usual dosing for this is 50–200 mg daily.

So, it was quite a shock when physicians found that tiny doses dramatically helped pain! But when the dose went over 4.5 mg a day, the pain-relieving benefits often disappeared. A common optimal dose seems to be 3 mg a night. But it varies considerably (0.1-15 mg) from person to person.

Put simply, it is reasonable for most people with severe chronic pain, or autoimmune illnesses, to be put on LDN if they are not taking narcotics. There is a large body of both research and clinical experience showing this low-cost medication to be profoundly beneficial for these conditions.

The problem? The medication is off patent and relatively inexpensive, so it is nearly impossible to put through our regulatory process, regardless of the available research. But your physician can prescribe it through any compounding pharmacy. If this were a patentable medication, it likely would have sailed through the full FDA process, cost $24,000 a year instead of $350, and have major pharmaceutical marketing behind it.

The bottom line? Many physicians are only familiar with this medication for its traditional role in blocking the effects of narcotics. But you might be able to talk them into writing you a prescription for 50-mg pills (see below on how to make lower doses) so that you don’t ask for narcotics.

LDN treatment can not only dramatically decrease pain, but it can improve many other symptoms—especially in autoimmune illnesses, fibromyalgia, and CRPS. The way that it works is different from the PEA, making these two treatments wonderfully synergistic.

What else helps central sensitization brain pain?

Treating the source of the pain can also help settle down the brain pain. Which is why I go after each of the key pain components together.

Some of the medications discussed earlier also may somewhat help the central sensitization component—for example, Neurontin, Lyrica, and even opioids. Interestingly, the medications metformin and the antibiotic doxycycline also decrease microglial activation.

But in clinical experience, PEA and LDN are often among the most helpful options for this component of pain.

For Severe and Persistent Pain, Address NMDA Receptor Activation

Our brain contains a wide array of signal chemicals (called neurotransmitters) which are important for cells to communicate with each other. Most of you are familiar with concepts like the serotonin “happiness molecule,” or the dopamine “reward molecule.” Some of these molecules, such as GABA, glycine (in low doses) and cannabinoids tend to be calming.

Other neurotransmitters, such as NMDA, tend to be more stimulating. This can be helpful as it can facilitate learning and recognizing patterns and coincidences. But in chronic pain, it can become markedly overactive and irritate the nerve cells, amplifying pain and even causing depression.

Although some common medications mildly decrease NMDA overstimulation, the effects of these are usually not strong enough to be helpful for severe pain. One medication that has been shown to significantly affect NMDA activity is the anesthetic ketamine. The problem is that this medication routinely triggers hallucinations (it is used as a street drug for this reason), making it harder to use. But lower doses can still have pain relieving effects without the hallucinations.

Ketamine may be helpful for some cases of severe pain that do not respond to other treatments, especially pain like CRPS and severe, treatment-resistant allodynia, where normal touch hurts.
Additional “side benefits” that have been studied include potentially decreasing even severe depression, and possible short-term modulation of pain-signaling pathways.

Another key challenge is the cost, but there are workarounds for this. Unfortunately, insurance will not cover ketamine in most cases. Both the prescription nose spray and the intravenous injections cost about $1,000 every 3-4 weeks of use.

But once somebody has received one or two doses of ketamine under supervision, they can see that the intoxication effect, which lasts a few hours, is comfortable. Then a physician may be able to prescribe compounded nasal ketamine at a markedly lower cost than standard esketamine products. Compounding pharmacies can also make sublingual troches that melt under the tongue. In some cases, low-dose troches (for example, around 10 mg taken 1–3 times daily) may reduce pain with minimal to no intoxicating effects.

Another excellent tool is using ketamine in a topical cream over the area of pain. This minimizes systemic side effects and can be helpful for some people at a much lower cost. It can also be made by compounding pharmacists.

Central Sensitization (Brain Pain) Recipe

While addressing the other root cause of the pain, add in:

• PEA 600 mg twice a day for 1 month, then 1,200 mg twice a day for 2 months. Then you can lower to whatever is needed to maintain the benefit. When offering PEA, I like the PEA Healthy Inflammation Response by Terry Naturally.
• If not on narcotics, I also add prescription LDN.

You’re Invited! Dr. Teitelbaum is now personally answering questions in his new Facebook support group: Recovering from Fibromyalgia, CFS, and Long COVID. The group is also open to anyone dealing with chronic pain or related health challenges. Join the community, ask your questions, and connect with others!