• Louise H Connolly MD

NMDA Receptor: The Drugs



NMDA receptor antagonist drugs definitely have a place in controlling chronic pain. But my goodness, we haven't found the right one yet! Maybe a combination of supplements and one of the drugs listed below can help you out. All target decreasing brain inflammation by calming down your microglia, decreasing NMDA signaling, and/or blocking glutamate release.

Any damage to brain cells, inflammation, infection, trauma, causes the neurons to release glutamate. So I will include in this post drugs which can decrease brain inflammation as well as drugs which inhibit glutamate release. Glutamate is the primary excitatory messenger in the brain. When glutaminergic transmission gets too high, it causes uncontrollable seizures. Therefore seizure medications and the general anesthetics used to break a seizure have a role here. Since inflammation and infection trigger glutamate release, one generic antibiotic which does more than kill bacteria may help. Now NMDA is a calcium channel. Therefore calcium channel blockers may be of use. Furthermore, when we look at the specific type of calcium channel, NMDA is an "N" type channel. N type calcium channels are highly concentrated in the brain and are the primary type of calcium channel specific to controlling pain signals. Of the "N" type calcium channels, NMDA is the only one which requires glycine to co-activate it.


Doxycycline:


What! Isn't that just an antibiotic? Yes it is, but it's much more.

It's used to treat everything from acne to sarcoidosis, aortic aneurysms, to autoimmune diseases. It targets multiple secondary injury systems in our bodies and readily crosses the blood brain barrier. Amazingly it is structurally similar to PCP, a psychedelic and a strong NMDA receptor antagonist. Doxycycline can inhibit microglial inflammation, dampening inflammatory cytokines, metalloprotinases, and hydrolases. (Whatever they are) None of these is related to its antibiotic activity.


Dextromethorphan:


This is a common cough suppressant found in Robitussin DM. It has dual action at both blocking NMDA and activating endorphins. In one study it led to a 30% decrease in pain but the effects lasted for only a few hours. It also had side effects of dizziness and drowiness. Perhaps it could be helpful as a sleep aide when pain interferes with sleep. Some people metabolize it slowly and could get more lasting rest. Others can't.

I like Robitussin DM especially because it combines dextromethorphan with guifenisen, which has been popularized by Dr St Armand for the treatment of fibromyalgia. Of course the OTC dose is quite low. Going higher should be under a doctor's care.

Another NMDA receptor blocker in this class is Antazadine, an old fashioned antihistamine found in nasal sprays and eye drops.


Carvedilol:


This is a more modern version of propranolol, a blood pressure drug used to slow heart rate, steady hand tremor, and help nervous public speakers. It not only slows heart rate (alpha and beta blocker), it acts as a calcium channel blocker and an allosteric receptor NMDA antagonist. It is also neuroprotective. If you tend to be anxious and manic, this one may help.

Now carvedilol is primarily a beta blocker, but it's action in this case is as a calcium channel blocker. This class of drugs was developed to lower blood pressure. And indeed, the original calcium channel blocker, magnesium, lowers blood pressure as well. Later we figured out that there are a different types of calcium channels. L lowers blood pressure, N and P decrease pain. N and P type calcium channels are concentrated in the parts of the brain which control pain, L type are on the blood vessels themselves. Each calcium channel blocker is a little different in it's sites of action. So if one doesn't work, or lowers your blood pressure too much, try another in a slightly different class.

How effective can N type calcium channel blockers be for chronic pain? How do I know that I'm on the right path to give you pain relief when everybody else just prescribes Percocet or Demerol? Because an N type calcium channel blocker is used for those in whom all narcotics fail. It's called Ziconamide. But unfortunately it has to be injected directly into the cerebral spinal fluid. No thanks!


Cardiazem:


Yes, cardiazem lowers blood pressure. But its main activity is NOT through the L type channel. And it certainly has activity on numerous different calcium channels in the brain including NMDA. It's been used off label for cluster headache prevention and research is ongoing for migraines as well. It stimulates endorphin release and decreases cravings. I like its profile for those with occasional high blood pressure readings.


Memantine:


This is one of my favorites! It only blocks NMDA receptor activity when the channel is excessively open. And it doesn't stay there long. Thus it doesn't disrupt normal NMDA activity. Therefore it is well tolerated with few side effects. In addition, as an N and P type calcium channel blocker, it can block presynaptic glutamate release. It's been used with success for migraines, TMJ, as well as fibromyalgia.

Memantine was originally developed for Alzheimers disease but failed to help much. (Alzheimers may be an inflammatory disease, but it is NOT a pain syndrome!) Still, if you have a bit of brain fog associated with your migraine or TMJ, you may want to try it.

Two other calcium channel blockers you can try are verapamil and nifedipine both have been used successfully for chronic pain and also lower blood pressure.


Lamictal:


Lamictal is primarily used to treat seizure disorders and as a mood stabilizer. It has multiple mechanisms of action including N type calcium channel blockade. It blocks glutamate release from the presynaptic neuron, thus inhibiting NMDA activity indirectly. This drug may be of use to you if you suffer both from a central sensitivity syndrome and depression. But it needs to be carefully monitored. Another anti-seizure medication which blocks glutamate is topamax.


Gabapentin:


Gabapentin (Neurontin) also inhibits the influx of calcium into nerve cells in the brain. In addition it helps dispose of excess glutamate by turning it into GABA, a relaxing neurotransmitter. It binds to the allosteric NMDA receptor. Gabapentin is sedating and should be taken at night. Start with a low dose. Gabapentin binds to yet another "pain" receptor we've mentioned. What type? You guessed it. It's a P type calcium channel blocker.


Ketamine:


IV treatments for everything from hangovers to nutritional deficiencies are springing up all over the place. So no wonder illicit IV ketamine clinics are appearing as well. Ketamine is the strongest NMDA receptor antagonist known and has been used as an adjunct to general anesthesia for years. It's another old tired drug with new a application. This drug binds the NMDA receptor tight and just won't let go. "Burst" IV ketamine can help those with major depression when nothing else works. It also works for intractable pain resistant to strong opioid narcotics. The beneficial effects of ketamine are very rapid. They are observed within hours and last up to one week. Almost a miracle!

Unfortunately this relief doesn't come without a price. Hallucinations, out of body unpleasant sensations, lightheadedness, fatigue and nightmares head the list. I look at ketamine as a "proof of concept" drug. NMDA antagonists work for pain and depression! We just haven't found the right one yet.


There you have it. A bewildering display of diverse drugs for itchy eyes, nasal congestion, and cough. (Eyes, nose, and throat are our direct connections to the brain.) Then a broad class of calcium channel blockers originally created to lower blood pressure. Only later they were found to block different types of calcium channels. Then we have some atypical anti-seizure medications. Then a failed Alzheimer medication which is one of the best. Finally an IV anesthetic with tons of side effects. If that's not invasive enough, how about that drug injected directly into the brain's cerebral spinal fluid! OK, pick your poison. Or don't. Supplements were made to be supplemental. Drugs are for dessert. You probably should skip dessert if possible. But pain is a multi-headed beast and you need to get on with your life. I'd try a combination formula specific to your situation, starting with the supplements, blocking different receptors, working up through the list.

LHC MD


#centralsensitivity #pain #NMDA

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