Red Rover, Red Rover, send Calcium Right Over

It is unlikely that the average person with central pain cares about WHERE the burning is coming from, but in the end, the locus of activity tells us what drugs should rationally have benefit.

Twenty years ago, it was de rigeur to test all those CLAIMING to have Central Pain with infusions of local anesthetics. Hey, dental pain is bad, and so if stops that, then why shouldn’t it stop Central Pain. Not especially rational, but it seemed like a good idea at the time. Lidocaine was the local anesthetic of choice, although bupivicaine is used more now because it is so common in epidural blocks. What did this really prove? Well, it is hard to say. In some ways they were more trying to learn about CP than to cure it. If IV Lidocaine stopped the pain, what did that prove? Hard to say. IF IV lidocaine did NOT stop the pain, what did that prove? Just as hard to say. So why run the test. Well, they were trying to learn about it. One thing they did learn was that if you give enough lidocaine to stop the pain, ie. to cross the blood brain barrier, you would kill the patient. This was actually already known before the pain clinics began giving the IV infusions, but it never hurts to check.

Since the development of animal models of central pain, the rigorous testing for malingering and hysteria have kind of vanished. It is just too silly to say we need a multidisciplinary group to tell us if CP actually exists. The Flat Earth Pain Society is definitely out of fashion. There are just too many rats crawling around in cages, hoping not to be touched, not to be stroked, not to be placed on warm surfaces, and hoping not to move (AND chewing off their legs to get rid of the dysesthetic burning) for the old time religion of doubt. This is at least true among pain researchers. Grudgingly, they have quit doing idle ceremonies like making “ANALOG” pain diaries (a fancy name for rating your pain from one to ten) and conducting intense psychiatric evaluations to extract the psychos. Now that we know so much about central pain and how common it is after cord injury, stroke, and MS, it is funny how the role of the psychiatrist has diminished.

Back when the psychiatrist could rule people out, they were at the center of pain evaluations. Now that only a few diehards disbelieve Central Pain, and their role has become to counsel and help the patient, they have sometimes evaporated from the clinic. Now that the way our mothers treated us, our birth order doesn’t correlate, and Worker’s Compensation is essentially abolished so they cannot speak any more their outlandish identification of “Secondary Gain” (the traditional pain clinic witch hunt) and nearly everything psychological is, to say the least, irrelevant to whether or not we have pain kinases in the DRG, the psychiatrists have abandoned us.

We demand help. They cannot just disappear into the night and pretend they never brutalized and accused us. Since they were dead wrong, now they have to make up for it by comforting us, helping us find coping strategies. Our families need counseling and to know what to expect and what NOT to expect. Sad thing is, Central Pain is just so severe, they really don’t know how to do this except by snockering us out of our heads with medication. What happened to psychotherapy?

Anyway, the day of the Psychiatric Inquisition is gone, but so far, we haven’t seen much rational psychiatry to replace it. There is just too much lag time in the Psych residencies to get them to study biology over psychology. It was so much easier to fit people with the white coats with long sleeves that buckle in back than to work out the nearly impossible issues with severe unbearable pain. The Pain Clinic Police are having a hard time becoming Pain Clinic Chaplains.

What about the lidocaine infusions? So far, nowhere in the literature, do we find anything to justify all those “tests” that gave us hope, cost a lot of money, but never seemed to go anywhere. However, bupivicaine in rats is going great guns. The reason is that scientists really NEED to know WHERE molecules are working.

From prior articles here, you know that presynaptic activity leads to Calcium 2+ flow, which awakens glutamate, which explodes NMDA and its receptors. Calcium can travel across the membrane on the other side of the synapse through several routes. One is the voltage gated ion channels (ionotrophic). Another is the ion channels which open which chemicals bind to them (metabotrophic). There is even a direct Calcium crossover in what is called “ionophore” fashion. Each of these calium currents, including especially the calcium/sodium exchange channels (which is blocked by BDNF, leading to way too much calcium inside the cell. You would not be far wrong by saying that too much calcium is behind the creation of hypersensitivity (sort of “lockjaw” at the cellular level). ERK matters relate primarily to what is happening OUTSIDE THE CELL. BDNF is a growth factor which is manufactured by activity occuring inside the cell, but acts AT THE MEMBRANE.

Coull has also shown that the lack of chloride prevents the balance in a cell, eliminates inhibitory feedback that would like to form, and makes ALL firing by pain nerves excitatory. If we were trying to stop this last step, we would want something that binds to the membrane.

If we conclude central pain is primarily based on extracellular events then we look hard at p38 ERK, which is extracellular receptor activated kinase which is phosphorylated at the 38 position (p38 ERK), then we really want to focus on extracellular events. It is clear enough that pERK is going bananas in central pain, but is that the primary step?

Many scientists would say “no” to pERK as the primary thing. The reason is that there is a huge amount of evidence that the genes are completely messed up by CP. Genes, by the way, are INSIDE the cell, so perhaps the focus should be there. Now what do we find inside the cell. In addition to boxcar loads of messenger RNA for pain chemicals, what we mostly find is Protein Kinase C (PKC). This little demon might actually be the evil which stalks us, or at least the DNA coding for it.

It was discovered that PKC knockout rats cannot get central pain. PKC is INSIDE the cell. The interest in PKC roused once again the scientists’ interest in what was INSIDE, what was within the membrane, and what was OUTSIDE. This has caused a renaissance in local anesthetic study. An example is the work by Yanagidate and Stricharz in Anesthesiology. 2006 Apr;104(4):805-814.

What they found is that pERK sensitive cells in the dorsal horn could be blocked by bupivicaine, as were the ionotrophic glutamate receptors. However, the metabotrophic receptors for glutamate and substance P were not sensitive to bupivicaine. Most significant. the INTRACELLULAR Protein Kinase C, which is currently the leading suspect for the crime of central pain, is NOT reduced by bupivicaine. Since IV Lidocaine should, but does NOT stop central pain, these studies suggest why. Bupivicaine doesn’t do squat for Protein Kinase C, nor the metabotrophic glutamate receptors. This should come as a surprise to everyone, and a relief to those poor souls who got IV Lidocaine infusions for their CP and greatly disappointed the pain clinic people when they indicated it did nothing for their pain.

It was all so confusing back then, but as usual, the patient turns out to be right. Isn’t this the way it always goes. When the patient simply does not conform to existing theory, instead of opening the trap door to the psychiatrist’s lair, clinicians should rethink existing theory. If you go to enough pain meetings and listen to people laboring under the same misconception you are, it is amazing how durable these myths can be. The Wall/McHenry database had disproved lidocaine for CP as early as 1994, but now we have good company, and even some researchers to tell us why. In the past, it was not uncommon for doctors to say, “If you claim to have pain, why isn’t it relieved by lidocaine?” The not too subtle accusation was that the CP patient was faking. For the privilege of being called a fake, we generally were billed about six hundred dollars for the IV infusion. We also passed “GO”, failed to collect money, and went directly to the psychiatrist.

Once again, we invite clinicians to believe the patient. It saves so much wasted time. Doctors will just have to get used to the idea that they are not really there yet on Central Pain, and go back to the drawing boards and find something that actually works. Right now, the most promising candidates are the new oral N-type calcium channel blockers, but they are still in clinical trials. If you live in a city where these trials are being conducted, maybe you should check it out. Merck is the company to ask about NMED-160. If the feds realize patients are really suffering over pain, without any help from opiates, then maybe they will accelerate the trials, maybe even make it an orphan drug, with fast track approval.

If you are getting help from opiates, more power to you, but it may just be sedating you or treating non-neuropathic pain. This is less than what we want, a specific for nerve injury pain, nothing less.