Central Pain: Time is Not on Our Side, by Robert Reese and Janet Frank

Nerve repair is simply unlike repair elsewhere in the body. Much of it in the CNS seems aimed at eliminating and culling out the defective or injured nerves, accompanied by a bizarre and futile attempt by the glia to regenerate neurons by turning on genes haphazardly. It is as if something present in early living organisms, such as birds or fish, is missing in man, making human glial cells unable to repair damage. What goes on is not repair at all, but rather weakening and eventual death of more neurons. Peripheral nerves can repair by regrowing along the axon sheath which remains, but in the brain and cord, so far the news is all bad. Our brains can be repaired, but we must do it cognitively because Nature did not include this in the automatic repair mechanisms.


Injured pain neurons die gradually, sometimes over many years, but they do not go easily. Even after death, they continue to cause suffering.

In a previous article, we pointed out that recent investigations indicate that not only injured but DEAD neurons as well seems capable of inducing tyrosine kinases and Nav ion channels which would be expected to maintain pain. We also pointed out that at least two of the four required aspects of inflammation have been demonstrated and the other two are highly suspected to be present. In other words, once injury is set off in the nervous system, it tends to be self perpetuating. Many investigations, both clinical and experimental, point to this as a fact, but finally declaring it proven has been slow.

As listed prior, the four requirements for inflammation, which implies a number of related processes, are dolor (Latin for “pain), calor (Latin for temperature, or warmth), rubor (Latin for redness) and tumor (Latin for “swelling”) Dolor, Rubor, Calor, Tumor have been taught to medical students to define inflammation.

Dolor.In nerve injury, pain, or dolor, is of course common and is the entire focus of this site. The brain and cord are themselves not capable of perceiving pain, but the artificially generated pain qualifies.
Rubor. Redness is blocked by the layers of the body, but redness can be presumed from any increased blood flow to an area, be it skin or be it cortex, so the rubor is satisfied as well.
Calor. Increased blood flow cannot normally happen without some warming to the area, so calor can be presumed from the functional MRI and PET scans which show increased blood flow and increased oxygen extraction (oxgyen use) in certain areas of the brain related to pain.
Tumor. Similarly, if one had exquisitely sensitive instruments, the same brain imaging should reveal slight swelling where blood has increased, since fluid from blood leaks out slightly through the vessel wall, which is permeable and responds to any increased pressure by slight leakage of fluid.

Let us assume then that the brain is inflammed in central pain. What does inflammation mean in the brain, or in any other part of the nervous system? Typically it means release of certain chemicals, including cytokines, which induce inflammatory cells, including mast cells, to migrate to the area. If infection were present, white cells would also be drawn, but infection has not been identified as part of central pain so that part is omitted in consideration of central pain inflammation. The brain is certainly capable of infection, but that is not the process which is under discussion in central pain.

Historically, the evidence for progressive damage to a nerve injured site is relatively recent. It came first from clinical stories of divers. The scenario went like this. Divers tend to be extremely atheletic and fit individuals. The big international diving firms hire teams for diverse underwater work, such as maintaining drilling rigs, to undersea exploration. Because nitrogen bubbles in the blood are under great pressure deep under the water, ascent from the deep is dangerous. It must be done slowly to allow the nitrogen to absorb chemically into the blood, rather than gather and form bubbles, which of course, do not provide oxygen and which damage nervous tissue. Divers injured from the “bends” or decompression incidents, often have little training in other areas and apply for worker’s compendsation benefits rapidly in order to live.

Many countries where companies are not shielded by worker’s comp as found in the U.S. permit open civil suits against negligent dive operators. Dive companies learned it was to their advantage to try these cases as rapidly as possible, since TIME caused further deterioration. Around 1985 studies began to be published of the deterioration over time in injured divers. Healthy men, robust and vigorous who experienced dive accidents could hardly walk, lacked strength, and were “different” mentally. It was a scandal of course. The area of expertise is very limited in the medical profession with few doctors “qualified” to testify and nearly all of them either on retainer as professional witnesses for the dive companies, or else ignorant of the progressive nature of dive injury.

Around the mid eighties articles in the neurologic literature began to report the ongoing deterioration in injured divers, mainly because they could not work again. At the initial incident, the diver would be placed in a decompression chamber, often onboard a large diving vessel, then flown to a better one at a specialized location, usually receiving increased oxygen pressure or hyperbaric oxygen.

There was an initial improvement from the nitrogen bubbles, at which time in serious cases, companies settled quickly for modest amounts, knowing privately that worse things lay ahead, perhaps five years down the road. Some divers seemed to recover from incidents which put others down. There was individual variation in resistance to injury, although most divers could look forward to progressive neurological worsening. Nitrogen was not the whole picture.

The behavior of an injured neuron was at issue, and all the evidence began to point to progression, to the never healing, deteriorating, and dying neuron. This was the real beginning of the realization of how profoundly delicate neurons are and how prone to get worse. Testimony on this was corrupted by the large fees paid to “experts” in court, the whores of court always enjoying a good living and fine circumstances. They created credentials of their own, and juries knew nothing of the real power and money behind credentialing agencies, namely the big corporate interests. It is possible to become “Certified” by an “American Board” of disability by paying a fee and taking a one week course, but the group exclusively testifies for industry that their workers are NOT disabled. This is ironic, specialists in disability are certified only to say that the person is not disabled. We need not rehearse what such experts predicted in the future for nerve injured parties, if they could not acknowledge present injury.

Little has changed in this area, with pain as a disability being disallowed because only “objective evidence” may be heard in court. If pain can never be objective, why do courts routinely award huge punitive damages for pain and suffering. Why is pain a huge factor once injury is found, but not eligible as an injury in itself. It makes no sense. Jurists accept junk science, right on up to the Supreme Court. The NIH is freely available to them, with top experts. Judges have the right to order unbiased experts to appear and give opinions but this option is virtually NEVER exercised. This is a real shame. Eclectic articles of marginal validity or outdated concepts continue to appear in appellate opinions as if they represented serious medical investigation.

Even if expected worsening was acknowledged by experienced companies, they did not want to pay the increased insurance rates which serious injuries would produce. Then over time, the diver would find himself going downhill with no particular explanation. Some of the early clinicians began to suspect there was some factor in nerve which caused progressive damage. They had no idea what these factors were. Then, Dr. Marshall Devor, discovered that injured nerves release factors into the immediate environment which cause uninjured neighbor nerves to begin firing. Research has ultimately shown that these factors are kinases, growth factors, and cytokines, including the interleukins.

Tarek Samad looked for and found interleukins in the thalamus of animals with central pain. Now we have studies by Fitzgerald, Lawson, and many others which leave no doubt that genes in the glia which surround neurons, pour out the chemicals of inflammation when nerves are injured, even if they are dead. The conclusion seems to be that nerves do NOT heal like other tissue. In fact, they do a very poor job of healing, so poor that the most likely scenario is to continue damaging themselves, and even to damage neighbor neurons over time. What do you do with a tissue that once it is injured, makes certain that those around it suffer an equal fate. How did such a crummy healing process, if it can be called that, find its way into the human organism. What possible function could it serve. Aversive learning is one possibility, but that seems a pathetically poor reason for nature to gang up like sharks in a feeding frenzy on the poor injured neuron and its friends. Nerves are nourished in a very odd way in the brain. Blood vessels are usually very far distant.

Nutrients flow through the cells via small pores, so that nutrition and even oxygenation is more like water soaking through a sponge than like blood flowing through vessels, although it is not osmosis which moves nutrients to cells, it is the odd behavior of their membranes and the “cave river” system which exists in the labyrinthine channels which go from cell to cell. An injured cell can become the weakest link and break the chain for many cells. This process seems fundamentally at work in aging, with some much more vulnerable to the effects than others, due to genetic predisposition. Protein structure and composition is inherited, and some durable octagenarians are simply more fortunate. Their proteins don’t clog up the nutrient courseways of the brain so rapidly.

So what about injured divers, and what about nerve injury of any sort. What is going on with injured nerves and what can be done about it. Well, for one thing, cytokine inhibitors have now been developed. We have received anecdotal reports that morphine pain pumps implanted to communicate with the spinal fluid, may have greater effect if clonidine, an alpha 2 adrenergic blocker. is added to the morphine.

There is also an interesting study by Romero-Sandoval and Eisenach at Wake Forest (See Anesthesiology. 2006 Feb;104(2):351-355) showing that Clonidine may reduce mechanical hypersensitivity and cytokine production in EXISTING nerve injury. The cytokines released in this model of peripheral nerve injury were interleukin 6 and interleukin 1 beta (see discussions of the interleukins elsewhere at this site using SEARCH). Basically, cytokines are one of the synergistic group of acidifiers which lead to perineural acidosis in nerve injury. Acidosis may be presumed to induce inflammatory changes. The cytokines are thought to be released via the action of alpha2 adrenoreceptors (part of the autonomic or unconscious nervous system).

Studies in this area have tremendous implications as to aging, but of course, any study of nerve deterioration and damage will have direct benefits in the study of nerve injury pain, where continued release of acidifying cytokines and growth factors is necessary to maintain central pain. Over time, CP sufferers probably suffer deterioration more rapidly in areas such as memory and cognitive function. Neurons go slowly, but they go. The question is, why doesn’t the pain go away or may even worsen. The answer is probably that the growth factors trying to accomplish repair backfire and utilize whatever brain cells remain to perpetuate the pain state.

We are intrigued by the more than expected instances of those with syringomyelia who have improvement or even elimination of their central pain, and also their apparent greater likelihood of responding to implanted morphine pumps.

We recently reviewed an article here claiming that syringomyelics (increased size of canal carrying spinal fluid in the MIDDLE of the cord) have unique injury to the spinothalamic tracts, but we pointed out the weaknesses in that as a sole explanation. We also are aware of the caution by Dr. Marshall Devor that too many orphan proteins (proteins discovered in pain neurons by genome studies, but whose function remains unknown) exist in pain areas to conclude we know all about the chemical processes. Dr. Devor thinks we have been too quick to jump entirely and without reservation on the inflammation bandwagon, (BDNF from the microglia being the current darling of researchers), and that we must await further study on the orphan pain proteins which will surely be forthcoming in the next few years, before we decide we have central pain in our hip pocket.

And of course, there are still those so far behind as to lack even basic knowledge about the cascade of pain chemistry even to believe that central pain exists, or that if it exists, it is severe; but this group of benighted nincompoops is growing smaller by the day. It is just too easy to create CP in rats, dogs, monkeys, etc. and to measure the huge outpouring of pain chemicals in their dorsal root ganglia with commercially available proteomics gel columns. Since these are the same chemicals which pour out in ordinary pain, it is beyond silly to declare that they would not act as pain chemicals in patients with nerve injury. Proven alterations in gene expression in nerve injury cannot be ignored. They mean something. They mean a great deal. They mean suffering.

A neurosurgeon who was trained forty years ago may still speak of the “myth” of central pain, but science is making clear that what is mythological is his expertise, no matter how good he looks and sounds in court. The credentials of such people are ZERO. Real scientists know only too well the discouraging tendency of injured neurons to deteriorate. We hope soon to be able to kill and extinguish injured nociceptor cells (see prior post on Lawson’s work) so that the glia which remain will quit torturing the poor central pain patient. Stem cell work even suggests that healthy new neurons may be able to be placed in such areas once they have been “sterilized” of injured neurons which refuse to quit kicking out the growth factors and cytokines, which lead to that damnable neuronal acidosis which condemns the CP subject to a life of burning hell.

We are hoping to see stem cell work come on quickly and brilliantly. If we can get the politicians to see it our way, it will all happen. What a foe unnecessary pain has been to mankind. Why it has not previously been a priority is a mystery.