Dark Pain

Dark Pain.

Central Pain is the Dark Pain of suffering. Dark matter is thought to be responsible for the majority of gravitational pull in the universe, yet no one can see or detect it. It is an assumption from elimination and observation of how things operate. Watch a CP rat try to chew of its legs to relieve the distal pain of CP and you draw conclusions pain is there, but you cannot measure it. Actually you can measure it in rats by counting the increase in glia around the dorsal root ganglion cells which transmit pain, by studying neuroinflammatory chemicals and cytokines in the superficial lamina, maybe even by placing delicate probes into the zona incerta of the subthalamic nucleus, but these operations are not possible in the intact human.

You know dark matter is there because of the way things behave in nature, but dark matter is exceedingly difficult to see. In fact, it is not only impossible to see, it is also impossible to detect. Central Pain is not much different. Serious researchers in pain can observe the presence of central pain by the way people (or experimental animals given cord injury) behave, but there is no way to measure it. For that matter, any central pain patient will tell you they are simply using the words they have, but in fact, the physical agony is a new sensation, or perhaps a mix of existing sensations to the point they are unrecognizable.

The ordinary spinal cord injury person, focusing on mobility, is cheered on, or even driven on, to develop as much function as possible.

This is simply an extension of the principles of athletic training. No pain no gain. However, with sensory nerve injury pain, the principle may not hold at all. “No gain in pain” may be the real guiding principle. The question is whether rehab centers can do a one hundred eighty degree turn and advise those confronting central pain to pace themselves carefully, so that they do not become overdrawn on emotional resources. Is it possible to urge more performance on the motor side of things while encouraging avoidance of stress on the sensory/emotional side? It is a challenge, but there must be a realistic awareness that the central pain actually exists, is quite possibly terrible, and like any person in severe pain, some ongoing soothing of feelings is essential, if at all possible. This easing of stress may involve proper education of family members or even of the patients local physician.

The habit of trying to make patients keep moving forward, fighting as it were, can become a habit in medicine. It is not however a universal tool. Pain requires retreat, rest, withdrawal. If one watches a wounded deer, pain is there specifically to cause the animal to hole up somewhere until the pain lessens. Stopping movement and avoiding further injury is in fact the specific message of pain. It makes no sense therefore to assume that when severe pain arrives, the patient is to be “driven”. Ordinary people are permitted to live ordinary lives. Nothing could be further from the truth in central pain. When facing this suffering, the patient is typically told they must be a fighter, must get going, must write a book, must become a “superhero”. This is balderdash and runs counter to the bodies innate reaction to pain.

The same physician, if he does not think, will say that pain is a warning not to use the part to avoid further injury; and, with the other side of the mouth say that if central pain is really, really severe, then it is time to really, really get going, to prevent its immobilizing of the will..

Therefore, conservation of self (thin though the self may be in the identity eroding grip of unbearable pain) is usually the best weapon against pain. Since the injury will not heal, the most logical approach is to modify life so that less stress is coming at the person. This is not easy to do since the patient is trying to describe their plight to others in order to gain help. CP seems too heavy to bear on one’s own. Based on this hope, and a desperate search for some relief, many pain clinics prosper without any real solutions to offer. Their own prosperity is given as support for their efficacy, when in fact it is the severity of the pain, not the potency of the relief which is driving the system.

Most pain clinics fail miserably in treating central pain. This is not their fault because there are no medicines to dispense which accomplish such a thing. They are open for business, but the shelves are empty, yet they are doing a booming business. The irony is all over the operations. What they can accomplish is treating the non central pain, ordinary pain which often follows spinal cord injury. These pains come from the fundamental touchiness of spinal cord segments (C1, C2 etc down to S5) with aberrations in the precise configurations necessary for bending and weight bearing. The body is efficient and in the spine, every little structure has its function. The skeleton can sacrifice in some areas without fouling up every other bony part. The spine, however, is highly integrated. A shift in bearing or position in one area is likely to put abnormal loading on discs. It becomes just a matter of time until remaining discs begin to malfunction, soften, dry out, crack, shrink, herniated or give up. Most spinal surgery is a temporary matter, where pain is concerned. There is hope the new flexible polymers will be able to replace discs and provide the cushioning which has been missing in bone grafts.

There are MANY patients who do well and function happily after a bone graft for disc replacement. However, these happy campers tend to have a SINGLE disc replacement at ONE level without injury or displacement of the lamina, the facet joints or uncus (zygoapophyseal joints). Strangely medicine exists today accepting that the donor graft from the hip can and does often hurt for life, while the area in the spine where a great deal was removed and the hip bone inserted is going to be pain free. This really does not make sense.

For these secondary pains, there is justification for a system to monitor opiates or other meds. To avoid legal complications, many pain clinics refuse to dispense pain meds. This is quite a contradiction in terms. Others are simply unofficial drug store police, who remind one of a hall monitor of opioids. No matter how exacting a pain center is on dosing controlled substances, the perfectionism on record keeping and dosimetry has no influence whatsoever on the ability to help central pain. It is about methodology of compliance with the law and ethics, not about pain relief.

A truly functioning pain clinic would be very much like a social organization, getting the word out to society, organizing charitable fund raisers and in general acting like organizations dedicated to solving a medical problem. Consider, for example, Jerry Lewis and muscular dystrophy. That organization is fundamentally aiming toward research money. Pain clinics generally play no such function.

Some clinics are fundamentally anesthesiology driven. These naturally tend toward blocks of various kinds. There is also the technology of inserting catheters in the epidural space. While most success is about relieving spasticity, there have been some claims of help by steady release of opiates into the spinal area. While the reports on central pain are possibly valid examples of relief of neuropathic pain, the generalized failure of the pumps to stop central pain makes one wonder whether the pain relieved was actually CENTRAL.

Injury to the long tracts of the spine at any level, and also to the brain pain tracts at any level, is capable of causing central pain. This pain typically has “burning” as its most prominent aspect. However, the burning of CP has the paradoxical component of “cold”, so it is obvious we cannot simply use the word “Pain”. To consider whether spinal pumps are working for central pain, we need careful descriptions of what agonies are present, and which were benefitted, and to what degree. These descriptions are glaringly absent from the literature and so we cannot do much with it.

Pumps play an important role for many, but they seem not to work for many severe cases. Pain blockage usually does not work this way. Lidocaine makes EVERYONE go numb. Since the implanted pumps help SOME of the time, we are back to square one. We must make sure which type of pain is actually being benefited. The same may be said of the centers which use transcranial stimulation, either by DC current, or by magnetism. We must first be assured they know what central pain is, and what it is not, before we can weigh the benefit reported.

We do not know that pain clinics are breaking as many or more hearts than they ease. They are very expensive, and typically very regimented. A sick person in pain is not a good candidate for any kind of regimen. They may be too ill to travel, and require special accommodations for sitting. These accommodations are often absent from pain clinics. A person who saves money to travel long miles to a “pain center” may or may not benefit from being given some militaristic schedule for opiates, along with “CONTRACTS” which are aimed at protecting the doctors license, not at pain relief. This is not to say such measures are not necessary. It is simply that as we see buses going around town to conduct students to special schools, it seems something similar ought to occur for many who wish to visit pain clinics. Should they really be out of reach costwise for the severely injured patient, who is not fit to travel? We think not. The assumption that it is only pain, so the person can simply travel to the clinic is often an unintentional brutalization in itself. What is needed is some kind of pain ombudsman to advocate for the CP subject with the clinic.

Until actual cures are developed by the dedicated pain researchers, more effort at pain clinics should be directed at assisting at the social level. Large pain clinics should have therapists trained to educate the patients family about the adjustment and accommodations necessary to deal with central pain. This sort of assistance is available in nearly every other serious handicap. However, the obsession with preventing addiction seems to swamp other considerations when time is allocated at many clinics. In the meantime, every CP patient must take a careful measurement of their own resources and make sure they are retaining enough peace of mind to get by. It will always be in short supply when severe chronic pain is involved. Stress is to be minimized. Boredom and being “locked in” to the bare functions of life with no distractions for relief, is NOT a minimization of stress.

We take injured kids to camp for a little R&R. Shouldn’t pain patients have something similar. Maybe an official “friend” at the pain clinic. Maybe an occasional massage for the kinesthetic dysesthesia. Maybe a free subscription to cable TV. Maybe government could assist with stress producing situations, such as court appearance, or other compliance activities, which the stressed out CP patient finds overwhelming. Certainly, family counseling should be provided, not to chide the patient, but to reassure the family that their efforts are really necessary, that the CP person is actually very ill.

Hedging against stress, not demanding that anyone in severe pain ‘write a book” about their experiences (who wants to read that kind of whining anyway?), or “start” an organization” or “open a website” is more realistic than driving the sick person like a donkey to make superhuman accomplishments and really get involved in society. The wounded deer affect is in operation in central pain and it must be acknowledged. The deer does not withdraw from the herd for its safety, because the herd exists for its own preservation. Yet, the withdrawal may avoid endangering the herd. Nevertheless, it is necessary so that the deer can heal. Human, however, are not deers. The crowd, the public, the group can reach out to help the ill, just as it does for countless pains. Human compassion makes us more than intelligent apes. We should not ask what the injured person can do for us (make us feel competent despite our incompetence, by being “brave” a “fighter” a “book writer”). Instead society needs to help themselves along with us by devoting the resources to understanding how it is that the pain message is created by neurochemistry and neuroanatomy. In doing this, they will make obsolete the millennia old reliance on addicting opiates and move on to sophisticated medicine. An important offshoot will undoubtedly be a block for the neuropathic pain of Central Pain, which probably is not much different in its neurochemistry than ordinary noxious sensations in a healthy nervous system.

For every “hero” with central pain, there are hundreds collapsing in defeat as they find not only can they not do something extra, but that they cannot even do the ordinary day to day activity which life requires because they cannot handle the stress on top of their pain.

Presently, most of what passes for treatment of CP works via what is fundamentally sedation. Serious pain relief is not usually available for severe cases. And so, until that day when someone finds a way to close off the TRPV-1 calcium channel, or otherwise block central pain, we say, “Avoid stress”. You are not going to conquer your pain, you can only save your strength so it does not conquer you.

And to the pain clinics. We love you, even if you are wildly expensive. You are all we have. Please do more. And remember, our families are hurting too.

Central Pain press release from the Univ. of Maryland

 

UM SCHOOL OF MEDICINE SCIENTISTS DISCOVER KEY BRAIN MECHANISM INVOLVED IN POORLY UNDERSTOOD CENTRAL PAIN SYNDROME

Findings Could Lead to Treatment for Painful Condition Common in Spinal Cord Injury, Multiple Sclerosis and Stroke Patients

 

            Scientists at the University of Maryland School of Medicine have discovered a key mechanism in the brain related to a devastating, painful condition that affects people who suffer from spinal cord injury, multiple sclerosis and stroke. The condition, called Central Pain Syndrome, causes chronic pain that patients compare to being stabbed with a thousand burning knives. The pain can be severe and untreatable and suicide is a leading cause of mortality among those who have the syndrome. Now, a team led by University of Maryland School of Medicine researchers has traced the syndrome to a malfunction in the zona incerta, or “zone of uncertainty,” an area of the brain about which little was known until now. Their study has been published in the online version of The Journal of Neurophysiology.

            “We hope that by understanding this underlying mechanism of Central Pain Syndrome, we can begin to think about potential treatments or preventive techniques,” says lead author of the study Asaf Keller, Ph.D., a professor of anatomy and neurobiology at the University of Maryland School of Medicine. “We are continuing our research into how the zona incerta is related to Central Pain Syndrome, and we hope to begin studying spinal cord injury patients who suffer from the condition very soon.”

            “This study is an example of the kinds of discoveries that are possible in an interdisciplinary environment like our School of Medicine, where world class researchers from every discipline have easy access to each other’s expertise,” says E. Albert Reece, M.D., Ph.D., M.B.A., John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine. “We hope this work will lead to a solution for the patients who suffer so terribly from this now-untreatable pain condition,” say Dean Reece, who also is vice president for medical affairs of the University of Maryland.

            Pain travels from the limbs to the spinal cord to the brain. The zona incerta reduces pain by filtering out or inhibiting sensory cues it deems unimportant before they pass on to the rest of the brain. The zona incerta allows only certain pain information to be experienced by the brain. The study, called “Zona Incerta: A Role in Central Pain,” traced Central Pain Syndrome back to a malfunctioning zona incerta. The scientists found that the zona incerta in animals with Central Pain Syndrome is not inhibiting pain as it should. The zona incerta in these animals is allowing too much pain information through to the rest of the brain, causing the animals to experience unusually high levels of pain.

            Central Pain Syndrome affects as many as 80 percent of patients with spinal cord injury, about 30 percent of multiple sclerosis patients and almost 10 percent of patients who have suffered a stroke. The pain associated with the syndrome can be a heightened sensitivity to ordinarily painless activities as simple as putting on clothes or feeling the wind on the skin. The syndrome also causes spontaneous pain that occurs for no apparent reason and can be unrelenting. There is no treatment for the condition, and scientists have known little about the source of the pain until now. Dr. Keller published a paper five years ago that found the zona incerta was a filter that allows only certain pain information to move on to the thalamus, where it is processed. From the thalamus, the pain information goes to the cerebral cortex, where sensations are perceived.

            Dr. Keller collaborated on the new study with Radi Masri, Ph.D., an assistant professor at the University of Maryland Dental School and the Department of Anatomy and Neurobiology at the School of Medicine, and their colleagues Raimi Quiton, Ph.D., and Peter Murray, Ph.D., both postdoctoral fellows the Department of Anatomy and Neurobiology, and Jessica Lucas, a graduate student in the Program in Neuroscience, as well as Scott M. Thompson, Ph.D., a professor of physiology at the School of Medicine. The study was funded by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, and the Christopher & Dana Reeve Foundation.

            Co-investigator Dr. Thompson recently completed a study with his associate Gexin Wang, Ph.D., a post-doctoral fellow in the Department of Physiology at the School of Medicine, showing that animals with Central Pain Syndrome respond to a drug called ethosuximide, a U.S. Food and Drug Administration-approved treatment for childhood epilepsy. Dr. Thompson’s study found that ethosuximide appeared to calm the over-activity and excitability in the thalamus that seems related to Central Pain Syndrome. Some of that excessive activity may be a result of inactivity in the zona incerta, according to Dr. Keller’s and Dr. Thompson’s latest joint study. “Our two studies examine areas of the brain that are very near each other, very similar and clearly related,” says Dr. Thompson. “We believe our two studies are basically indicating the same thing — that there is some imbalance of activity in the thalamus. These studies could finally mean relief for these patients for whom there is really no treatment. They’re desperate for anything.”

            The scientists plan to continue their research to investigate new treatments and ways to prevent Central Pain Syndrome. Dr. Thompson will begin a study of ethosuximide in human patients very soon. Since that drug already has earned FDA approval for treating epilepsy, if it proves effective in Central Pain Syndrome it could be approved for treating that condition far more quickly than a new drug.  

            Dr. Keller is planning to investigate other avenues as well. His study showed that, after an injury to the spinal cord, the zona incerta gradually stops working properly over a period of several weeks. Dr. Keller and his colleagues hope to find a way to intervene during those weeks and keep the zona incerta active. “We’re considering options such as non-invasive brain stimulation, stem cell implants or even occupational therapy — exercises patients could do to stimulate the zona incerta,” Dr. Keller says. “A successful treatment regimen one day could include a combination of exercises and drug therapy. We’re hopeful we’ll find relief for these patients, at last.”

Breakthrough in Central Pain Understanding

Painonline has at times been hardpressed to explain why central pain patients have so much muscle pain.  Both kinesthetic dysesthesia (pain with muscle loading) and confinement cramps, aka isometric dysesthesia (the largely spontaneous sensation of cramps in the muscles) are exceedingly common in central pain. Although often glossed over because the patient complains of such agony from burning sensation on the skin, as Beric has pointed out, the muscle pains may be so severe that a person with an intact motor unit may be functionally paralyzed. Muscle pains have been the stepchild of CP.

They also confound cliniicans who often confront ACTUAL musculoskeletal pain in post spinal cord injury patients, which pain is NOT neuropathic. Devising treatment strategies is much more difficult because verbal descriptors are lacking by which the clinician may distinguish between Central Pain in the muscles and the musculoskeletal pains which are to be expected whenever there is alteration anatomically at any motion segment of the spine. The former is neuropathic, and may be utterly resitant to opiates, while the latters is nociceptive and should respond to conventional pain therapies, such as opiates.

In a prior article here, the increasing focus on the posterior nucleus of the thalamus was discussed. This largely ignored nucleus is at the very back of the thalamus. The prior article dealt with connections being uncovered between pain tracts and the posterior nucleus or PoT (also called PO)

Now Masri, Keller and others at the University of Maryland have published a landmark study in the online J. Neurophysiology April edition ** which suggests that the PoT has inhibitory input from the zona incerta. The zona incerta is part of a nucleus which sits BELOW the thalamus, known as the Subthalamic nucleus. The Subthalamic nucleus is itself divided into areas. Nothingi n the brain seems to do just one thing. One neurophysiologist suggested that no area of the brain does just one thing, and that no nucleus has more than thirty percent of its neurons devoted to any one function.

Zona Incerta has always been a mystery as to its function. Its very name means in Latin, the zone of uncertainty, meaning no one had a clue what it did. (If you want a little look at this area, go to Brainmaps.com) Now, the ZI is turning out to be massively important to Central Pain patients. Its failure to inhibit the PoT may be the actual mechanism of CP.

This multifunctional aspect is revealed in the zona incerta. However, proximity often means some RELATION between the various functions should be suspected, or at least looked for. The posterior part of the Zona Incerta is the area of interest. The very most posterior part of the ZI is the area which is sometimes lesioned in Parkinson’s because there are links to the cerebellum and hence the motor functions of the body. (Coordination etc) The forward part of the most posterior region of the ZI was discovered to serve the function of INHIBITING the POT. When Central Pain is present, the inhibitory signal from the ZI is missing.

This leads to the rather logical conclusion that without input from the ZI, the PoT cannot distinguish between something like a breeze on the skin and a burn. (The University of Maryland news release on the discovery called Central Pain a mysterious disease. Perhaps an analogy might be made to color blindness. The color blind cannot distinguish between red and green. Thus, the brain of a person with Central Pain cannot distinguish between a breeze on the skin and a burn)  

The clinical description is hardly surprising, since most of those in the survey here attest to the fact that anything bringing a temperature change, especially a blast of cold air< will evoke burning pain powerfully. However, the more the press refers to Central Pain as “mysterious”, the less mysterious it becomes. This alone is a help to CP subjects. Even more help is the notice that attention and focus must be given to the surprising role of an allegedly ”MOTOR” area, the Zona Incerta, plays in interpretation of pain signal. Perhaps we should say “sensory signal” since most of what causes agony in CP is not inherently a pain stimulus at all.

Carl Saab, noted for identifying an area in the cerebellum which inhibits central pain, ie the vermis, has written here of the unexpected cerebellar link between that structure and pain inhibition. His first paper on the subject was so unexpected that it caused not only an uproar, but anger, at the Ninth World Congress of Pain, when Dr. Saab presented it. However, we now have more backing for the former author at painonline in yet another link between the cerebellum and pain. Namely, the area which connects to the cerebellum, and is a point of interest in Parkinson’s, is immediately adjacent to the pain interepreting area of the posterior region of the ZI which inhibits the PoT.

Look for more material on this, as some Parkinson’s patients have pain. It may be a touch of central pain, given this recent finding. We congratulate the authors (there are a number) and feel this may be the most significant article ever published on Central Pain.

**We are indebted to Mary Simpson for first noting this article when it appeared.

 

 

Cold Fire and the Thalamus

                                                    

 

            Eighty five percent of those responding to the question on the survey indicate that cold is a more rapid and powerful sensitizer (causing an evoked or heightened level) of their dysesthetic burning than heat. What can the explanation for this be??? See below.

 

 

Please note that in this article, the word Layer and Lamina mean the same thing, referring to the Rexed layers of the Spinal cord, which have the lowest numbers most superficially. Layer I is the marginal layer, where single C fibers have been documented to sensitize as much as half of the body. Layer II, the substantia gelatinosa, is the traditional pain layer. C fibers ascending to the dorsal root ganglia and horn of the cord recruit the big powerful A fibers to make for hypersensitization of the pain system. C fibers themselves are slow and imprecise.  We are learning that the traditional view that Layer II is most of the pain story is probably wrong. Somatosensory area I in the brain (the posterior ridge of the central sulcus) probably tells the LOCATION of the pain, Somatosensory II (parietal cortex) probably determines the SIGNIFICANCE of the pain, and the insular cortex appears to create the PAINFULNESS of the pain. It is still the majority viewpoint that Layer II feeds to SSI, the central sulcus. Pain ascends in the multistranded tracts which are known collectively as the spinothalamic tract, but this is a tract like telephone wires in a bundle are a tract. Dr. Patrick Wall, co founder of Painonline, in  1985 traced out as many as SEVEN discrete spinothalamic branches feeding into the thalamus.

 

 

As described in earlier articles, the thalamus, which is really two structures, there being one on each side of the brain, sits more or less straight back from the eyes at the center of the brain structures. The thalamus is probably far more important than we know, and we know quite a bit. One of the authors here, Dr. Francis Crick, even published a book opining that the human perception of the soul resides in the thalamus.

 

 

Just as identifying the part of the brain responsible for pain has been very difficult (although Dr. Crick and Dr. McHenry’s article here on the insular cortex broke new ground in locating the site of the painfulness of pain, ie. the insular cortex, scientists are presently trying to determine precisely the origin of fibers which carry pain to the insular cortex.

 

Al-Khater et al writing in the J. Comp Neurol 2008 Nov 1:511(1) 1-18 performed surprising studies which identified the posterior triangle of the thalamus (ie. the very caudal end) as the site which apparently feeds TO the insular cortex, where the painfulness of pain is appreciated. This pathway, the PoT nucleus pathway, is probably very important in central pain. This nucleus has not been included in prior studies of the pain in the thalamus because it was assumed that pain went to the VPM and VPL nuclei of the thalamus. Now we have a new area which seems dedicated to painfulness. This certainly bears further examination.

 

The spinothalamic cells which travel in the deeper lamina of the cord feed to the PoT. In the rat, there are approximately 90 spinothalamic neurons per side, some of which feed ONLY to the PoT.  The authors state that “85% of the lamina III/IV NK1r-immunoreactive neurons in C6 and 17% of those in L5 belong to the spinothalamic tract, and these apparently project exclusively to the caudal thalamus, including PoT.

 

Considering that few neuroscientists are even aware of a nucleus at the extreme end of the thalamus relating to pain, these scientists deserve credit for identifying a likely pathway for modulation of painfulness of pain.

 

 

This information and the resaons for it follow in a review of  the remarkable article,

 

Davidson S, Zhang X, Khasabov SG, Simone DA, Giesler GJ JrJ Neurophysiol. 2008 Oct;100(4):2026-37.

Termination zones of functionally characterized spinothalamic tract neurons within the primate posterior thalamus.

 

These authors found that ONE THIRD of the pain transmitting neurons going to the posterior thalamus respond to thermal heating, while TWO THIRDS respond to cooling.

 

Those with central pain have always found that hypersensitization of the BURNING dysesthesia is more rapidly and powerfully evoked by a cold blast of air than by heating. Davidson et al may have an anatomical explanation for this paradoxical clinical feature of central pain. More work is certain to be done on the posterior thalamus.