chronic pain is essentially a neurodegenerative disorder. Any damage to brain or spinal cord can result in chronic pain, such as post-stroke, or trauma. This is due to neruonal plasticity and sensitization. Some individuals are higher risk for developing chronic pain such as those suffering from PTSD or depression. This is a challenging population to treat and likely require adjuvant therapy and cognitive behavioural strategies. I have attached some articles for your reference.

Another reference.

In my opinion there are only 5 basic causes of chronic pain. 1. Chronic nociceptive painful condition (arthritis for example, misdiagnosis is common in this category). 2. sympathetic mediated/maintained pain (RSD, RSD was the most commonly seen misdiagnosis in my practice) 3. Central pain. (emanating from the CNS. 4 psychological pain. 5. malingering. All of these need to be looked for in these patients, don't assume it is a centrally emanating pain until you have eliminated the other options. In my experience the most likely explanation in most of these patients would be RSD (Reflex Sympathetic Dystrophy, now called CRPS but RSD is a much better name as it definitely involves the sympathetic nervous system because sympathetic blockage to the area relieves 100% of the symptions without affecting nociceptive sensation.). RSD occurs after peripheral trauma. Since these patients have had trauma and it is not possible to have head trauma without also having peripheral trauma it may simply be RSD. I would have to know more about the specific symptoms in each patient to be able to make a judgment. Treatment for RSD can be very straight forward and successful but you need to find an anesthesiologist interested in and experienced in treating this disorder as the most effective treatment involves anesthetic blocks of the sympathetic nervous system in the involved area. The blocks are also used to confirm the diagnosis. I used to do epidural blocks (similar to a labor epidural) because I found bilateral blocks to be more effective than peripheral unilateral blockade (there seems to be a percentage of cross innervation in many although it isn't described in the anatomy books). It would typically take a series of blocks (3-6) to invoke a cure in those capable of being cured (about 50-75% in my experience). A cure is much more desirable than palliative care as narcotics are not very effective at treating RSD type pain. Other options exist but the first thing that should be done is to make the diagnosis.

If central pain is involved I used to get pretty good results using iv lidocaine in doses similar to those used to treat cardiac arrythmias. 100 mg bolus will commonly eliminate the pain. (might also fix RSD) Occasionally it doesn't come back. Worth a try.

When the patient has pain that is beyond what can be explained physically. When they use any of these words to describe their pain, constant, burning, tightness, sensitive, hot think RSD. (RSD can also be present when there is no pain but only a muscle movement disorder, think of it whenever something doesn't make any sense.) Whenever the pain doesn't follow any normal nerve distribution think of RSD (the sympathetic nerves follow the blood vessels, not the nerves) think of RSD. It is my impression that these types of pain result from the normal feedback systems getting out of whack. Temporarily blocking these systems seems to allow the body to reset itself back to normal. When it works it is like magic. When it doesn't then you (and the patient) struggle to find good solutions.

Consider sleep factors in explaining high incidence of pain in TBI. Insomnia and headaches are not uncommonly comorbid conditions ( Ref: Culebras A. Headache disorders and sleep. In: Culebras A, ed. Sleep disorders and neurologic disorders. New York: Informa Healthcare USA; 2007).

In the postconcussion syndrome, insomnia and headaches are main symptoms. Those who work in sleep are aware of the effect of sleep on terminating attacks of headaches. There are links between REM sleep and acute headaches attacks (n Ref. Kayed K, Goadtlibsen OB, Sjaastad O. Chronic paroxysmal hemicrania. IV. “REM sleep locked” nocturnal headache attacks. Sleep.1978; 1: 91-95). Patients with migrane or cluster headaches can wake up with acute attack more often in REM sleep ( for differential diagnosis).

Common sleep disorders (SRBD, PLMS, circadian rhythms disorders, etc.) and poor sleep hygiene are highly prevalent in patients with brain injury. Thus, sleep factors should be reflected in a diagnostic workup of patient with TBI and pain.

There is good evidence that malingering of cognitive impairment has a high incidence in US soldiers claiming disability for mild TBI (e.g., search for Armistead-Jehle and MSVT; 50% failed MSVT). In general, both mild TBI and chronic pain syndrome have high rates of failure on PVTs (performance validity tests, such as the Word Memory Test or MSVT). At least 40% fail tests like these.

It is likely that many cases who are claiming both chronic pain and mild TBI are malingering. Both are conditions that, if present, can lead to greater pension benefits. So one obvious thing to rule out by proper objective validity testing (PVTs and SVTs) is gross symptom exaggeration and malingering.

In my database, I have 511 cases of mild TBI claiming compensation or already receiving it. I have 166 moderate to severe TBI cases. How do they compare on pain complaints on a scale from 0 to 5, where 0 is no pain and 5 is severe pain?

The mild TBI group score significantly higher than the severe TBI group on pain ratings at the time of testing (means 2.4 and 1.6, p

I have been interested to see if the vestibular system may have a role in chronic pain in humans. There are animal studies that have been done in the past few years regarding damage to the inner ear, barometric pressure, and pain.

I believe there are neural pathways related to both chronic pain and anxiety along the inner ear. Perhaps someone better versed in neuroscience could verify this. If so, could it be possible for a TBI to cause subtle damage in this area of the brain to cause a greater perception of pain?

Funakubo, M., Sato, J., Honda, T., & Mizumura, K. (n.d). The inner ear is involved in the aggravation of nociceptive behavior induced by lowering barometric pressure of nerve injured rats. European Journal Of Pain, 14(1), 32-39.

I'd be interested to get people's thoughts on any links between fibromyalgia and RSD. Frank Day's observations above are very interesting.

I am also interested in explanations of how botox works in migraine treatment. Obviously botox isn't going to be much use in a body-wide problem, but in coming to understand its mode of action has lead me to explore the role of the sympathetic system in peripheral pain pathways. I'm not sure I would agree totally with Frank's thought that sympathetic pathways follow only the blood vessels since you can measure sympathetic tone in peripheral nerves, and this leads me to wonder whether the info coming from the free nerve endings via the c fibres can be considered a meeting point between the sympathetic and the somatic sensory pathways.

I don't really agree with a division between the autonomic and somatic systems, and interestingly migraines can be considered a primarily sympathetic mediated CNS disorder (as opposed to cluster headaches which are primarily have a parasympathetic symptomatology). and my hunch is that the peripheral nocciceptive afferent info that is a trigger for some sufferers is in part via the sympathetic system via the trigeminal ganglion and not just the nocciceptive afferents that end up in the trigemino-cervical tract.

The interesting thing here is to find ways of integrating the two systems in a 'bigger picture' and exploring how the specifics of migraines can be applied to the general pain seen in fibromyalgia and reflex sympathetic dystrophy, and beyond that into chronic pain conditions in general.

Regarding Chris Blatchley's comments. In my opinion fibromyalgia and sympathetic mediated/maintained pain are two separate entities. And, it isn't a good argument that sympathetic nerves are not distributed with blood vessels (primarily) because sympathetic tone can be demonstrated in nerves since nerves are served with blood vessels. (talk to your local anesthesiologist, they should be able to help you with the anatomy here)I think it is clear that the sympathetic nervous system modulates a lot of peripheral feedback systems beyond affectiing blood vessel tone and heart chronotropy and inotropy. Further, it is hard to imagine that nerves that leave the CNS below the head and either above T2 or below L2 (and are distributed throughout the body) could somehow match up and follow the dermatomes. I have seen so many patients labeled as malingerers simply because their pain pattern doesn't follow a standard nociceptive dermatomal pattern yet a short series of sympathetic blocks completely cure them despite several years of pain. You have never seen such grateful patients. That having been said, occasionally the pain of RSD does follow a dermatomal pattern - the pain of shingles is a sympathetic mediated pain. Another sympathetic pain that is usually not recognized as such is that of interstitial cystitis, at least in my experience.

Not all patients with RSD even have pain. I remember a marine who had a chronically blue trigger finger from extremely poor blood flow. Zero pain. The orthopods were ready to amputate his finger for they feared gangrene. Luckily they sent him to me. After about 3 stellate ganglion blocks he was back to normal. If something doesn't make sense and there is the least history of trauma, think RSD as a possibility.

Oops I think I might have been misunderstood!

I'm only exploring the idea that the differentiation between the autonomic nervous system and the somatic nervous system may overlap on anatomical grounds and that if we explore the idea of functional integration between them across the anatomical divide then we don't need to explain the strong sympathetic tone signal in somatic sensory fibres in terms of impulses from the presumably quantitatively weak signals from the sympathetic fibres controlling the tiny blood vessels.

Fibromyalgia and sympathetic pain may well be two separate disorders but my thought is to explore where the pain mechanisms may overlap. The main point I am making about free nerve ending pain via c fibres is that it is relatively poorly localised and in that sense has similar characteristics to say cardiac pain relayed by autonomic afferents from similar free nerve endings.

Maybe sympathectomy is unlikely to help in fibromyalgia but I was interested to hear of people's ideas how, hypothetically at least, there could be an overlap and whether any new insights in understanding might help with the treatment of either disorder.

It might be caused by a co-morbidity with PTSD. It is known that there is a comorbidity in patients with whiplash trauma, chronic pain and PTSD

Birgitta Peilot specialized in chronic pain and rehabilitation medidcine

I'd like to second Dr. Lipsky's point regarding chronic central inflammation following TBI. We know that TBI can lead to microglia- and astrocyte-mediated inflammatory processes that extend well beyond the original site of injury, and may persist beyond the original injury. The inflammatory factors produced by those immune cells can interact with neuronal systems -- enhancing pain processing and negative affect. Depending on the spread of the inflammation, it might manifest as a circumscribed problem, a more systemic problem such as depression, or may generalize to something like cytokine-induced sickness behaviors. In the worst case, the TBI could lead to reactive gliosis that would severely damage neuronal cells. If you were interested in pursuing that literature, the key words would be: TBI; microglia; astrocytes; proinflammatory; cytokines; pain. There is some great work out there on the topic.

oxidative stress markers can be considered. of oxidative stress in neural pathways, especially in cases of traumatic brain I think that is important.

Addressing Chris Balser's request for "new insights" in helping the treatment of these disorders. Here is what I always tried to d. First, I tried to make a correct diagnosis and then I tried to gather as much information as I could as to what works and doesn't work in relieving the pain if a "correct diagnosis" didn't lead to fixing the problem. Missed diagnoses commonly seen in my practice included, 1. RSD 2. cervical instability/arthritis (headaches, upper extremity issues) 3. shoulder impingement syndrome (headaches, upper extremity issues) 4. hormone issues (hyperthyroid for example). Missed diagnoses almost guarantee failure. I remember once being at a saturday pain grand rounds and the experts at UCSF were handing around this MRI of a patient with upper extremity issues who had all of these CNS lesions suggestive of MS but he really didn't have any symptoms of this. We heard his story and our group immediately thought this sounded like a cervical spine instability/arthritis problem from an old injury. The "experts" laughed at the idea, in view of that MRI they had. Then they brought the patient in and when opened up to questions I asked if he had ever been in an accident or had any head trauma. He stated, "I used to box in the Navy and I was in a plane crash once" at which point the lightbulb went on for all the "experts" to explain the MRI findings. They got so focused on that lab finding they couldn't even take a good history. If one doesn't have the correct diagnosis one can expect treatment to fail. Then, if a correct diagnosis, for which a treatment exists, cannot be found (or no good treatment exists) then I tried to get as much information as I can about the pain and what it responds to (or doesn't) to to lead me to the best treatment option. As I said, I saw there being 5 basic types of pain. 1. Nociceptive (ordinary) pain 2. sympathetic mediated pain, 3. central pain (source CNS) 4. psychological pain, 5. malingering. Only 1 (nociceptive pain) tends to be responsive to opiods. In all the others opiods tend to only dull the pain and, while helpful, are not a great treatment solution. 4 and 5 should only be invoked if all the others are eliminated (that is not to say that those with real pain issues don't have psychological issues as a result or that patients might want to emphasize their real symptoms for secondary gain). 2 will usually respond with complete pain relief with sympathetic block. 3 would respond to iv lidocaine. At least that was my basic approach. What one does must frequently be individualized for each patient as there can be no "one size fits all approach" for these complicated patients.

One thing that always bothered me about most of the research out there is all chronic pain tends to get lumped together so I don't know which of the above categories the researchers were dealing with. What may work well for one category may fail miserably in another.

post traumatic nrain injury results in the activation of microglia activity and the generation of oxygen radicals. Because once micoglia is activated its difficult to stop their ongoing, pain propagating activity resulting în long-lasting chron pain which is difficult to treat with the usual pain medication. Non pharmacological approches using oxygen radical scvangers present an option

Could someone point me to the evidence that supports the supposition that "micoglia activity" is "pain propagating" and if so how does one diagnose and then treat such. How does one know if "micoglia activity", if correlated to pain, is the cause or the result of pain?

One more thing, if micoglia activity is indeed the cause of neuropathic pain, as some suggest, what would be the mechanism to explain sympathetic block completely removing neuropathic pain for the period the block is active and for a period thereafter.

Glia. 2011 Jan;59(1):152-65. doi: 10.1002/glia.21087.

Astrocytes are GABAergic cells that modulate microglial activity.

Lee M, Schwab C, McGeer PL.

Author information

Abstract

GABA is assumed to function in brain only as an inhibitory neurotransmitter. Here we report a much broader CNS role. We show that human astrocytes are GABAergic cells, and that human microglia are GABAceptive cells. We show that in adult human brain tissue, astrocytes immunostain for the GABA synthesizing enzyme GAD 67, the GABA metabolizing enzyme GABA-T and the GABA(A) and GABA(B) receptors. The intensity of staining is comparable or greater to that observed for known inhibitory neurons. We show that cultured human astrocytes strongly express the mRNA and protein for GAD 67, as well as GABA-T, and the GABA(A) and GABA(B) receptors. We further show that cultured human microglia express the mRNA and protein for GABA-T, in addition to the GABA(A) and GABA(B) receptors characterizing them as GABAceptive cells. We demonstrate that GABA suppresses the reactive response of both astrocytes and microglia to the inflammatory stimulants lipopolysaccharide (LPS) and interferon-γ by inhibiting induction of inflammatory pathways mediated by NFκB and P38 MAP kinase. This results in a reduced release of the inflammatory cytokines TNFα and IL-6 and an attenuation of conditioned medium neurotoxicity toward neuroblastoma SH-SY5Y cells. These inhibitory reactions are partially mimicked by the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen, indicating that GABA can stimulate both types of receptors in astrocytes as well as microglia. We conclude that the antiinflammatory actions of GABA offer new therapeutic opportunities since agonists should enhance the effectiveness of other antiinflammatory agents that operate through non-GABA pathways.

@Birgitta Peilot

I am confused and intrigued by your answer. How would comorbidity with a psychological disorder cause a brain injury to synergistically produce pain? I lack an understanding of pain on anything beyond an elementary scale, but it seems to be that concussive damage anywhere within a neuronally-rich tissue would be liable to cause localized pain, if not neuropathy in areas of the body with a strong signaling pathway to the respective region of the brain.

Can you explain the mechanism behind that idea of TBI and PTSD pain synergy?

A fewof points

Pain after TBI is not a necessary complication however common it is. Pain may be a complication of a stroke but is not particularly common

After damage to brain tissue from both trauma and stroke the same repair mechanisms are occurring.

Interestingly the anti-inflammatory functions of minocycline (a tetracycline that crosses the blood-brain-barrier) has been used on an experimental basis in strokes and has been found to be effective in some studies though no large scale trials have been done. If it works then the supposition is that the damping down of glial cell inflammatory response reduces collateral damage around damaged ischaemic areas affected by the stroke.

Sympathetic over-activity is also associated with increased inflammatory response and minocycline has been used experimentally in hypertension though more work is needed to assess whether it is having an effect

There are no pain nerve endings in the brain, so neurogenic pain is more related to something that has stimulated/altered the way that the sensation of pain is initiated centrally.

Pain levels are modified by psychological factors such as PTSD. In people abused in japanese POW camps you could induce the lashing red wheals by getting them to relive the occasion through hypnosis, so the relationship between physical symptoms and psychological stress is complicated. My own view is that it is mediated through the autonomic nervous system

One of the difficulties of discussing such things is defining what we are talking about. The original question dealt with pain following traumatic brain injury. To me, neuropathic pain follows PERIPHERAL nerve injury and, in my clinical experience, almost always involves the sympathetic nervous system and its feedback mechanisms. I always classified pain following stroke and other CNS injury as CENTRAL pain, constituting a completely different (and much more nebulous) mechanism. Of course, there might be sub-species to my classification system (since my treatment cure rate was never 100%) but I always believed that treatment success is maximized if one makes the correct diagnosis. It seems unlikely to me that glial cells are the cause of neuropathic pain when a neuropathic pain located in a hand or foot can be successfully cured (with a reasonably high success rate) with a completely peripheral procedure such as a BIER block (intravenous regional anesthesia) but it seems reasonable that glial cells might be important to the treatment of central pain.

The problem here is that patients who have had traumatic brain injury almost always have substantial associated peripheral injuries also. Is the pain or central origin, peripheral origin, or some combination? Treatments will be enhanced when clinicians have a reliable method of figuring out what is going on in diagnosing pain rather than just trying to treat it.

I would like to get some clarifications on the question itself. Is there an industrial norm on how many minutes or hours a person suffering from deep psychological trauma (with prolonged release of stress hormones) can last before he develops long-term brain disorders? As stress hormones will block microcirculations in most part of the brain, and sedation won’t help much unless the person can move around by himself and raise heart rate. I doubt that the brain can last very long without much blood before some brain cells start developing chemical imbalance and/or giving out wrong signals. Pain can be felt easily and that is why it is the most common problem. Other more serious brain problems or associated chronic diseases started at the same time may not be detected until very much later when something triggered them, perhaps.

Hello,

Found the article below, very interesting discussion:

Headache and sleep: Shared pathophysiological mechanisms.

Holland PR. Cephalalgia. 2014 Jul 22.  [Epub ahead of print]

Tatyana