Central Nerve Pain

[mike]

Although it is nice to see so much research going on today regarding Central Nerve pain. I haven't noted from the articles I have read,that we are very close to a treatment. I am a C5 incomplete with severe central nerve pain and even with the minimal help that I have received by taking neurontin and other drugs, the pain continues to get worse.

Am I missing something or are we close to some sort of treatment?

mike

[Joe B]

Mike

I thought it was great when NIH put up some award and grant money for research on SCI pain. But when I saw the research programs that were awarded the funding I was severely disappointed. I saw a program to test the effectiveness of Elavil (amitryptiline), another for methadone, another for behavior modification versus physical therapy (stretches). All of these had been tried and anecdotal results received. I guess the difference was that there was no "scientific" evidence and so studies were performed on therapies that have been in place for over 20 years. (Use of capsaican and botox were also lookedd into and are relatively new, results were either negative or minimal relief).

I didn't see any awards for potential new meds that a researcher was secretly working on but just needed some funding to put the research over the edge. SCI and other similar centralpain are so poorly understood the researchers dont know where to begin. I was hoping R.P. Yezierski and Carolyn Fairbanks would get some money for more work on agmatine which seems to give relief to rats with SCI. I dont know how you can tell if a rat has SCI pain unless you ask him.

Then I began to see the same studies being duplicated a year or two later by a different hospital. I participated in a study in the mid 1990s on behavior mod vs methadone and have seen variations on the methadone study at least 4 times since then.

Methadone and other opiate derivative do not work on central pain. Its not a noxious stimuli in the first place. Its an abnormal response to normal stimuli. Opioids dont affect normal stimuli.

hang in there.

Joe B
C6-7
1988

[David Berg]

mike,

I can't imagine that we're too close yet to a satisfactory and effective solution. For one thing, even if "bench-top" researchers found the perfect answer in the lab, it would take years to bring it to human trials and then to market. My hope is that something already in the pipeline is a decent answer.

Keep in mind that central pain is an extremely complex problem. There are many things involved and several different types of pain that may require different treatments. Ideally, someone will find a way to "turn off" the pain response, but I'm not necessarily counting on that right away. Just as an example of the complexity of the problem, some pain messengers in the nervous system are chemically gated and some are electrically gated. We might have to figure out how to shut down each type of signal in order to stop all facets of the pain.

If you'd like to read a little more on nerve pain research, I have a couple of articles at PainOnline (http://www.painonline.org) that might interest you. The articles can be tough reading at times, so you might want to print them out to study at your leisure. The primary articles are How Pain Nerve Cells Act When They Are In Pain (http://www.painonline.org/NerveCells.htm) and Guessing at the Cause of Central Pain: A Primer on What We Think We Know (http://www.painonline.org/guessing.htm). You should also read the page submitted by Dr. Carl Saab at Yale called Pain in the Little Brain (http://www.painonline.org/LittleBrain.htm), which summerizes much of his research over the past few years. There is a lot of promising work going on, so don't lose hope.

I believe the best thing we can do for now is to keep advocating for additional pain research. It's great to see the additional money being invested in this cause in the last few years, but I won't be satisfied until we have the ability to stop everyone's pain, from root canals, to migraines, to central pain.

David Berg

[Wise Young]

David, thanks for writing and posting the links to the articles. After reading it, I thought that perhaps I can give the topic a try, to try to get around some of the mechanistic aspects for people who are encountering it for the first time.

What is Neuropathic Pain?
Central or neuropathic pain differs from nociceptive pain in several ways.

1. Location. Neuropathic pain not only can occur in areas where there is no sensation but tends to occur in areas where sensation is absent. Therefore, most scientists have concluded that the activity leading to central pain comes from the central nervous system itself. In recent years, neuropathic has been classified according to the location of the pain in people with spinal cord injury: below the injury site, at the injury site, above the injury site, and visceral (deep organs).

2. Cause. Neuropathic pain frequently occurs after injury to the central or peripharal nervous system that reduces or eliminates normal sensory input. For example, injury to the peripheral nerve (which reduces or eliminates sensory input from that nerve) usually will produce neuropathic pain in that area. Likewise, amputations will produce "phantom limb pain" which is a form of neuropathic pain. Diabetic neuropathy, multiple sclerosis, transverse myelitis, spinal cord injury, injury to the sympathic nerves (sympathodystrophy), or even chronic inflammation of a part of the body can lead to neuropathic pain.

3. Timing. Neuropathic pain usually does not occur right away after an injury. It may take weeks, months, or even years for the pain to develop. This strongly suggests that the pain itself may result from abnormal growth or connections or other changes in the central nervous system. In some people, the pain may have a regular schedule and may occur daily or even every other day. The pain may be intermittent, remitting, or unremitting. It is frequently associated with spasticity and autonomic dysreflexia.

4. Quality. Neuropathic pain is is frequently described by people as "burning", "pressure", "freezing", "vibratory", "itching", and other abnormal sensations that appear to be localized to a part of the body, most often in an insensate part of the body. Like many forms of pain, the intensity depends on attention and your mental state.

5. Hypersensitivity. One of the manifestations of neuropathic pain is the tendency for minor stimuli to evoke pain. When pain can be evoked by light touch, it is called mechanical allodynia. However, many other forms of hypersensitivity

I like to think of neuropathic pain as the sensory counterpart of spasticity. Spasticity, as most people here know, is increased excitability of the parts of nervous system controlling parts of the body where there is less or no motor control. In the same way, I think of autonomic dysreflexia as increased excitability of the sympathetic nervous system (which controls blood pressure, blood flow, sweating, and other autonomic functions). Therefore, it makes sense to think of neuropathic pain as increased excitability of the parts of the nervous system that have less or no sensory input.

Treatments

Let me list the usual list of treatments that are often prescribed for neuropathic pain.

1. Monoamine oxidase (MAO) inhibitors. This includes the drug amitryptaline or Elavil. Although these are called "anti-depressants" because they block the enzyme that breaks down catecholamine neurotransmitters, usually these drugs are given at much lower doses than are usually used for depression. For example, anti-depressive doses of Elavil are on the order of 100 mg per day but it appears that 20 mg per day of Elavil may be sufficient to take the "edge" of neuropathic pain. This class of drugs often can be combined with others on the list below.

2. Antispasticity drugs. A number of therapies that reduce spasticity may reduce neuropathic pain. In particular, baclofen (a drug that enhances the inhibitory neurotransmitter GABA activity) may help in cases of mild neuropathic pain. Likewise, clonidine or tizanidine (both of which are alpha adrenergic agonists) may reduce neuropathic pain. This is particularly true of neuropathic pain that appear to be associated with spasticity.

3. Benzodiazepams. These drugs include valium, etc. and they bind to GABA receptors. Unfortunately, these drugs tend to be addictive and have side effects on memory, as well as mood-altering qualities (they are called tranquilizers). Their beneficial effects on neuropathic pain may be also related to their effects on the brain.

4. Electrical stimulation. Stimulation of the peripheral nerves or the spinal cord with implanted electrodes have been reported to relieve or reduce neuropathic pain in people. These probably act by altering the activity of the spinal cord and changing the levels of neurotransmitters.

5. Anti-epileptic drugs. A number of anti-epileptic drugs have been reported to reduce or control neuropathic pain. The most popularly used one currently is a drug called Neurontin or Gabapentin. This drug reduces excitability of neurons by blocking enzymes called phosphokinase C. In particular, it may block phosphokinase C gamma (PKCg), an enzyme whose presence appears to be necessary for the development of neuropathic pain in animals. Alan Basbaum at UCSF reported several years ago that mice that had their gene for PKCg do not develop neuropathic pain. Carbemapazine and other anti-epileptic drugs appear to have similar effects. Note that the brain tends to accomodate to these drugs relatively quickly and the neuropathic pain may come back. However, recent reports suggest that gabapentin can be increased to very high levels, as high as 4000 mg per day and the beneficial effects can be maintained at high doses without unacceptable side-effects.

6. Glutamate receptor blockers. Glutamate is the main excitatory neurotransmitter of the central nervous system and it binds to several different receptors that contribute to painful and other sensations. Some glutamate receptor blockers are very commonly used. For example, dextromethorphan is commonly used in cough syrups. Others include oral ketamine which is not getting increasing popular for the treatment of cancer pain which may have a strong neuropathic component. Several recent studies have reported that agmantine (a glutamate receptor blocker) effectively prevents neuropathic pain in animal models.

7. Standard analgesics. Neuropathic pain is believed to be less responsive to standard analgesic therapies, such as opiates and non-steroid analgesic medications such as aspirin, acetaminophen (Tylenol), cyclooxygenase 2 (COX-2) inhibitors. However, I think that this is not always true. The reason that these drugs appear to be less effective is because people accomodate to these medications or the injured spinal cord may have downregulated their receptors to opioids.

8. Alternative therapies. Acupuncture is frequently used to treat neuropathic pain. The mechanism of acupuncture-mediated analgesia is not well understood but I think that it may be effective for some people, at least in providing some short-term relief. When I was visiting China a few years ago, I asked the head of acupuncture therapy at the China Rehabilitation and Research Center in Beijing whether he thought acunpuncture was effective. He said that it was effective but impractical. The reason is that the effects of acupuncture usually do not last more than a few hours and it is impractical to be doing acupuncture daily.

9. Surgical therapies. A number of surgical therapies for neuropathic pain have been tried in the last few decades. The most commonly used approach is dorsal root rhizotomy (cutting of the dorsal roots) or dorsal root entry zone (DREZ) lesions. The latter attempts to destroy the part of the spinal gray matter that is believed to be the source of neuropathic pain activity. It is effective in a proportion of people but really can only be applied in situations where the neuropathic pain is localized to a particular dermatome or a limited number of dermatomes.

Recommendations

There is no single solution for neuropathic pain, probably because it may be several different entities and can be initiated by many different stimuli. I believe that if a person has onset of neuropathic pain, the first thing to do is to find out if there is an associated abnormal activity such as autonomic dysreflexia and spasticity. If so, the first effort should be to identify the cause of the dysreflxia and spasticity. For example, this may be a result of a decubiti, an ascending syrinx, gallbladder stones, kidney stones, bladder infection, intestinal problems, and other preventable causes. Once all these causes have been ruled out, the first step should be to start with low dose Elavil (20 mg per day). The second step is to include add anti-spasticity drug such as baclofen, tizanidine, or clonidine. The third step would be to add dextromethorphan or other glutamate receptor blockers, usually in low doses. The fourth step is to use electrical stimulation. The fifth step would be intrathecal baclofen. I would leave surgical approaches to the last, to be used only if none of the above are effective.

Because opiates are addictive and seldom are effective in eliminating the pain, I would suggest avoiding opiates. There are some drugs that are beginning to be popular that combine opiates and antidepressive effects. For example, Ultram is such a drug. I would strongly recommend against using such drugs unless you are under the care of an experienced and good doctor who is willing to work closely with you to wean you off these drugs if they do not work.

Emerging Therapies

Much recent research have implicated growth factors and inflammatory cytokines as proximal causes of neuropathic pain. Many drugs are also being developed that directly target enzymes in neurons that regulate excitatory activity of sensory neurons. Finally, there is much interest and excitement about the use of capsaicin (the essence of pepper) to target sensory neurons. Combinations of these new approaches with some of the more established ones should improve the quality of life of people who are now suffering from chronic pain.

Wise.

PS I am typing this in an internet cafe in Hong Kong.

[Joe B]

Thanks Dr. Y for posting such a thorough discussion of the treatment of central pain. It's amazing to me that only a few years ago, most doctors could not put a name on it and sometimes acted as though they thought the pain was in your head. Once a problem is recognized and a name has been given, there is hope for a treatment.

I believe it is important that researchers emphasize that central pain cuts across several conditions, SCI, TBI, and certain peripheral maladies. This makes the population needing treatment much larger.

Dr. Y, your optimism is always a boost.

Joe B
C6-7
1988

[Joe B]

A presentation by a researcher gives some interesting insights into the effect of baclofen on nerve synapses. The article text follows:

Embargoed for Release at 10:15 a.m. PST Monday, July 1 (1:15 p.m. EDT)

Wake Forest Investigator Shows New Way That Alcohol Affects Brain

WINSTON-SALEM, N.C. - A Wake Forest University School of Medicine researcher today challenged a commonly accepted view on how alcohol acts in the brain in a plenary session presentation at the Research Society on Alcoholism meeting in San Francisco.
Jeffrey Weiner Ph. D., 2001 winner of the society's Young Investigator Award, said many scientists had thought for years that one of the ways that alcohol works was in much the same way as benzodiazepines (such as Valium and Xanax) or barbiturates (such as Nembutal). "But recent data from our laboratory and others challenge this concept and suggest that alcohol may have more complex effects."
Weiner's work focuses on what is called the GABA synapse which he says contributes to many of alcohol's behavioral and cognitive effects, especially intoxication, dependence and withdrawal. "The GABA synapse is the main inhibitory synapse in the brain."
The synapse is the gap between individual nerve cells in the brain. Nerve cells communicate with each other across these synapses by using chemical transmitters.
GABA is one of several of those neurotransmitters, targeting what are known as GABA receptors. Barbiturates and benzodiazepines act only on these receptors, which is the source of their inhibitory or tranquilizing effect. Anesthetics also work on these receptors, as does alcohol.
But Weiner, a member of Wake Forest's Center for the Neurobehavioral Study of Alcohol, recorded extensive evidence that alcohol also affects the nerve cell in the region before the synapse, which is called a pre-synaptic interaction.
"Unless you really focus on all of these mechanisms, you don't get the full picture of what alcohol is doing," said Weiner, assistant professor of physiology and pharmacology. "By looking
at both pre- and post- synaptic mechanisms, we discovered a whole new way that that the sensitivity of the synapse to alcohol is regulated."
That makes alcohol "very different" from the two comparison classes of drugs -- barbiturates and benzodiazepines.
He said that this pre-synaptic activity may open the door for new drugs that might be used to treat alcoholism by focusing on that mechanism. For instance, he has already shown that a chemical called baclofen blocks the effect of alcohol on GABA synapses, but has no effect on benzodiazepines or barbiturates.
"By doing this work, we gained new insight into what determines the overall sensitivity of the GABA synapse to alcohol," said Weiner. "That might help explain some of the individual variability and sensitivity to alcohol and aid in identifying individuals at risk of abusing alcohol."
"Exploiting the targets we have found may aid in the development of pharmacotherapy," he said.
In making the discovery, Weiner made use of a technology that was not widely used until the 1990s, known as the whole cell patch clamp electrophysiological method. The technology lets scientists focus on activity within individual brain cells.
Using the technology in rat brains, Weiner was able to measure and document the variations in sensitivity to alcohol.
The result of his research is a tentative conclusion that alcohol effects on GABA synapses "may involve a complex interplay between pre- and post-synaptic processes and likely differs fundamentally from the effects of other modulators" of these inhibitory synapses.
Weiner is one of only six plenary speakers at the five-day meeting.

Joe B
C6-7
1988

[David Berg]

Joe B,

You're right that people need to realize that central pain is common to a number of different conditions. For a webpage, I compiled a list of conditions that can result in central pain. I'm confident this list isn't complete.

Stroke (generally involving the thalamus to some extent)
Multiple sclerosis
Spinal cord injury
Cancer (when it damages CNS sensory nerve cells or the thalamus)
Physical trauma (such as surgery, gunshot, falls, vehicle accidents, etc.)

AIDS, especially end-stage
Aneurysm
Arachnoiditis
Arteriovenous malformation
Cauda equina syndrome
Cervical myelopathy
Chemical toxicity
Cluster headaches (some think this might be a form of central pain)
Gunshot wounds
Infection (bacterial or viral)
Lead neuropathy
Meralgia paresthetica
Mercury toxicity
Myelomalacia
Neurofibromatosis
Posterior myelitis
Post-polio syndrome
Radiation exposure
Reflex sympathetic dystrophy syndrome
Spinal cord infarction
Surgery
Syringomyelia
Tethered cord syndrome
Transverse myelitis
Vascular malformation
Vitamin B-12 deficiency
Any condition that causes nerve demyelination or other nerve or brain damage.

I'd be happy to hear from anyone that can think of anything I should add to the list. (david@painonline.org)

David Berg

[brucealexander]

Re Central Nerve Pain

I would like to start by saying Gidday from Australia to everyone. I have felt like a peeping tom [one who looks through closed windows] since logging on to this forum. I would like to congratulate Wise Young and the moderators for all their hard work.

My injury occurred 1976, the result of a diving accident. A poorly executed swan dive off the car port roof into a swimming pool. Originally diagnosed as C 5/6 complete. After 6 months hospital and rehab I walked out. I went back to work as a cop on restricted duties working in the court. Hello white rabbit.

In 1980 I felt I was losing motor function a laminectomy was performed. The result was a flail left arm almost useless left leg.

In 1994 I was losing sensation in my right hand. My little finger first then progressing to the others. A syrinx was revealed by way of MRI from C1 TO C7.

1997 I had surgery to detether the cord. I had 2 weeks in hospital. I feel it took another 12 months to recover from surgery.

Since that operation I have continued to lose sensation and motor function over my whole body. In its place I have gradually at first started having neuropathic pain.

In the beginning it was more of a nuisance. Now the burning, pins and needles and itching drives me to drink. I have tried every drug mentioned by the good doctor Young, all to no avail. A bucket full of scotch may not stop the symptoms but one is able to bear it.
About 12 months ago I was selected to trial a new drug 'Pregabalin'. I had previously spent two weeks in a rehab hospital. I had started having Autonomic Dysreflexia. I was also told I needed to catheterize every four hours

Pregabalin has been around since about 1989 for the treatment of a variety of ills, including anxiety, etc. There is a host of information available on the net. Pfitzer the manufacture of the drug are commencing trials in Australia. Nominating 16 hospital under strict guideline for the treatment of neuropathic pain. This is very exciting as good results are expected. I am pissed off because my name was the first on the list to start in two weeks on a blind trial . To day I was kicked off the trial because I told the doctor I felt my pain and motor function were worsening. Part of the requirements are that the patient is to be stable. What a load of B.S. I was advised to contact my neurosurgeon who had 2 years ago told me my problems were probably caused by adhesions the result of previous surgery and more surgery was required to relive the adhesions. When does it stop. I have had over 64 trips to hospital and more operations then birthdays. I turn 50 in August .

Ladies and gentlemen sorry this was drawn out. It is my first post and probably my last. Pain appears to be a major burden for most people who suffer a spinal injury. I sincerely hope a positive result is forthcoming from the 'Pregabalin' trial. The trial is for 12 months. I will endeavour to keep you informed of the results.

Wishing you all a pain free future
Pops

[Joe B]

Pops

Sorry you aren't on the trial. With your luck, you would have been on the plaebo anyway. Sounds like you have many things going on not just neuropathic pain though that seems to be worsening. I know you said you have tried all the drugs listed by Dr Young with no effective relief. Myself, I have found that I need more than one type of med working together to make my pain livable.

I still take baclofen, diazepam (Valium), and now Neurontin. I used to take amitryptiline but it was ruining my memory. The Neurontin replaced it though I can tell there is a difference in the type of pain relief. On bad days I take 20 mg of amitryptiline at night and it helps me feel better for about 24 hrs.

Just a suggestion.

Nice to hear from someone from the home of the Southern Cross.



David

I have often heard that endstage cancers have untreatable pain. I wonder if that is because between the cancer and the treatments they haven't caused nerve damage hence the pain. What a choice to have to make.

G'day Pops and David

Joe B
C6-7
1988

[David Berg]

Joe B,

End-stage cancer is notorious for causing intractable pain. In my list I restricted it to cancer that directly affects the CNS, but other cancer can certainly cause horrible pain, too.

I saw an article awhile back that I wish I'd had more time to read. If I remember correctly, it mentioned that they thought cancer might be able to activate or secrete some chemicals that have a nasty effect on the nervous system and can activate pain messages in the nerves. If I'm wrong, I hope someone will correct me.

David Berg

[alan]

I'm still looking for something that helps. Cyanide isn't an option.