Study Evaluates Use of Anticonvulsants to Treat Fibromyalgia

[slccom]

Search the title in xxxxxx
Sharon

[litliwlowa]

I never have good luck searching xxxxxx for articles. However, it is interesting about anticonvulsants being used to treat fibromyalgia.

When we see how many sjoggies are on Neurontin, as one example, for pain. Well Neurontin is also an anticonvulsant. Part of my pain management for far too many years to count includes currently Keppra - SR, which is also another anticonvulsant.

Shame we can't post links to make it easier for the challenged such as moi to find.

[jazzlover]

Shame we can't post links to make it easier for the challenged such as moi to find.

-
Amen to that! I hate that rule. I always post the link without the www .. that is allowed. Then at least you can copy and paste.

[slccom]

Put both the title and the "Pro health" in the search box and it comes right up.

Sharon

[Nat]

I think I can explain why anticonvulsants would be used in the treatment of fibromyalgia. Under the thread, "Sjogrens and Missing Enzymes" I posted some information about the activation of a pathway in Sjogrens called the "kynurenine pathway" due to these missing enzymes. This pathway is a tryptophan degrading pathway.  The activation of this pathway produces toxic metabolites, such as "quinolinic acid", that are directly linked to seizures, as the following study demonstrates.

Epilepsia. 1990 Mar-Apr;31(2):172-7.
Quinolinic acid concentrations in brain and cerebrospinal fluid of patients with intractable complex partial seizures.
Heyes MP, Wyler AR, Devinsky O, Yergey JA, Markey SP, Nadi NS.

?Quinolinic acid (QUIN) is a neurotoxin and convulsant when injected directly into the brains of experimental animals and as such has been implicated in the etiology of human seizure disorders??


The following study shows that this pathway is also activated in fibromyalgia.


Kynurenine Pathway Activity Linked to Fibromyalgia Fatigue
Chad S. Boomershine1, Dina Titova2, Chongbin Zhu1, Annette M. Oeser1, M. Wade Calcutt1, Aihua Bian1, Tebeb Gebretsadik1, Raymond Johnson1 and C. Michael Stein1, 1Vanderbilt University

"Increased KYN-p activity is associated with FM fatigue in humans and a murine model. IDO enzyme inhibition may be a novel method for treating FM fatigue."


Here is an additonal study on the association of fibromyalgia with the kynurenine pathway.

http://www.ncbi.nlm.nih.gov/pubmed/23922501

[quietdynamics]

I take Topamax and find it helps with Fibro pain.
Today at Rheum appt. resident talked about Fibro/headache/migraines and neuro ...then teaching Rheum talked about SJS/headache/migraine and neuro...Hmmm?

Combo of Cymbalta, Topamax with a pinch of neurontin..is working...a neuro med cocktail.

DH was patient and drew a schematic of the dynamics of the sodium channel action.

The explanation of Topamax below is clear and meshes with the overactive electrical impulses of Fibro.

Topamax contains topiramate, an anticonvulsant used to treat epilepsy and control seizures. Nerve cells throughout the central nervous system communicate by sending out electrical signals, generated by the movement of electrically charged particles in and out of nerve cells, which travel to the all parts of the body via chemical messengers called neurotransmitters. This usually happens in an orderly fashion to control all our actions and thought processes. Epileptic seizures are thought to be caused by abnormal electrical activity in the brain, with uncontrolled, rapid and repetitive electrical signals being sent continually to various parts of the body, although the trigger for this abnormality is not known. Topamax works directly on the brain cells to reduce the rate at which electrical signals are generated, calming the overactive nerve activity, by three different mechanisms. Conduction of electrical impulses is dependent on the flow of positive sodium ions into and out of the nerve cell through special sodium channels. Topiramate blocks these sodium channels and therefore reduces the neurons' ability to send out continuous signals which cause seizures. Topiramate also has the ability to enhance the activity of gamma-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter that regulates how much neurons can be excited (stimulated to send out electrical impulses), and inhibits the activity of the excitatory neurotransmitter glutamate, which adds to the calming effect on brain electrical activity. These three mechanisms are thought to contribute to the anticonvulsant activity of Topamax which control seizures in epilepsy, but cannot cure them.

[Nat]

I think the reason the toxic metabolites produced through the kynurenine pathway are so directly involved in many of the symptoms experienced by patients with fibro and Sjogrens is not just because they are directly toxic, but also because they reduce GABA and increase glutamate.

For instance, researchers in the following study discovered that the tryptophan metabolite "kynurenine" was able to induce convulsions by displacing GABA. The researchers concluded, "The data suggest that the convulsant activity of L-kynurenine might be due to interaction with GABA receptors."

Kynurenine may directly interact with GABA receptors in rat brain.
Pinelli, A., S. Govoni, C. Ossi, F. Battaini, B.R. Caimi, S. Trivulzio. 1985. Pharmacology 30(5):255-8.

"Previous studies have shown that kynurenine may have convulsant activity?kynurenine was able to displace 3H-GABA from rat brain membrane preparations. The data suggest that the convulsant activity of L-kynurenine might be due to an interaction with GABA receptors?"


In the next study the researchers discovered that "quinolinic acid" reduced GABA in a dose-dependent manner.
Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid.

Harris, C.A., A.F. Miranda, J.J. Tanguay, R.J. Boegman, R.J. Beninger, K. Jhamandas. 1998. Br J Pharmacol. 124(2):391-9.

"?Intrastriatal infusion of quinolinic acid also produced a dose-dependent reduction in striatal GABA content?"


Not only does quinolinic acid (QUIN) reduce GABA, it increases glutamate, as the next study confirms.

Int J Tryptophan Res. 2010; 3: 157?167.

Understanding the roles of the kynurenine pathway in multiple sclerosis progression.
Chai K. Lim,1 Bruce J. Brew,2,3 Gayathri Sundaram,1 and Gilles J. Guillemin1

"?QUIN is capable of increasing the release of glutamate by neurons and decreasing glutamate uptake by astrocytes and can also inhibit astroglial glutamine synthetase consequently leading to the accumulation of glutamate in the microenvironment and excitotoxicity; QUIN can kill astrocytes resulting in neurotoxicity because of the loss of astrocytic detoxifying function; QUIN is associated with lipid peroxidation. Some studies have also shown that QUIN can potentiate oxidative stress through generating and working synergistically with ROS in the mitochondria.This leads to lipid peroxidation and energy depletion that ultimately results in cell death?"


Since the kynurenine pathway is activated in fibromyalgia, you would expect to find elevated glutamate. Here is some info from my fibro book on this.

"As our next study confirms, fibromyalgia patients have significantly higher levels of glutamate in their cerebrospinal fluid. Glutamate mediates central sensitization (Gudin, 2004). Central sensitization is a condition of the nervous system that is associated with the development and maintenance of chronic pain. The following study discusses the association between central sensitization and the "tender points" found in fibromyalgia, due to the increase in glutamate levels.

Central sensitization can lead to heightened sensitivities across all senses, not just the sense of touch. Fibromyalgia patients often report other sensitivities, such as those to light and odors.

Research shows that central sensitization is also associated with chronic low back pain (O'Neill, 2007) and chronic neck pain (Chua, 2011), both of which are associated with fibromyalgia. A recent study found 28 per cent of women with chronic low back pain also met the criteria for fibromyalgia (Nordeman, 2012).

The following study also discusses the association between elevated glutamate and migraines. The significantly higher levels of glutamate, along with the damaging effects of homocysteine on the blood vessels, would clearly explain the comorbidity of chronic migraine with fibromyalgia.

Cerebrospinal fluid glutamate levels in chronic migraine.
Peres, M.F., E. Zukerman, C.A. Senne Soares, E.O. Alonso, B.F. Santos, M.H. Faulhaber. 2004. Cephalalgia 24(9):735-9.


"Both preclinical and clinical data link glutamate to the migraine pathophysiology. Altered plasma, platelets and cerebrospinal (CSF) glutamate levels have been reported in migraine patients. Chronic migraine is comorbid with several conditions. It has been recently shown chronic migraine comorbidity with fibromyalgia?CSF glutamate demonstrated significantly higher levels in patients with fibromyalgia compared to those without fibromyalgia?Tender points, the hallmark of fibromyalgia? is probably mediated by central sensitization, with increase in CSF glutamate levels."

So, this would explain why drugs that increase GABA and decrease glutamate are used in the treatment of fibromyalgia, Sjogrens, MS, or any disease that involves the kynurenine pathway.

[SjoAmy]

Nat, maybe you can answer this....


I know that old school anticonvulsant Tegretol aka Carbamazepine, also treats TMJ, and some problems with nerves.  Tegretol shares a different makeup than the GABA related Gabapentin/Neurontin and Lyrica/ Pregabalin  (also used for nerve damage in Peripheral Neuropathy, Fibro & Sjs).  Gabapentin & Lyrica are Gaba based, I get that......but what makes the Tegretol work on nerve damage too?

Anticonvulsants with "other nerve damage" uses:

Tegretol
Gabapentin
Lyrica
Topamax

Anticonvulsant doubling as mood stabilizer:
Depakote
Depakene
Melaril

and there's a few more uses to anticonvulsants......my brain haze won't let me remember the rest of the names & functions tho.

[quietdynamics]

The mechanism of action of carbamazepine and its derivatives is relatively well-understood. Carbamazepine stabilizes the inactivated state of Voltage-gated sodium channels, making fewer of these channels available to subsequently open. This leaves the affected cells less excitable until the drug dissociates. Carbamazepine has also been shown to potentiate GABA receptors made up of alpha1, beta2, gamma2 subunits.[27]This may be relevant to its efficacy in neuropathic pain and manic-depressive illness.

Do selected drugs increase the risk of lupus? A matched case-control study
RESULTS

There were 875 incident cases, of which 12% (n= 107) had evidence of a prescription for one or more of the suspected drugs, and 3632 matched controls. For some drugs, prescriptions were too uncommon to be able to estimate associated risk of lupus. Despite small numbers of exposed patients and low statistical precision we observed an increased risk of lupus for hydralazine (OR = 6.62, 95% CI 1.03, 42.74), minocycline (OR = 4.23, 95% CI 2.65, 6.75) and carbamazepine (OR = 1.88, 95% CI 1.09, 3.22). There was some indication that the effect of carbamazepine was restricted to women (P for interaction by gender = 0.047).
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2010.03733.x/abstract

[Tivia]

Interesting Quiet, not only do drugs have a relation with lupus but also tardive dyskinesia.

http://www.nlm.nih.gov/medlineplus/ency/article/000685.htm

http://www.dystonia-foundation.org/pages/more_info/76.php

Really need to research what we take, they started me on reglan and I am going to have to really consider this. Sometimes when trying to fix one issue with a med we may cause an even worse problem.

[Nat]

Hi SjoAmy~I think quietdynamics answered your question.

I think one of the important things to keep in mind is "why" glutamate is elevated in these diseases. Unless you address the source of low GABA and elevated glutamate, you will not ever get ahead of the game so to speak. Even though some drugs can mitigate some of the damage caused by elevated glutamate, the toxic tryptophan metabolites, such as kynurenine and quinolinic acid, which led to the elevated glutamate and low GABA, will still be present and the damage they cause is unrelenting.

For instance, I noticed that quietdynamics has listed "IBS" and "ringing in the ears" in her profile. These conditions would be directly associated with the metabolites being produced through the kynurenine pathway.
Here is a section from my book on this.

"The following studies confirm that both males and females with irritable bowel syndrome (IBS) have abnormal tryptophan metabolism. Abnormal tryptophan metabolism is indeed the "common pathogenetic mechanism" that both fibromyalgia and IBS share. In addition, the researchers found that the higher the level of kynurenine, the more likely the patients were to suffer with anxiety and depression.


Tryptophan catabolism in females with irritable bowel syndrome: relationship to interferon-gamma, severity of symptoms and psychiatric co-morbidity.
Fitzgerald, P., E.M. Cassidy, G. Clarke, P. Scully, S. Barry, E.M.M. Quigley, F. Shanahan, J. Cryan, T.G. Dinan. 2008. Neurogastroenterol Motil. 20(12):1291-7.

"Irritable bowel syndrome (IBS) has been linked with abnormal serotonin functioning and immune activation. Tryptophan forms the substrate for serotonin biosynthesis, but it can alternatively be catabolized to kynurenine (Kyn) by the enzyme indoleamine 2,3-dioxygenase (IDO)? Irritable bowel syndrome subjects had increased Kyn concentrations compared with controls?and there was a trend for Kyn:Trp to be increased in the IBS group... There was a positive correlation between IBS severity and Kyn:Trp... Those with severe IBS symptoms had increased Kyn:Trp compared to those with less severe symptoms and controls, and were over twice as likely to have depression or anxiety compared to those with less severe IBS? Females with IBS have abnormal Trp catabolism. The Kyn:Trp is related to symptom severity, and those with severe IBS symptoms have increased shunting of Trp along the Kyn pathway which contributes to the abnormal serotonergic functioning in this syndrome."


Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort.
Clarke, G., P. Fitzgerald, J.F. Cryan, E.M. Cassidy, E.M. Quigley, T.G. Dinan. 2009. BMC Gastroenterol. 9:6.

"Both kynurenine levels and the kynurenine:tryptophan ratio were significantly increased in the IBS cohort compared with healthy controls?These findings suggest that the activity of IDO, the immunoresponsive enzyme which is responsible for the degradation of tryptophan along this pathway, is enhanced in IBS patients relative to controls."

[Nat]

I also wanted to comment on the post concerning medications, such as Minocycline, that have been found to induce lupus.

I have posted research to show that lupus patients lack the necessary enzymes to digest dietary proteins (protease and DNase 1).  The basis of the lupus disease process is the inability to properly metabolize proteins. Any drug that inhibits these enzymes or interferes with the synthesis of proteins can induce lupus or other autoimmune diseases.



For instance, as the following information states, Minocycline's effects are related to the inhibition of "protein synthesis".

http://neurolex.org/wiki/Category:Minocycline

[SjoAmy]

Dilantin / Phenoytin also has a good sized history of inducing DIL /drug induced lupus.