How Do Anti Convulsants Work For Neuropathy

Today's post from painhq.org (see link below) looks at a common treatment for neuropathic pain and that is anti-convulsants or anti-epilepsy drugs. Many people living with neuropathy are prescribed these drugs after anti-depressants have failed and they are generally a pre-cursor to opiates (if they don't work for you). It is wise to consult carefully with your doctor (especially with Lyrica)depending on which anti-convulsant is prescribed and what the cause of your neuropathy is, as the side effects can be significant and for certain groups these drugs haven't been proven to work at all. It is a useful article in that it explains what they are and how they work and very often patients are not given this information by their doctors because it's assumed the patient will have difficulty understanding the science behind the drug's working process.

Anticonvulsants 
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What are Anticonvulsants?

Anticonvulsants are a group of drugs that were designed to help manage seizures, but have since been used in the treatment and management of neuropathic pain. It is a fairly large and diverse family of drugs, sometimes referred to as ‘anti-seizure medications’ or ‘antiepileptics’. These drugs are thought to work through a number of different mechanisms: some may block different neurotransmitters; others may affect nerve signalling and ‘firing’ through binding to different receptors; altering ion channels in the brain; or ‘stabilizing’ some of the nerve cell membranes to ‘quiet’ pain signalling. On balance, it is thought that through these various mechanisms anticonvulsants affect pain communication pathways for patients with neuropathic pain.

How do they work?

Anticonvulsants were first used in pain management because it was thought that the nature of pain was somewhat similar to that of epileptic seizures – too much nerve cell firing. A number of these drugs have been shown to block the signals from damaged neurons which would normally communicate pain within the body.

What kinds are there? 
 
Gabapentin (Neurontin): Gabapentin works by binding to the calcium channels in neurons. These calcium channels help communicate pain within the body and, when blocked, help to dull the signal. Gabapentin is one of the only drugs used to treat neuropathic pain that is solely metabolized through the kidney (most are metabolized through the liver). It is considered one of the ‘first line’ medication treatments for most neuropathic pain syndromes. It is often used for treating post-herpetic neuralgia and diabetic neuropathy. 

Pregabalin (Lyrica): Developed as a more potent follow-up to Gabapentin, Pregabalin has been prescribed for postherpetic neuralgia, diabetic peripheral neuropathy and central neuropathic pain. Pregabalin is also associated with a lower risk for dependency and potential abuse. 
 
Carbamazepine (Tegretol) / Oxcarbazepine (Trileptal): Carbamazepine works by binding to sodium channels in neurons and limiting pain signals. Used It is frequently used to treat trigeminal neuralgia, but also diabetic neuropathy and potentially other forms of neuropathic pain (though more research is necessary). 

Valproate (Sodium valproate, valproic acid): Valproate helps block calcium channels and increases the levels of GABA in the brain. The calcium channels help to communicate pain while GABA helps to black dull pain signals in the brain by blocking communication channels and affecting nerve transmission. More evidence is needed to determine the use of Valproate in the treatment of neuropathic pain. 

Lamotrigine (Lamictal): Lamotrigine helps to block sodium channels and helps to regulate signals between neurons. Used it is sometimes used in the treatment of trigeminal neuralgia, diabetic neuropathy and central neuropathic pain. There are increased risks of side effects in woman using Lamotrigine, which also poses certain risks for pregnancies. 

Topiramate (Topamax): Topiramate has a number of mechanisms of action including sodium channels, calcium channels, GABA receptors, AMPA receptors and carbonic anhydrases. More evidence is needed to determine the use of Topiramate in the treatment of neuropathic pain.

Levetiracetam (Keppra): Levetiracetam works by binding to calcium channels in neurons, though it’s mechanisms aren’t fully understood. It can be used in the treatment of peripheral neuropathic pain. 

Lacosamide (Vimpat): Lacosamide works by binding to sodium channels in neurons, which prevents them from firing. Lacosamide also targets the cell which have been active for a longer period of time; in other words, damaged, over-active nerve cells that are sending pain signals (versus healthy cells). Lacosamide is used in the treatment of diabetic peripheral neuropathy.

What kind of Anticonvulsant is most effective for you?

Gabapentin (0)

Pregabalin (0)

Carbamazepine (0)

Valproate (0)

Lamotrigine (0)

Lacosamide (0)

Levetiracetam (0)

Topiramate (0)

Related evidence

Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012 Feb 15;2:CD009318. doi: 10.1002/14651858.CD009318.pub2.
Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD007076. DOI: 10.1002/14651858.CD007076.pub2
Moore R, Wiffen PJ, Derry S, Toelle T, Rice AS C. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD007938. DOI: 10.1002/14651858.CD007938.pub3
Price MJ. Levetiracetam in the treatment of neuropathic pain: three case studies. Clin J Pain. 2004 Jan-Feb;20(1):33-6.
Wiffen PJ, Derry S, Moore RA, Aldington D, Cole P, Rice AS, Lunn MP, Hamunen K, Haanpaa M, Kalso EA. Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews. Cochrane Database Syst Rev. 2013 Nov 11;11:CD010567. doi: 10.1002/14651858.CD010567.pub2.
Wiffen PJ, Derry S, Lunn MPT, Moore R. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD008314. DOI: 10.1002/14651858.CD008314.pub3
http://www.painhq.org/learning/knowledge-base/category/treatments/traditional-medicine-and-surgery/anticonvulsants

HIGHLY EFFECTIVE NEW ANTI CANCER DRUG SHOWS FEW SIDE EFFECTS IN MICE

A new drug, known as OTS964, can eradicate aggressive human lung cancers transplanted into mice, according to a report in Science Translational Medicine. The drug, given as a pill or by injection, inhibits the action of a protein that is overproduced by several tumor types, including lung and breast, but is rarely expressed in healthy adult tissues. Without this protein, cancer cells fail to complete the cell-division process and die.

When taken by mouth, the drug was well tolerated with limited toxicity. An intravenous form, delivered within a liposome, was just as effective with fewer side effects. Both approaches -- described in the October 22, 2014 issue of Science Translational Medicine -- led to complete regression of transplanted tumors.

"We identified the molecular target for this drug ten years ago, but it took us nearly a decade to find an effective way to inhibit it," said study author Yusuke Nakamura, MD, PhD, professor of medicine at the University of Chicago and deputy director of the University's Center for Personalized Therapeutics. "We initially screened 300,000 compounds and then synthesized more than 1,000 of them, and found a few that were likely to work in humans. We focused on the most effective. We think we now have something very promising."

OTS964 targets TOPK (T -- lymphokine-activated killer cell -- originated protein kinase), a protein that is produced by a wide range of human cancers and is believed to promote tumor growth. High TOPK expression correlates with poor prognosis in patients with breast and lung cancer.

Initial studies of the drug, and a precursor called OTS514, found they were effective in killing cancer cells. But they could disrupt the production of new red and white blood cells, causing hematopoietic toxicity such as mild anemia and increasing the risk of infection. At the same time, the drugs increased the production of platelets, which help in blood clotting.

When the researchers encapsulated the drugs in liposomes -- microscopic bubbles similar to a cell membrane, commonly used to transport drugs within the body -- the drug no longer caused this decrease in red and white blood cells. This approach "completely eliminated the hematopoietic toxicity," the researchers wrote.

They tested OTS964 alone and in liposomes in mice with a highly aggressive human lung tumor known as LU-99. They allowed the tumors to grow to 150 cubic millimeters -- about the size of a raisin -- and then administered the drug intravenously to six mice, twice a week for three weeks. The tumors shrank rapidly and continued to shrink even after treatment stopped. In five of the six mice, the tumors completely disappeared -- three within 25 days of the first treatment and two within 29 days. Mice that received the liposome-coated drug had no detectable toxicity.

The drug also proved effective when taken in larger doses by mouth. Six mice with LU-99 lung tumors were fed 100 milligrams per kilogram of OTS964 every day for two weeks. Again, continuous tumor shrinkage was observed after the final dose of the drug. In all six mice the tumors completely regressed. All of the mice had low white-blood-cell counts after treatment, but they recovered within two weeks.

Although this was a small study, the outcome was dramatic. Seeing these results was a "quite exciting moment," said Nakamura, who stepped down from his role as Director in the Japanese Government's Office of Medical Innovation to join the faculty at the University of Chicago in April 2012. "It is rare to see complete regression of tumors in a mouse model," he said. "Many drugs can repress the growth, but it is uncommon to see them eradicated. This has rarely been reported."

Similar studies of the drug's effects on tumor cells growing outside the body enabled the researchers to videotape the process as the cancer cells died. TOPK appears to play a central role late in cytokinesis, the final stage in cell division. Dividing cancer cells would begin to separate into two new cells, but were unable to fully disconnect, retaining an intercellular bridge.

"Without TOPK the cells can't seem to divide; they can't make the break," Nakamura said. "They can't complete the process. Instead they remain tethered by a tiny bridge. When that finally breaks apart, they can't close the membrane. Everything within the cells spills out, they suffer and then die."

TOPK may provide a good drug target for several types of cancer. This study involved primarily lung cancers, but the gene is frequently upregulated in breast, brain, liver, bladder and other solid tumors as well as certain types of leukemia. The researchers are working with oncologists at the University to begin a phase-1 clinical trial as soon as the fall of 2015.

Anticonvulsants Anti epileptics For Neuropathy

Today's post from painhq.org (see link below) looks at the main anticonvulsants or anti-epileptic drugs that are prescribed for neuropathic pain. Many people are prescribed anti-convulsants after other pain killers and anti-depressive drugs have failed and many wonder why. The implications of being prescribed drugs that are essentially meant for a totally different condition, can be alarming, so this sort of article is useful in explaining which drugs are involved and what they do. If you are prescribed an anti-convulsant, it's also worthwhile discussing any possible side effects with your doctor, so that you're fully aware of any future complications.

What are Anticonvulsants?

Anticonvulsants are a group of drugs that were designed to help manage seizures, but have since been used in the treatment and management of neuropathic pain. It is a fairly large and diverse family of drugs, sometimes referred to as ‘anti-seizure medications’ or ‘antiepileptics’. These drugs are thought to work through a number of different mechanisms: some may block different neurotransmitters; others may affect nerve signalling and ‘firing’ through binding to different receptors; altering ion channels in the brain; or ‘stabilizing’ some of the nerve cell membranes to ‘quiet’ pain signalling. On balance, it is thought that through these various mechanisms anticonvulsants affect pain communication pathways for patients with neuropathic pain.

How do they work?

Anticonvulsants were first used in pain management because it was thought that the nature of pain was somewhat similar to that of epileptic seizures – too much nerve cell firing. A number of these drugs have been shown to block the signals from damaged neurons which would normally communicate pain within the body.

What kinds are there?

Gabapentin (Neurontin): Gabapentin works by binding to the calcium channels in neurons. These calcium channels help communicate pain within the body and, when blocked, help to dull the signal. Gabapentin is one of the only drugs used to treat neuropathic pain that is solely metabolized through the kidney (most are metabolized through the liver). It is considered one of the ‘first line’ medication treatments for most neuropathic pain syndromes. It is often used for treating post-herpetic neuralgia and diabetic neuropathy. 

Pregabalin (Lyrica): Developed as a more potent follow-up to Gabapentin, Pregabalin has been prescribed for postherpetic neuralgia, diabetic peripheral neuropathy and central neuropathic pain. Pregabalin is also associated with a lower risk for dependency and potential abuse.

Carbamazepine (Tegretol) / Oxcarbazepine (Trileptal): Carbamazepine works by binding to sodium channels in neurons and limiting pain signals. Used It is frequently used to treat trigeminal neuralgia, but also diabetic neuropathy and potentially other forms of neuropathic pain (though more research is necessary). 

Valproate (Sodium valproate, valproic acid): Valproate helps block calcium channels and increases the levels of GABA in the brain. The calcium channels help to communicate pain while GABA helps to black dull pain signals in the brain by blocking communication channels and affecting nerve transmission. More evidence is needed to determine the use of Valproate in the treatment of neuropathic pain. 

Lamotrigine (Lamictal): Lamotrigine helps to block sodium channels and helps to regulate signals between neurons. Used it is sometimes used in the treatment of trigeminal neuralgia, diabetic neuropathy and central neuropathic pain. There are increased risks of side effects in woman using Lamotrigine, which also poses certain risks for pregnancies.

Topiramate (Topamax): Topiramate has a number of mechanisms of action including sodium channels, calcium channels, GABA receptors, AMPA receptors and carbonic anhydrases. More evidence is needed to determine the use of Topiramate in the treatment of neuropathic pain.

Levetiracetam (Keppra): Levetiracetam works by binding to calcium channels in neurons, though it’s mechanisms aren’t fully understood. It can be used in the treatment of peripheral neuropathic pain. 

Lacosamide (Vimpat): Lacosamide works by binding to sodium channels in neurons, which prevents them from firing. Lacosamide also targets the cell which have been active for a longer period of time; in other words, damaged, over-active nerve cells that are sending pain signals (versus healthy cells). Lacosamide is used in the treatment of diabetic peripheral neuropathy.

Related evidence

Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012 Feb 15;2:CD009318. doi: 10.1002/14651858.CD009318.pub2.

Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD007076. DOI: 10.1002/14651858.CD007076.pub2

Moore R, Wiffen PJ, Derry S, Toelle T, Rice AS C. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD007938. DOI: 10.1002/14651858.CD007938.pub3

Price MJ. Levetiracetam in the treatment of neuropathic pain: three case studies. Clin J Pain. 2004 Jan-Feb;20(1):33-6.

Wiffen PJ, Derry S, Moore RA, Aldington D, Cole P, Rice AS, Lunn MP, Hamunen K, Haanpaa M, Kalso EA. Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews. Cochrane Database Syst Rev. 2013 Nov 11;11:CD010567. doi: 10.1002/14651858.CD010567.pub2.

Wiffen PJ, Derry S, Lunn MPT, Moore R. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD008314. DOI: 10.1002/14651858.CD008314.pub3

 http://www.painhq.org/learning/knowledge-base/category/treatments/traditional-medicine-and-surgery/anticonvulsants