Researchers explore many uses for Neurontin; no CFIDS trials planned
By David Hoh

Why might a drug that was designed and approved to treat epileptic seizures be useful in treating CFIDS?
 
Dr. Jay Seastrunk of Texas, who has been using the anticonvulsant drug Neurontin for several years to treat people with CFIDS and multiple chemical sensitivity (MCS), says CFIDS and MCS patients usually demonstrate a brain dysfunction, typically in the left frontal lobe--a focal brain injury. The cause of the injury could be many things, from a childhood head injury, a period of oxygen deprivation at birth, whiplash in an automobile accident, a high fever or toxic exposures. An infection with an organism such as mycoplasma, chlamydia, Lyme or even a simple flu of further chemical exposure could trigger further brain injury. Dr. Seastrunk explains the Neurontin helps treat the brain injury and helps "detoxify" the brain by modulating the action of various brain chemicals.
 
He is not alone among CFIDS specialists. Dr. Paul Cheney of North Carolina believes Neurontin can help "protect the brain" from further damage He has said that an injured brain may respond to lesser stimuli than a healthy brain, and this overstimulation of the brain may contribute to feelings of fatigue and pain. He has found that Neurontin seems to raise the sensitivity threshold of the brain’s pain response in CFIDS patients.
 
And Dr. Jay Goldstein, in his 1996 book, Betrayal by the Brain, described the complex electrical activity in the brain and suggested that imbalances of neurotransmitters and the substances that modulate them play an important role in CFIDS and fibromyalgia. He used lower doses and reported that many of his patients experienced a marked increase in energy after the first dose, with some also experiencing an antidepressant effect. 

A unique drug 
Neurontin, Parke-Davis’ brand name for gabapentin, is a unique anticonvulsant, chemically unlike any other drugs available to treat seizures. It was approved in 1993 for the treatment of seizure disorders after extensive testing with epilepsy patients. Ever since, clinicians and researchers have been experimenting with and studying Neurontin for a growing assortment of conditions, particularly mood disorders and neuropathic pain (pain associated with a nervous system injury or disease). Here’s a partial list gleaned from a simple search of medical journals:

• Migraine headaches
• Trigeminal neuralgia (severe sharp nerve pain in the face) in multiple sclerosis
• Postsurgical neuropathic pain
• Postherpetic neuralgia (intractable pain following a case of shingles
• Severe nerve pain associated with diabetes
• Anxiety disorders
• Mood disorders
• Social phobia
• Restless leg syndrome
• Orthostatic tremor (a quivering of a muscle associated with standing erect)
• Myokymia-cramp syndrome (a rare condition of persistent muscle cramps in the limbs)
• Muscle wasting in amyotrophic lateral sclerosis (Lou Gherig’s disease)

There apparently have been no papers published in peer-reviewed journals about the use of Neurontin in CFIDS.
 
Dr. Elizabeth Garofalo, senior director in charge of new indication studies at the Parke-Davis Research Division in Ann Arbor, Mich., explained the broad appeal of Neurontin:

Trial and error 
"We have some information about how it’s being prescribed, and we know that there’s a lot of use in epilepsy, of course, and in pain and anxiety," she said in a recent telephone interview. The trials the company has done in pain and anxiety disorders resulted in part from the way doctors were prescribing it.  

"Then we know there’s another large group--about 30% of the prescriptions--that being used in literally 30 different things. I don’t know if chronic fatigue syndrome shows up in that, but it may be subsumed in the other categories.

"There really is a lot of trial and error going on right now with Neurontin because of the perception of its safety and the ease of use, so people are trying it in a lot of different neurological and psychological diseases."

Safe and fast acting 
Neurontin, in addition to having an apparently broad range of action in the brain, is an easy and relatively safe drug to experiment with. Physicians can try out a drug for an unapproved use where there is a rationale for a possible benefit, especially with a patient who has been resistant to other treatments. In past trials, patients taking Neurontin have experienced few and benign side effects, mostly sleepiness, dizziness, ataxia and fatigue. Neurontin does not interact with other medications, including opiods, benzodiazapines or other medications that affect the brain. "It is well tolerated by most patients," Dr. Garofalo said.
 
It is also fast acting.
 
"In animals, we see an effect right from the first dose in seizure models. And in our clinical trials, we can see an effect within days, so it’s not a drug that you have to start and then wait for weeks, necessarily, to see an effect. In most of our studies, the medication is given chronically, so we don’t look for awhile, but with pain, in the one study that has been published, we looked weekly and we did see an effect that was already significantly different from placebo at two weeks, and that effect was sustained over the eight weeks that we studied."
 
While studies have not looked for efficacy (effectiveness or the treatment) in long-term use, patients who have taken Neurontin for a number of years have had no problems with the medication and many continue to receive benefit from it.

Still a mystery 
But how exactly does Neurontin work? That’s still largely a mystery to researchers.
 
"I don’t think we have a full understanding of how it works in the brain at this time," Dr. Garofalo said. "We believe that it works in the brain and the spinal cord, and we know that it binds to a novel receptor associated with the calcium channels, but we don’t understand the full scientific meaning of that.

"It certainly affects GABA levels, increasing GABA levels in the epilepsy patients who are treated with Neurontin. It binds to this receptor that’s called the alpha-2-delta receptor on calcium channels and it reduces polysynaptic neuronal activation. It decreases neuradrenaline and dopamine release, decreases glutamate synthesis and increases the 5-HT concentration in the serotonergic systems."
 
In lay terms, Neurontin modulates or evens out the nerve messages in the brain and helps the brain respond to impulses at a steady rate.
 
It is interesting to clinicians treating a variety of illnesses perhaps because it makes subtle changes in so many nerve impulse systems. Rather than being a specific target for a single neurotransmitter that might be implicated in a specific condition, it does a range of different things that might be implicated in a number of conditions.
 
It is not particularly expensive--about $3 a day for an average epilepsy patient who would take 1,500 mg per day. Pain trials have used a lower dose than that. Dr. Seastrunk uses much higher doses, about three times higher. Parke-Davis does have a system in place to help make the drug available to indigent patients.

New and improved 
Currently, the company’s research attention has shifted to a new drug.
 
"We have a new drug that we think is more potent that we’re just beginning to study in research trials. It’s called Pregabalin, and we’re really looking for a new and improved Neurontin," Dr. Garofalo said. Initially, the company is studying Pregabalin in anxiety, epilepsy and pain, and the first results of clinical trials should be reported late this year.
 
"It’s a very interesting compound. I’m not aware of any other compound that is being studied so broadly at this point the way that Pregabalin is being studied or that seems to have such utility."
 
Meanwhile, the use of Neurontin continues to increase, as trials in pain and other conditions are being reported and physicians are being more aware of its potential.
 
Presently, no trials are planned in CFIDS, but the door is open, Dr. Garofalo said. "We are still receiving proposals from the outside from physician investigators who are interested in doing trials, and we review every proposal that comes in, so if there is someone out there who is interested, we’re always happy to look at proposals."

David Hoh is completing his second year of service to the Association as editor of the Chronicle.

One doctor's experience
Dr. Jay Seastrunk, a psychiatrist in Duncansville, Texas, said he has been successful in getting insurance reimbursement for Neurontin as treatment of a brain injury, which he documents through MRI and SPECT scans. In an assessment designed to indicate the presence of a focal brain injury, Dr. Seastrunk gives his patients a questionnaire called an organic evaluator, and he reports that 95% of those with CFIDS or MCS show some evidence of brain dysfunction. Among the conditions he says indicate brain injury are imagined smells and tastes, visual distortions such as colors or spots, inability to understand what people are saying to you, using the wrong word in conversation or losing one’s train of thought in the middle of a sentence, dizziness, and abnormal feelings of hot or cold.
 
It can take as much as two years to get the full effect of the treatment, although most will start to see improvement within three months. He has reported that Neurontin relieved symptoms in about 15-20% of his patients and provided significant improvement for another 60-65%. About 10% of patients did not respond. He typically prescribes 3,600 to 4,200 mg per day, sometimes more, in four doses. He noted that magnesium blocked the action of the drug.
 
When patients showed improvement but continued to be sick, Dr. Seastrunk said he tested for something that could be causing continued injury to the brain--for instance, a mycoplasma or chlamydia pneumoniae infection. However, Dr. Seastrunk said he believed that CFIDS symptoms are a manifestation of the brain injury and brain dysfunction. By treating the brain and correcting its responses, along with decreasing stress and removing toxic stimuli, the brain is able to correct the immune system malfunctions, which he said he believed were secondary to the brain injury.