NAMENDA AND FACIAL PAIN

Joseph K. Vaughan, Jr., M.D.

Diplomate, American Board of Psychiatry and Neurology

General Neurology

Speaker, Dallas TNA Regional Conference, February 18, 2006

Excerpted in the Summer  2006 TNALERT

Trigeminal neuralgia is certainly the most painful of the facial pain syndromes, and while there are a variety of treatments, both medical and surgical, available to help patients with these problems, an unfortunate significant number of patients get little or incomplete relief with the currently available therapies.  From a clinical standpoint, treating these patients requires a lot of creativity and “out of the box” thinking.

An example of such would be the use of a fairly new medication which has been approved to treat moderate to severe Alzheimer’s disease.  Namenda, or memantine, is the fourth such drug available for use in these patients.  While the other three medications exert their effects on the neurotransmitter system involving acetylcholine, which has long been known to be crucial to the production and maintenance of memories, Namenda works in a completely different way than these medications:  it works on preventing cellular death by the entry of an excessive amount of calcium in nerve cells, specifically in the brain, for the Alzheimer’s patient.  Namenda does this by working on the N-methyl-D-aspartate (NMDA; hence the name “NaMenDA”) calcium channels, or pores, which exist in the walls of cells to allow for calcium, under the appropriate conditions, to enter cells.

Not only is calcium, and the associated biochemical reactions and neurotransmitters involved with calcium, important in memory, there are a multitude of other diseases or conditions in which these drugs have been used in both research and clinical patient groups.  These include:  Parkinsonism, migraine, seizures, spasticity, alcoholism, other addictions, neuroleptic malignant syndrome, phantom limb pain after amputation, Huntington’s disease, obesity, binge eating disorders, ataxias (Friedrich’s), the nystagmus seen in some multiple sclerosis patients, stroke, other roles in neuroprotection (such as head trauma), glaucoma, and depression.  This allows us to look at this body of research, particularly in the various pain syndromes, and learn a way to perhaps help patients with facial pain syndromes, as we now know calcium and its associated biochemistry play a crucial role in generating and modulating pain.  There are a variety of syndromes in which working on blocking calcium’s effects have proven to be effective ways of alleviating or stopping pain.

Since the early 1960’s more and more research has been devoted to the NMDA receptors in cell membranes and their involvement in pain as a way of blocking these harmful effects of calcium.  Ketamine (a veterinary anesthetic, primarily), dextromethorphan, amantadine, and now Namenda are the best-known medications which have been shown to have such benefits for chronic pain patients.  They are the best-known medications which are clinically available to work in such a unique fashion.

Pain, facial pain included, is detected by certain nerve fibers which stimulate the body to release a chemical, a neurotransmitter, known as glutamate in the spinal cord (and brain) which acts at NMDA receptors and stimulates them.  This stimulation then causes the spinal cord to become more sensitive to the firing of the pain fibers, increasing the amount of pain signals reaching the spinal cord, and consequently the brain.  Calcium-channel blocking drugs at the NMDA receptors, then, wouldn’t prevent the nerve fibers from detecting a painful stimulus, but they would decrease the number of such signals being handled in the spinal cord, and then reaching the brain.  Importantly, there is some evidence that such drugs would also keep people from becoming as chemically tolerant to narcotic medications, which are often used in people whose pain could not be controlled otherwise.  This would be an extra benefit for these patients.

There is some evidence that ketamine, and potentially other drugs which prevent the glutamate from causing excessive calcium entry into nerve cells in the spinal cord and brain, can actually block the transmission of pain at the very beginning, preventing the two major pain-transmitting nerve fibers from firing and thus actually reducing the total amount of pain signals brought to the spinal cord.  The major effects of such medications were thought to be in prevention or reduction in “central pain,” pain signal handling in the central nervous system (brain and spinal cord).  Any additional benefit before these signals are processed in the central nervous system is obviously very helpful.  The current management of chronic pain conditions of various types is focused on trying to block pain at as many places as possible, often requiring a few to several different drugs which come from various classes to achieve the desired result.  It is exciting that in keeping with this management principle some of the drugs which are in use or being developed may themselves carry this additive benefit of working at more than one place in the body to block pain.

Ketamine has a history of at least some efficacy in treating chronic pain, including orofacial pain.  Specifically, ketamine was helpful to a patient with glossopharyngeal neuralgia, a pain disorder quite similar to trigeminal neuralgia, but involving the ninth cranial nerve instead of the fifth.  Dextromethorphan has been used in facial pain syndromes with some success, and is occasionally now added to other medicines for this benefit. 

Currently the development of important drugs along the lines of Namenda include trying to identify which subtypes of the calcium channels may be most important for both handling pain and the cause of side effects; they do not appear to always be the same, suggesting drugs can be designed to act on the pain-mediating receptors in the cell membranes, but avoiding the receptors which may be the ones which cause the side effects.  Changing the chemical properties of the medications can be important.  Many of the severe side effects from these medications are felt to be the result of the drug completely blocking the entry of calcium into nerve cells.  There should be a normal amount of calcium allowed in through these pores to allow the cells to function, but to prevent pain the excessive amount allowed in is what is trying to be blocked.  A drug which blocks for a while but then moves on works better, with fewer side effects, than a drug which binds onto the cell and stays forever.  This is the case for Namenda.

Namenda is usually titrated to a dose of 10 mg twice a day, taken in a pill.  For use in pain, a higher dose could certainly be reasonably considered.  Typically we think of nausea and stomach pain as the major side effects, but fatigue, constipation, and rash are other common possibilities.  While there are a variety of reported side effects in using Namenda, generally this is a very well-tolerated medication.  It is quite easy to begin and continue using Namenda with the majority of the commonly prescribed medications used to treat trigeminal neuralgia and other facial pain syndromes, including the anticonvulsant and antidepressant types of medications.  If adding Namenda to a drug regimen stops the pain, consideration to tapering the previously ineffective medications can be given after a while of pain control.  Like most other medications which act on the brain and spinal cord, tapering Namenda would be the best way to stop its use should it prove to have intolerable side effects or not effective in helping the pain. 

Currently, the easiest drug to use in blocking calcium’s entry into nerve cells, of the ones clinically available, is Namenda.  It is very well-tolerated, safe, easy to dose, and seems to cause little in the way of interactions with other medications patients are taking.  The use of Namenda in all facial pain syndromes, headache, and other painful conditions is beginning to accelerate.  As the research progresses, and as we get more familiar with this medication in its currently approved indication of Alzheimer’s, I think that more and more physicians interested in preventing pain will find this medication (and its progeny) a very effective tool in improving the lives of patients who heretofore may have had incomplete relief of their painful condition.

Updated 7-03-06