Despite the long standing availability of pain medication, confusion still exists as to which medication is best for the treatment of pain. This is due in large part to a relative lack of understanding of pain receptor types and the large number of pharmacologic agents that can be used to treat both the symptoms and the underlying disorder.

Several neuropathic disorders including diabetic peripheral neuropathy, postherpetic neuralgia, Reflex Sympathetic Distrophy (Complex Regional Pain Syndrome), post surgical/traumatic neuropathy, toxic and idiopathic neuropathies share similar pain perception pathways.

Theoretically the use of a single agent that is directed toward the responsible pain receptor is preferred over an agent that is nonspecific for the condition being treated. Likewise, the use of multiple agents with different mechanisms of action should increase effectiveness for conditions where more then one receptor problem exists. This approach may make sense if the receptor generating the pain can not be identified.

The focus of this article will be to review various receptor types that are important in neuropathic pain generation, and the agents available that can be used to treat them. By in large these receptor targets are different then the Opiate (narcotic) or Non Steroidal (NSAID) receptor sites that are commonly thought of.

In the majority of cases, pain signals are first generated from peripheral nerve fibers and then transmitted to the central nervous system. Once in the central nervous system, the pain signal is modulated so that it is either ignored, moderated or enhanced. In order to effectively treat pain, both peripheral and central receptors may have to be addressed. There is ample evidence, however, that the central receptors can be influenced simply by treating the peripheral receptors.

The key receptor in the central nervous system for pain modulation is the NMDA receptor. Glutamate and Glycine have been found to be important NMDA stimulants. They work on the NMDA receptor by opening its voltage dependant channels at the cell membrane level. There are also Non-NMDA receptors. One important one is called the AMPA receptor. N-methyl-D-aspartate is an example of an AMPA receptor stimulant. AMPA receptors are typically found near NMDA receptors.

When these receptors are made more excitable, the pain experience is upgraded. This upgrading involves other systems such as the recruitment of Substance P, Alpha agonists and antagonists, GABA agonists and free radicals. Agonists are things that make something stronger and antagonists are things that make something weaker.

In fact all receptors are functionally dependant on the status of their voltage dependant channels, or gates. These gates are typically specific for minerals such as calcium, magnesium, potassium or sodium. It is therefore very important to make sure that your minerals are in proper balance to begin with when treating pain. GABA and Sodium channel activity have been found to have important down regulatory effects on the NMDA receptor.

Agents that are antagonistic to GABA,such as Baclofen, can be given along with drugs such as Ketamine, which is antagonistic to the NMDA receptor itself, for an additive effect. Recently NMDA receptors have been found in peripheral nerve and skin as well. As a result, topical agents applied can offer effectiveness in down regulating the pain experience.

The antiepileptic Neurontin and the calcium channel blocker Procardia are examples of other drugs that reduce neuropathic pain. Neurontin works because it is a glutamate antagonist. Procardia works because it prevents calcium dependant voltage gate opening. Since the net effect of both of these drugs is to decrease NMDA responsiveness, there is less pain signal generation by the receptor.

The AMPA receptor has been found to be sensitive to sodium channel opening. Reduction of pain sensation can be accomplished with medicines that have sodium channel stabilizing effects. Examples include the anti seizure drugs Neurontin, Tegretol, Depakote and Dilantin. The cardiac antiarrythemic Mexitil has a similar mechanism of action. It has been used successfully for pain reduction as well.

Catapres has agonist effects on the alpha receptors in both the central and peripheral nervous system. As agonists, they block the release of norepinepherine from sympathetic nerve endings. As a result of the weakened sympathetic response to an inciting stimulus, pain reduction occurs.

In addition, Catapres has an agonist effect on opiod receptors, which in turn blocks the release of substance P. Both of these effects reduces the pain experience. Procardia's calcium channel blocking effect causes blood vessel wall relaxation. By increasing oxygen o the tissues, it therefore has a second mechanism of action to reduce pain. Unlike Clonidine, however, it does not work at the alpha or opiod receptors.

Zanaflex is an alpha agonist muscle relaxor. Because it reduces reflex activity within the spinal column, it reduces the release of excitatiory amino acids. This in turn inhibits the release of substance P and results in less stimulus for upgrading of NMDA activity.

Guanethidine is a drug that depresses the function for the postganglionic adrenergic fibers. Its major effect is to inhibit responses to sympathetic activation. Guanethidine also has considerable anesthetic activity. Bretylium is another example of a drug in this class.

Elavil, Pamelor and Deseryl are antidepressants with known pain relieving properties. They block the reuptake of norepinephrine, which presumably decreases alpha adrenergic tone. They also know to block sodium channels. Their sedating side effect probably plays a role in pain reduction as well.

Lidoderm and Emla Patches are topical anesthetics that reduce pain via their soium channel blocking activity. Capsacin cream inhibits the release of substance P. Antivirals such as Amantidine and Zovirax can reduce immune response related neuropathic pain.

Plavix, an antiplatlet agent and Pletal a vasodialating drug used for claudication can reduce pain by facilitating oxygen delivery to the tissues. Trental, by increasing red blood cell pliability has been used with success as well. Naturally co morbid disease management and good nutrition facilitates healing and nerve membrane stability.

Another example of co morbid disease management that may have a large impact on pain is hidden infection. When infection is present, appropriate use of certain antibiotics can provide dramatic relief. This is especially true for those who have a predisposition to rheumatic conditions.

While this is only a brief review of non-narcotic pain relieving medications, it should be clear that there is an important role for pain management with these agents. As our understanding of the numerous mechanisms that affect the pain experience increases we should expect to see more pharmacologic approaches for it's treatment that are either receptor, voltage gate or co morbid disease driven.