This is really going to be an evidence-based approach to the treatment of neuropathic pain. That is, a review of the results of randomized, double-blind, placebo-controlled clinical trials that were done, and that either support or fail to support the variety of classes of drugs that we tend to use for the treatment of these disorder.

There are a number of neuropathies that are associated with pain. Perhaps the most common in the western world is painful diabetic neuropathy. But you also have other metabolic neuropathies that can be associated with pain, such as alcoholic neuropathy. Then [there are] the neuralgias, such as trigeminal (TN) and post-herpetic neuralgias (PHN).

In the case of sympathetically maintained pain [there are] the complex regional pain syndromes, type 1 being what used to be referred to as reflex sympathetic dystrophy and type 2 being the causalgias. And then [there are] other conditions such as phantom limb pain, as well as central pain following [central nervous system lesions] such as stroke.

Just as a background we are going to briefly review the neuroanatomy of the pain pathways. There are a number of receptors known as nociceptors because they preferentially react to noxious stimuli whether they are thermal, mechanical or chemical. These are known as the A-delta fibers, which are lightly myelinated fiber[s] and the C fibers, which are unmyelinated fibers. The A-delta and C fibers synapse in the dorsal horn, preferentially in lamina[s] 1, 2 and 5.

From there they cross to the other side of the spinal cord and ascend in the spinothalamic tract until they synapse in the thalamus preferentially in the ventroposterolateral (VPL) nucleus from which they make a secondary connection in the sensory cortex, which is responsible for the sensory component of pain, as well as in the limbic forebrain system that accounts for the emotional component of pain.

There are also 2 important descending inhibitory pathways from the brainstem to the spinal cord. The first originate[s] at the level of the midbrain in the periaqueductal gray and it has predominantly serotonin its major neurotransmitter. The other originates at the level of the locus ceruleus in the medulla and it has norepinephrine as the major neurotransmitter.

A number of mechanisms have been postulated [for] maintaining neuropathic pain. In the past, we tended to focus mostly on the peripheral changes that occurred following deafferentation. And basically what you have is an upregulation of the sodium channel. There are a number of sodium channels that are created at areas of demyelination or axonal injury. As a result, the way to treat peripheral sensitization, which is characterized by decreased threshold and ectopic discharges, is by giving a sodium channel modulator.

But perhaps as important [are] the changes that occur more [rostrally] at the level of the spinal cord. Very early on following a peripheral nerve injury, the dorsal horn gets bombarded by a variety of neurotransmitters. Glutamate and aspartate, which are excitatory transmitters, interact with the N-methyl-D-aspartate (NMDA) receptors and [substance P and] neurokinin interacts with the neurokinin type 1 (NK1) receptors. This leads to calcium entry into the cell. Calcium acts as a very important secondary messenger. It activates nitric oxide synthetase which leads to the synthesis of nitric oxide. It leads to immediate early gene expression [(c-fos and c-jun)] and it also activates a number of [phospholipases], that phosphorylate a number of receptors at the level of the dorsal horn decreasing its threshold and leading to ectopic discharges, a phenomenon known as central sensitization.

And in order to treat central sensitization you are going to have to use NMDA-blocking agents, NK1- or substance P-blocking agents, or calcium channel modulators.