What is Neuropathic Pain?

Chronic neuropathic pain – this is a serious and debilitating disease that affects millions of people in the United States alone. We typically think of pain as a symptom, but chronic neuropathic pain is a disease, one with severe quality of life impairments. The ongoing social and economic costs from this disease are tremendous: between 50 and 60 percent of people with chronic pain are less able or unable to exercise, sleep normally, perform household chores, attend social activities, drive a car, or walk.

The clinical need for new treatments for neuropathic pain is large and undisputed. According to leading experts, despite the best of care and sequential trials of therapy, pain will remain unrelieved or inadequately relived for 40-60% of patients suffering from neuropathic pain. The most commonly prescribed first line therapies for neuropathic pain generally work in less than 50% of patients and, even then, provide only partial relief. In addition, these treatments are often not well-tolerated, and their dosages must be carefully controlled to limit the possibility of severe side effects. For example, opioids, which are the most typical second line treatment, can have devastating side effects and prolonged treatment can lead to addiction and tolerance. Sadly, those with the most severe cases of neuropathic pain are the least likely to receive relief from existing medications. The clinical need for a safe, effective, non-addictive treatment for neuropathic pain is overwhelming. This is what drives Xalud’s efforts: the need to develop new therapies that target neuropathic pain effectively, getting to the root of the disease.

What Causes Neuropathic Pain?

Chronic pain is a feature of several different diseases, originating primarily from damage to neurons. Neuropathic pain is poorly treated by FDA-approved drugs. Existing therapies are not well tolerated and often addictive. Current research indicates that these therapeutics fail for two reasons. First, the function of these compounds have been hijacked into serving as pain treatments. What little efficacy they possess in the treatment of low-intensity chronic pain is secondary to the primary function for which they were actually developed. As a result, these compounds exhibit complications during therapy.

Second, and most importantly, these drugs fail explicitly because they target only the neurons in the pain pathway. Although targeting neurons can modulate pain signals, currently available therapies provide only partial efficacy because they do not affect the persistence of neuropathic pain. The growing understanding of the source of this persistence, driven by work from the laboratory of Xalud’s co-founder, Dr Linda Watkins of the University of Colorado Boulder and developed in several laboratories around the world, is directed squarely at a population of cells in intimate anatomic and functional association with neurons: the glia.

These cells, comprised of astrocytes and microglia, greatly outnumber pain pathway neurons and surround their synapses. The synapse, once considered an exclusive neuron-to-neuron interface, is now known to consist of the functional interaction of neurons and glial cells. Glial cells are local actors and do not signal long distances like neurons. They detect the local chemical signals exchanged back and forth between neurons, and become activated in response to neuronal signaling caused by inflammation or trauma, resulting in the production of different pain-enhancing compounds. These compounds include pro-inflammatory cytokines, which act on neurons in pain pathways to sensitize and enhance pain signal processing – they turn up the volume of the pain system. Under conditions of low to moderate pain signaling, this communication loop, which acts on both neurons and glial cells, typically resolves itself naturally through a cascade of compounds that reduce the gain of the signaling system – turn down the volume control – and return the system to its normal functional state. Perversely, in the face of nerve damage, the system that would turn down the gain cannot keep up, resulting in inappropriate signaling, persistent glial activation, and severe, enduring pain. Because this is established by a positive feedback loop, this pain often persists beyond the resolution of the initial nervous system damage. Thus, activated glia play a major role in the development and maintenance of neuropathic pain.

Is There A Treatment for This Disease?

The key to this positive feedback loop caused by spinal glial activation is the ongoing release of pro-inflammatory cytokines from glia. Their actions on first- and second-order neurons of the pain pathway lead to amplification of pain transmission to higher centers. Some neuron-based therapies, the opioids, actually activate spinal glial cells directly, again causing glia to release more of the pain-enhancing, pro-inflammatory cytokines, thus counteracting the opioid’s own effectiveness. No approved therapy targets the glial cells that are critically responsible for the maintenance of the pathological activation state. Their activation persists unabated. This failure explains why these therapies are ineffective against chronic neuropathic pain.

Xalud’s solution? The anti-inflammatory cytokine interleukin-10 (IL-10), a novel non-opioid, non-addictive drug candidate to treat this disease. IL-10 is a relatively small, secreted protein, a naturally-occurring protein found in the central nervous system. The expression of IL-10 is increased under inflammatory conditions. IL-10 powerfully suppresses the production and function of pro- inflammatory cytokines released by activated glia. IL-10 accomplishes this not by affecting neuronal activity directly – in fact, pain neurons do not express the IL-10 receptor and are thus blind to its direct effects – but by targeting the primary pro- inflammatory cytokines active in the development and maintenance of neuropathic pain: IL-1β, IL-6, and tumor necrosis factor-α. IL-10 blocks the activity of these pro-inflammatory compounds at multiple levels: inhibiting the production of their messenger RNA, inhibiting the translation of their mRNA, up-regulating the expression of ‘decoy’ receptors for some of these cytokines. Although other pain therapies in development also target glial activation, these have been unsuccessful largely because they do not have the breadth to target each of the critical spinal pro-inflammatory cytokine pathways; IL-10 does. Thus, IL-10 is an example of a polypharmacy therapeutic: delivered to the right spot, it provides, in a single therapeutic, a multivalent response to the pro-inflammatory cytokine activity responsible for neuropathic pain.