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Emerging Treatments for Chronic Pain

Abstract:

Pain can be classified as acute (rapid-onset) or chronic (outlasting the original insult by months/years). Chronic pain is different from acute pain in that therapies that provide transient pain relief do not resolve the underlying pathological processes maintaining the pain; therefore, it is not simply the duration of the pain that differentiates between acute and chronic pain, but also the inability of the body to heal itself. Thus, damaged tissues and nerves can provide continued inputs into the central nervous system that drive multiple changes at many levels of the pain-signaling pathways. Since pain is not only a sensory response but also an affective state, the pain produces a series of comorbidities such as fatigue, anxiety, and depression. These interact to produce impaired quality of life in chronic pain patients.

The signal interpreted as pain can be altered at many points along the pain pathway, providing a multitude of strategic targets for rational therapeutic intervention. However, despite the huge increase in our understanding of the cellular and molecular mechanisms that initiate and maintain maladaptive pain processing, chronic pain remains a huge unmet clinical need. The pharmacopeia of available drugs is effective in some chronic pain patients, but not all of the time, due to disease progression, low efficacy, and, more often, intolerable side effects. Thus, efforts need to continue to boost the pharmaceutical profile of available agents by improving efficacy, tolerability, and pharmacokinetics, in addition to developing new chemical entities to manage pain refractory to current drugs. This article will focus on some of the molecular mechanisms and targets that are currently attracting interest in chronic pain research.

Excitatory Mechanisms—Blocking Aberrant Activity

Voltage-gated Sodium Channel Blockers

Sodium channel (NaV) blockers such as local anesthetics, carbamazapine, etc. have been the mainstay of pain medicine for decades, producing anesthesia and analgesia by preventing action potential propagation; however, blocking conduction is not their only role. Three of the nine isoforms of the human sodium channel family, NaV 1.7, 1.8, and 1.9, are expressed selectively in damage-sensing peripheral neurons.1,2 Animal studies have demonstrated a role for these channels in mechanosensation. Accordingly, mechanical hypersensitive behaviors akin to allodynia (painful experience to innocuous stimulation, e.g. touch) and hyperalgesia (heightened pain experience to painful stimuli) seen in chronic pain models are attenuated in tissueselective knock-out mice lacking these selective pain-related channels.3

Aberrant activity in damage-sensing peripheral fibers following inflammation arises from the processes of peripheral sensitization, whereas clustering of these channels at the site of injury and neuroma after nerve injury is thought to be a major drive for the induction of disordered central processing.3 The newly dense distribution along the sensory neurone supports spontaneous firing of action potentials along the neurone in the absence of peripheral stimuli. Additionally, a concomitant upregulation of the embryonic NaV 1.3 occurs, whose biophysical properties and re-expression in adult neurones after nerve injury have been associated with increased neuronal excitability and neuropathic pain.4 However, a recent study has refuted its role in nerve-injury or chronic inflammatory pain,5 although its role in central neuropathic pain could be considered on the basis of its upregulation in thalamic nuclei.6 Pre-clinical data point to a major role for NaV 1.7 in acute and inflammatory pain states.7 Differential mutations in the encoding gene, SCN9A, have been linked to the intense burning pain in erythermelalgia patients, a congenital absence of pain perception, and reduced lidocaine effectiveness in some pain patients.8,9 Understanding the genetic basis for altered nociceptive profiles in chronic pain patients could lead to selective therapy on an individual basis.