Pharmacologic agents directed at the treatment of pain associated with maladaptive neuronal plasticity

ABSTRACT

Introduction

The definition of nociplastic pain in 2016 has changed the way maladaptive chronic pain is viewed in that it may emerge without neural lesions or neural disease. Many endogenous and pharmacologic substances are being investigated for their role in treating the pain associated with neuronal plasticity.

Areas Covered

The authors review promising pharmacologic agents for the treatment of pain associated with maladaptive neuronal plasticity. The authors then provide the reader with their expert opinion and provide their perspectives for the future.

Expert opinion

An imbalance between the amplification of ascending pain signals and the poor activation of descending inhibitory signals may be at the root of many chronic pain syndromes. The inhibitory activity of noradrenaline reuptake may play a role in neuropathic and nociplastic analgesia. A better understanding of the brain’s pain matrix, its signaling cascades, and the complex bidirectional communication between the immune system and the nervous system may help meet the urgent and unmet medical need for safe, effective chronic pain treatment, particularly for pain with a neuropathic and/or nociplastic component.

KEYWORDS:

• neuropathic pain
• nociplastic pain
• maladaptive pain
• microglial activation
• pain matrix
• neuroplasticity

Article Highlights

• Nociplastic pain (defined in 2016) and neuropathic pain are maladaptive forms of chronic pain involving central sensitization, increased membrane excitability, amplified synaptic activity, and reduced inhibitory mechanisms making the central nervous system overly response to afferent inputs.

• The threshold for microglial activation can be altered, particularly with age, resulting in ‘priming’ which can maladaptively alter the homeostatic balance between the brain and the immune system and may result in sustained neuroinflammation, neuronal damage, and chronic pain. Activated microglia release an abundance of pro-inflammatory cytokines.

• Astrocytes can change morphology and genetic expression with insult or injury and may become a neurotoxic type A1 reactive astrocyte or a neuroprotective type A2 reactive astrocytes.

• Mast cells catalyze and recruit numerous substances that initiate, amplify, or continue both immunological and neuronal responses. There is complex bidirectional communication between immune and nervous systems.

• An imbalance between the ascending and descending pathways may underlie chronic pain syndromes. The ascending pathways can become aberrantly amplified while at the same time, the inhibitory effects of the descending pathways can be diminished.

• Numerous pharmacologic agents with different mechanisms of action are being studied for their role in the treatment of maladaptive pain. These include monoclonal antibodies, disease-modifying antirheumatic drugs, ‘food for special medical purposes,’ immunomodulators, ketamine, tumor-necrosis-factor-alpha blockers, and others.

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Declaration of interest

JV Pergolizzi, JA LeQuang and K Mitchell are all employees of NEMA Research while M Chopra is an employee of Decision Alternatives, LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.