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16 Articles in Volume 19, Issue #2
Analgesics of the Future: Inside the Potential of Glial Cell Modulators
APPs as Leaders in Pain Management
Cases in Urine Drug Monitoring Interpretation: How to Stay in Control
Complex Chronic Pain Disorders
Efficacy of Chiropractic Care for Back Pain: A Clinical Summary
Hydrodissection for the Treatment of Abdominal Pain Caused by Post-Operative Adhesions
Letters: The Word "Catastrophizing;" AIPM Ceases Operations; Patient Questions
Management of Severe Radiculopathy in a Pregnant Patient
Managing Pain in Adults with Intellectual Disabilities
Pain in the Courtroom: An Excerpt
Q&A with Howard L. Fields: How Patients’ Expectations May Control Pain
Special Report: CGRP Monoclonal Antibodies for Chronic Migraine
The Management of Chronic Overlapping Pain Conditions
Vibration for Chronic Pain
What are the dangers of loperamide abuse?
When Patient Education Fails to Improve Outcomes: A Low Back Pain Case

Analgesics of the Future: Inside the Potential of Glial Cell Modulators

Inside the potential of glial cell modulators for disease modification and pain management including OUD, opioid tolerance, and hyperalgesia.
Pages 56-59
Page 1 of 3

Overview

Glial cells are an integral part of the nervous system that differ from other nerve cells in their structure, size, and function.1 Unlike nerve cells, glial cells work as a type of support framework for the nervous system to maintain the essential synaptic contacts and signaling capabilities of neurons.1 There are three types of glial cells: microglia, astrocytes, and oligodendrocytes, each with their own unique role in proper functioning of a mature nervous system.1,2 Each type is involved in the pain pathway, making it a possible target for pain management. Specifically, through modulation of glial activity, pharmaceutical products have potential utility for several indications such as multiple sclerosis (MS) and neuropathic pain. Due to the functional capacity of glial cells in the pain pathway and the mechanism of action of glial modulators within the reward pathway, there is also promising data to suggest the future use for these medications as adjunct treatments in opioid use disorder (OUD).

 (See details of the star rating and review by Jeffrey Fudin,  PharmD, and Jeff Gudin, MD, at end of article.)

Microglia, Astrocytes, and Now Oligodendrocytes

Microglial cells are immunocompetent macrophages of the nervous system that differ from peripheral macrophages in their plasticity and morphology.2,3 Microglia perform immune surveillance, becoming activated during brain injury, infection, and neuronal degeneration.2,3 During activation, microglia proliferate and migrate into damaged tissue where they remove dead cells and invading organisms. Activated microglial cells have the potential to conform to different morphologies such as the “primed” or “sensitized” states, which are present in neurodegenerative disorders, including MS.2 When in these states, microglia are more reactive and will produce increased numbers of proinflammatory signals causing progressive upregulation of neuroexcitatory effects.2 While these functions are appropriate under normal circumstances, during dysregulation they can contribute to central nervous system (CNS) damage, especially in degenerative and inflammatory disease.4

Astrocytes, the most abundant cells in the CNS, are involved in regulation of neuronal functioning and play a supportive role in controlling neuronal signaling.2,5 Similar to microglia, astrocytes change into an activated state in response to nerve injury. This change is characterized by hypertrophy and increased expression of glial fibrillary acidic protein (GFAP).5 Astrocytes present in this reactive state are involved in the nociceptive signaling that accounts for the abnormal pain perceptions associated with chronic pain.5 The transition of astrocytes into a pain sensitive state relies on organized communication between damaged neurons, microglia, and astrocytes.5 Although astrocytes demonstrate clear involvement in the pain pathway, activation of microglia is required prior to astrocyte initiation and activation.5

The role of microglia and astrocyte dysfunction in neuropathic pain has been extensively described in the literature, but recent evidence indicates that the third glial cell type—oligodendrocytes—may be involved in this process as well. Oligodendrocytes are essential for the generation of myelin, which is responsible for axonal insulation within the CNS. In patients with MS, oligodendrocytes are a target for autoimmune attack by T-cell recognition of myelin oligodendrocyte glycoprotein leading to downstream cell loss, progressive nerve injury, and plaques.6

This nerve injury presentation may vary depending on the point in time of the disease and, while the exact pathology of these lesions is unknown, strong evidence suggests it is an autoimmune process which destroys myelin and oligodendrocytes.6 It is common for the demyelination, inflammation, and axonal injury to develop into neuropathic pain. Genetic ablation of oligodendrocytes has been shown to be involved with sensory changes that bear a resemblance to neuropathic pain in mice, emphasizing their role in neuropathic pain progression.7

(Source: 123RF)

Potential Impact as Disease Modifiers

Sphingosine-1-receptor (S1PR), subtype 5 within the CNS, is responsible for inhibition of oligodendrocyte progenitor migration.8 Through functional antagonism at this receptor subtype, an increase in oligodendrocyte proliferation and, thus, improved myelination of neurons may be achieved. Additionally, antagonism of S1PR subtype 1 prevents lymphocytes from exiting the lymph nodes, resulting in neuroinflammation that is responsible for the nerve degeneration in MS. Through these mechanisms, S1PR modulators may delay the onset of neuropathic pain that is characteristic in MS. Currently approved therapy for relapsing-remitting MS through this mechanism is limited to fingolimod (Gilenya, manufactured by Novartis) which is a S1PR modulator at subtypes 1, 3, 4, and 5. While its efficacy has been demonstrated in multiple phase III trials, its lack of selectivity for the pertinent subtypes is responsible for significant adverse effects and possible toxicities.9,10

First-dose bradycardia, as well as risk of macular edema, atrioventricular block, hypertension, QTc prolongation, and hepatotoxicity may all affect individuals taking fingolimod.11 Due to these notable side effects, a move to develop a more targeted approach has led to the investigation into drugs that are selective for S1PR1 and S1PR5. Ozanimod (Celgene) is a selective S1PR1 and S1PR5 modulator which was found to be superior to the previous standard of care (interferon-beta), and has also been found to have a high volume of distribution and delayed absorption, leading to low peak plasma concentrations.12 This low systemic exposure reduces the risk of first-dose bradycardia which was a major concern with fingolimod. Additional S1PR modulators in route to FDA for approval include ponesimod (Actelion) and siponimod (Novartis).

Last updated on: March 4, 2019
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Analgesics of the Future: NKTR-181
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