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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

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).

In Pain Management

Besides the S1PR modulators, there are a variety of medications that are classified as glial cell modulators that also have promising roles in the management of pain. These therapies are at varying phases of study for use in pain management and/or opioid use disorder. While some of these therapies are not yet approved in the United States, others have been around for some time and they offer additional benefits that are now being elucidated through previously unrealized mechanisms. Ibudilast (MedicaNova), for example, is a phosphodiesterase inhibitor, which is currently utilized in Japan and is under Phase II investigation in the US. Through modulation of proinflammatory glial cell activity, Ibudilast attenuates the levels of IL-1beta, a potentially damaging inflammatory cytokine.13-16 This effect plays a protective role against morphine-induced hippocampal injury.17

Additionally, it has been reported that lower doses of oxycodone are needed to produce similar analgesic effects when used in combination with Ibudilast.17 This suggests that increasing doses of Ibudilast leads to a reduction in the opioid doses required for adequate analgesia.17,18 In addition to these benefits, other studies have demonstrated the capacity of Ibudilast to reduce dopamine release in the nucleus accumbens when administered concomitantly with morphine.14,19,20 Minocycline is a readily available tetracycline antibiotic that has also been classified as a glial cell modulator due to its selective inhibition of microglial activation.14,15,21 It has been demonstrated that minocycline can block, but not reverse, certain neuropathic pain states through this mechanism.15 Additionally, minocycline has the capability to attenuate morphine tolerance, enhance morphine efficacy, and minimize the rewarding effects of opioids.14,22

In addition to minocycline and Ibudilast, a number of other medications have been implicated for use in allodynia, neuropathic pain, and attenuation of tolerance to opioid analgesia. Propentofylline is a phosphodiesterase inhibitor and glial cell modulator that has been shown to decrease pain behavior and allodynia in rats.17 Given its similar mechanism to that of Ibudilast, it has the potential to be effective for similar conditions.

Alternatively, pentoxifylline is a cytokine inhibitor that has the capability of decreasing inflammatory pain behavior through reduction of proinflammatory cytokine mRNA.14 Pentoxifylline has also demonstrated the ability to block development of morphine tolerance in mice with neuropathic pain.13 Fluorocitrate has similar evidence in mitigating morphine analgesic tolerance.13,14 This glial metabolic inhibitor can block and reverse neuropathic states and interfere with the production of the astroglial activity marker, GFAP, which increases with the use of morphine due to mu receptor activity.14,15 Since these medications have limited data in humans, additional research is necessary to fully understand their clinical utility in these conditions.

For Opioid Tolerance and Hyperalgesia

Besides the function of glial cells in neuropathic pain, they also play a role in opioid tolerance and hyperalgesia.3 Chronic use of opioids may lead to the development of tolerance, heightened sensitivity to painful stimuli, or allodynia. Opioids, like many drugs of abuse, affect dopamine and glutamate in the mesocorticolimbic reward pathway.2 Tolerance and dependence are associated with opioid-induced increases in glial cell activity.14 It has been speculated that glial cell activation may be involved with the cytokine release that contributes to tolerance of opioid analgesia as well as attenuation of the opioid-mediated dopamine release in the ventral tegmental area (VTA) and nucleus accumbens.2,14,21

Through effects of glial cells on cytokine, kappa opioid, NMDA, and toll-like receptors, the modulation of glial cells has the potential to improve analgesia, decrease the opioid burden, and decrease the rewarding sensations associated with opioid use.17 Through modification of the cause of pain, rather than symptomatic treatment, these agents may open the door to a new approach to pain management.

Discussion

Modulation of neuroinflammation, caused by the dysregulation of microglia, astrocytes, and oligodendrocytes, is under exploration as an option for pain management, especially in multiple sclerosis, to enhance currently available therapies. Medications available that may be classified as glial cell modulators come from a variety of drug classes with many different primary mechanisms of action. However, their underlying effect on the glial cells offers a new role in either symptomatic management or disease-modifying function. Perhaps of most significance is the emergence of the new medication that will likely be available by the end of 2019: ozanimod. By significantly slowing the progression of MS and enhancing myelination of neurons, SP1R inhibitors, such as ozanimod, may delay the characteristic neuropathic pain that is experienced by most patients with multiple sclerosis. This medication has been studied specifically for relapsing-remitting MS, but its disease-modifying activity lends itself to potential future benefit in those with neuropathic pain due to similarities in the underlying pathologies.

Aside from glial cell modulation for MS, other agents, such as Ibudilast and minocycline, have demonstrated early results indicating a role in pain management through enhancement of current therapies as well as attenuation of pain progression. Based on their capability to affect not only the efficacy of opioids but also disease modification of MS and neuropathic pain, these agents may soon offer new and practical approaches to pain management.

PPM Editors-at-Large Weigh In on Glial Cells

With its ability to continuously learn and plasticity to adapt, the human brain is truly amazing. Unfortunately, plasticity can be a bad thing when the brain circuitry remodels in a pathological way. Our understanding of these complex neurogenic processes has been increasing/advancing in recent years. There is now compelling evidence that the brain has the capacity to make new neurons into adulthood. The future of controlling pathological neurological processes will depend on our ability to limit damage caused by trauma, age-related pain, autoimmune disease progression, iatrogenic neuropathies, and to harness progenitor cells that can repair damage and promote constructive neural circuitry.

As this column explains, much attention has been placed on a group of brain cells previously thought of as “support” cells. These include: astrocytes, known to support neurons and their environment; oligodendrocytes, which myelinate neurons and speed up the transmission of signals between them, a process that goes awry in MS; and microglia, which act as the immune cells of the brain, cleaning up debris and providing local surveillance in the nervous system. Microglial cells react quickly to neurologic injury and pain stimuli to decrease inflammation and quell the pathological mediators before they damage any sensitive neural tissue. In the face of persistent painful input, glial cells may serve to turn down synaptic mediators, leading to sensitization and hyperexcitability, a phenomenon known as synaptic pruning.

From a clinical standpoint, all pain is neurologically mediated. We often claim that neuropathic pain is the most difficult pain to capture. It is unremitting, resistant to available therapies and may be debilitating. Preclinical and clinical evidence suggests that glial cell activation amplifies pain through various neuromodulators including cytokines (TNF a) and interleukins; importantly, selectively inhibiting activation of microglia suppresses pain. This opens the door to a potential new paradigm of treating pain. As reported herein, there is a beneficial relationship of glial cells to painful processes, including benefits in blunting opioid-mediated dopamine reward, and roles as pharmacodynamic inhibitors that may suppress resultant neuronal hyperexcitability. The legacy agents, those in development, and certainly glial cell modulators yet to be discovered earn

5 out of 5 STARS.* ★★★★★

*Review by Jeff Gudin, MD & Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB.

Star-rating based on: novelty, risk-benefit ratio, clinical utility, scientific rigor of studies, and market potential, along with the reviewers’ expertise and opinion.

 

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