Subscription is FREE for qualified healthcare professionals in the US.

Microglial Modulators: A New Therapeutic Class

Editor's Memo: June 2015

What does an antibiotic, an anticoagulant, an antiviral, and a treatment for glaucoma have in common? They are all being investigated for the treatment of neuropathic pain. These agents all have the ability to inhibit microglia activation, thereby preventing the development of allodynia and hyperalgesia following acute and chronic pain.

Evolving Focus of Pain Research

The understanding of two basic, central nervous system (CNS) physiologic mechanisms underpins modern pain management. The first is receptor activity. After the discovery in the 1970’s of the opioid receptor and its endogenous ligands, the endorphins, a new vocabulary and approach to analgesia began. Today we have opioid agonists and antagonists as well as the agents that target opioid receptors. In pain management we not only focus on opioid receptors but also target N-methyl-D-aspartate (NMDA) and (gamma-amino-butyric acid) GABA receptors.

The second basic physiologic mechanism of critical importance to pain management is the circulation of neurotransmitters in the synapse. Neurochemicals such as serotonin, dopamine, and GABA are secreted into the synaptic junction and re-circulated back into the secreting neuron. Blocking the circulation mechanism can increase synaptic levels of neuro-transmitters. Today we routinely administer agents we call “re-uptake blockers,” and we target neurotransmitters such as serotonin, norepinephrine, and GABA.

Today a third basic mechanism is now understood, conceptualized, and starting to advance pain management. It is the physiology of the microglial cell. This cell is one of 3 glial cells in the CNS—the other 2 are astrocytes and oligodendrocytes. Microglial cells have the specific role of immune protection of the CNS. They fundamentally act like white blood cells—they are inactive until confronted by pain, stress, electric shock (ie, from accidental electrocution), toxins, or another possible injurious challenge. When challenged, however, they activate, navigate, and stimulate an inflammatory reaction, similar to how white blood cells rally when challenged by a foreign substance.

If the injurious insult is severe or persistent, neuroinflammation results. Although somewhat unclear as to the precise mechanism, this inflammatory focus overly sensitizes the peripheral and CNS and may centralize or imbed the pain in the brain. The sympathetic and endocrine systems become overactive and patients complain of constant pain, fatigue, insomnia, and depression—among other symptoms.

Translating Basic Research to Practice

Thanks to basic research studies, it is now understood that microglia cells have receptors and can, to a great extent, be controlled or modulated by specific pharmacologic agents. Some agents stimulate and others suppress or inhibit microglial activity. Pain management is primarily interested in suppression of microglial activation because the over-activated microglia cell and its attendant neuroinflammation cause great pain and misery.

Various pharmacologic agents have been tested, in-vitro, and a few aggressive and inventive clinicians have tested some of these agents on patients.1-10 Guess what? The concept of glial cell modulation is sound. Patients can be helped and pain management is moving forward with this new class of compounds, which are herein called “microglia modulators.” If you wish, call these agents “suppressors” or “inhibitors,” because the idea is to calm down the over-activated microglial cell, reduce neuroinflammation, decrease the over-sensitization, and normalize the autonomic nervous and endocrine systems.

One of the most promising new agents is the drug minocycline, which has been shown to reduce microglial activation by 47% in treated mice.1 In an in-vitro study, intrathecal administration of minocycline delayed the induction of allodynia in two pain models.2 And now, my own clinical experience has shown it’s the “real deal.” Minocycline, originally marketed as a tetracycline antibiotic, exerts inhibitory effects on microglial cells and neuroinflammation. I initially felt a little foolish when I first prescribed this agent to patients with severe, chronic pain. However, more than half of the 30 centralized chronic pain patients I’ve treated reported better pain relief, fewer pain flares, reduced opioid use, and an increased feeling of well being. Some patients had a dramatic response. The dose I used in my preliminary trials was 100 mg, given 2 or 3 times a day. It should be pointed out that I have seen positive clinical responses from other tetracyclines; particularly doxycycline. In addition, I have one adhesive arachnoiditis patient who is literally bed-bound unless she takes clarithromycin on a daily basis.

Two other commercially available compounds have been shown in animal studies to suppress microglial activity and neuroinflammation: acetazolamide and pentoxifylline (Trental, Pentoxil).3-5 In an in-vitro study, acetazolamide, a carbonic anhydrase (CA), enhanced the efficacy of GABAergic inhibition in the context of neuropathic pain.3 Pentoxifylline has been shown to inhibit the development of hyperalgesia when given before painful stimulation in the mice-model.4,5 In addition, the antiviral agent ganciclovir has been shown to be a potent inhibitor of microglial proliferation and neuroinflammation in the CNS.6 I’ve seen some very positive results with acetazolamide (125 to 250 mg, 2 or 3 times a day) in a dozen adhesive arachnoiditis patients. As of yet, I have not used acetazolamide in patients without arachnoiditis, and I have no personal experience with pentoxifylline or ganciclovir.

Other agents are now being used that appear clinically to have glial cell modulation at least, in part, as one of their basic mechanisms of action. These include ketamine, naltrexone, and such neurohormones as oxytocin, human chorionic gonadotropin, and progesterone.7-10

This is an exciting, clinical advance. To date, microglial cell modulators, in my experience, improve pain control, reduce opioid use, and even reduce costs. If any of our readers have clinical experience with this new class of compounds, please share those experiences with Practical Pain Management.

Abuse-Deterrent Technologies

As we have been discussing in this journal, opioid overdose has become a major public health problem. Physicians and other health care providers can reduce the risk of opioid adverse effects with thoughtful prescribing and monitoring of patient responses. Some of these precautions include psychological screening, urine (or other matrix) toxicology testing, prescription drug monitoring database programs, informed consent, and ongoing risk assessment.

In Practical Pain Management’s online literature review PainScan, Drs. Michael J. Brennan and Jeffrey Gudin review influential studies on abuse-deterrent technologies. The authors comment on the latest studies to keep readers up to date on the progress being made in this field and the impact of these technologies on reducing the risk for opioid abuse, misuse, and overdose.

Last updated on: June 16, 2015
First published on: June 1, 2015
Continue Reading:
Chronic Pain Patients Who Fail Standard Treatment: Now What?