Next Fibromyalgia Advance: Manipulate Microglia Cells

To treat fibromyalgia, clinicians need a drastic change in approach to the disorder and a way to reduce inflammation in the brain, said Jarred Younger PhD at the Congress of Clinical Rheumatology 2015 in Destin, FL.

“It’s not about what the FDA-approved treatments directly target. Fibromyalgia is about neuroinflammation in the central nervous system [CNS]," said Younger, who is associate professor of psychology and director of the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama at Birmingham. “The key to treatment is to reduce that inflammatory process in the brain. We have to discover and employ both pharmaceutical treatments and other interventions that can get to the CNS and target the cells that drive the inflammation.”

Younger described the basic states of microglia cells, which act as the first form of active immune defense in the CNS, and how they relate to inflammation and pain. “Microglia cells are the brain’s Green Beret special forces. They produce dozens of compounds that push the CNS into an inflammatory, excitatory state,” he said. In fibromyalgia, microglia cells go from a resting to a primed state and become hyperexcitable and overexpress receptors.

Both leptin and glucose are potent microglia cell primers. That is why diet can impact inflammatory processes in the brain, he said. Leptin levels coordinate with the pain and fatigue of fibromyalgia. “Leptin may be a gateway to pain and fatigue in fibromyalgia and chronic fatigue syndrome,” he said.

Microglia cell modulators include naltrexone, minocycline, ibudilast, and dextromethorphan. “These drugs were developed for other purposes and subsequently were found to potently suppress microglia cells and get them back to resting state or prevent them from becoming activated,” Younger said.

Low doses of naltrexone block opioid receptors and toll-like receptor 4 on microglia cells. Two clinical trials of 4.5-mg daily doses of naltrexone in women with fibromyalgia show an effect after 2 months. Most patients feel better and their symptoms slowly decline, Younger said. Side effects are few, the most common being vivid dreams.

“Naltrexone works as a novel anti-inflammatory in the brain,” he said. “If we track inflammation over time, we see an effect on inflammatory processes.”

Naltrexone dosage is critical. Many fibromyalgia patients do not respond to a 4.5-mg daily dose, while others do well on up to 9 mg per day. “Some need to start on a lower dose. Start patients on a 1-mg dose and then increase every 2 to 4 weeks by 1.5 mg a day until you hit the desired response or side effects occur,” he said.

Younger noted that a commercial low-dose naltrexone product for fibromyalgia is in the works. Also, combinations of low-dose naltrexone with opioid agonists, dextromethorphan, and other agents are under investigation.    

In his lab, Younger is testing other compounds shown to be effective in inflammatory conditions, including botanicals and traditional Chinese medicines found to suppress microglia cells potently and that cross the blood-brain barrier.

He is also investigating PET imaging of microglia cells and brain thermometry to help identify neuroinflammation in fibromyalgia patients.

Behaviorally, he suggested that clinicians can have fibromyalgia patients reduce fat and sugar in the diet, have lower caloric intake, avoid stress-eating, eat low-glycemic index foods, eat an anti-inflammatory diet, and consume anti-inflammatory supplements, such as curcumin and resveratrol.

“New evidence suggests when bacteria in the gut are dysregulated, this causes an inflammatory response that breaches the lining of the gut and causes an inflammatory response in the body and CNS. We need to target inflammation wherever it occurs,” he said.

Research goals in fibromyalgia, he said, should include: develop new pharmaceuticals with targeted action, screen more existing compounds and botanicals, find ways to get current anti-inflammatories to the CNS, develop techniques to monitor central inflammation, and find peripheral markers of central inflammation.

“Evidence strongly supports abnormal microglia cell function may underlie fibromyalgia. The next huge advance in treatment will be when we figure out how to manipulate microglia cells," Younger concluded.