Accurate Education – "Getting Free:" Tapering Down/Off Opioids

 Neuroinflammation is implicated in:

1. Pain
2. Opioid tolerance
3. Fibromyalgia
4. Reward Deficiency Syndrome (RDS)
5. Traumatic brain injury (TBI)
6. Depression
7. Multiple Sclerosis
8. Alzheimer disease
9. Parkinson disease
10. Autism Spectrum Disorder

(1). Pain and Neuroinflammation

Until recently, opioids and medications such as gabapentin (Neurontin), pregabalin (Lyrica) and duloxetine (Cymbalta) have been the conventional approach to reduce pain by their action on transduction and transmission in neurons, which likely accounts for the limited success in controlling chronic pain and its  progression. This “nerve-based” view fails to address the fact that initiation and maintenance of neuropathic pain depends to a great extent on non-nerve cells such as spinal microglia and astrocytes, together with elements of the peripheral immune system.

(2). Opioid Tolerance and Neuroinflammation

(3). Fibromyalgia and Neuroinflammation

Coming soon…

(4). Reward Deficiency Syndrome and Neuroinflammation

See: Reward Deficiency Syndrome and Chronic Pain

(5). Traumatic Brain Injury and Neuroinflammation

See: Traumatic Brain Injury

(6). Depression and Neuroinflammation

Coming soon… See Treatment of Neuroinflammation (below).

Treatment of Neuroinflammation

Early studies suggest that medications or supplements that reduce neuroinflammation by inhibiting glial activation and/or stabilizing mast cells may reduce the development of chronic nerve pain or reduce the severity of existing nerve pain. They may also be useful in suppressing the development of opioid tolerance. Various inhibitors of glial activation that are being evaluated for clinical use in the managment of chronic pain include minocycline, a tetracycline-class antibiotic, low dose naltrexone, palmitoylethanolamide (PEA) and Acetyl-L-carnitine. There is some evidence as well that gabapentin may inhibit glial cell activation as another mechanism of action responsible for its effectiveness in treating nerve pain. Furthermore, there may be a role for antioxidants and NRF2 activators as well in the management of chronic nerve pain related to glial cell activation.

At this time, the following agents are considered good candidates for treating neuroinflammation through stabilization and/or suppression of glial cells and mast cells:

1. Palmitoylethanolamide (PEA)
2. Cannabidiol (CBD)
3. Minocycline – Recognized as a microglia inhibitor
4. Low-dose naltrexone
5. DHEA – Early/weak evidence for benefit in depression and regulation of the blood-brain barrier

Understanding Neuroinflammation

Understanding communication between the nervous system and the immune system is fundamental to understand neuroinflammation. Immune cell-derived inflammatory molecules regulate of host responses to inflammation. Although these molecules can originate from various non-neuronal (non-nerve) cells, their most important sources are immune cells: microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell—cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation.

Normal, optimal inflammatory responses and physiological levels of inflammatory mediators are beneficial and protect the body as they remove unwanted waste materials and repair damaged tissues. As such, the initial, acute inflammatory response is protective, and lipid mediators such as eicosanoids (prostaglandins and leukotrienes produced from the essential fatty acid arachidonic acid) play critical roles in the initial response, with interactions between prostaglandins, leukotrienes and pro-inflammatory cytokines amplifying inflammation.

 
Normally, these altered and reactive immune cells diminish their activity within 10–14 days after injury and the inflammatory response ceases. However, in some cases, this neuroinflammation continues and becomes chronic, leading to many of the manifestations of nerve pain, or “neuropathic” pain, such as hyperalgesia, allodynia and peripheral and central sensitization, all of which are characterized by a magnification of pain experience.

The Players in Neuroinflammation

The process of neuroinflammation can be understood on a (1) structural level, including the blood-brain barrier (BBB), on a (2) cellular level including immune cells such as mast cells, microglia, astrocytes and oligodendrocytes or on a (3) chemical level including cytokines, chemokines and others.

Although loss of BBB integrity is associated with several neuropathological disorders, treatments that improve or stabilise the BBB are scarce. A 2017 study suggests that dehydroepiandrosterone sulfate (DHEAS) supports the integrity of the BBB and DHEA has shown evidence for benefit in the treatmemt of depression. At this time, one focus of treatment of impaired BBB integrity lies in the stabilization of glial cells and mast cells.

The Blood Brain Barrier and the Intestinal Epithelial Barrier (IEB)

A growing body of evidence demonstrates that the integrity of the BBB is linked to the integrity of the intestinal epithelial barrier (IEB), the analogous structure to the BBB in the gut. In turn, the integrity of the IEB is linked to the gut microbiome, the populati0n of microbes in the intestinal tract, Disruption of the IEB leads to a condition called “leaky gut syndrome,” in which a disruption of the tight junctions of the cells lining the gut wall allows for the pathologic migration of agents within the gut into the blood and systemic circulation. These agents include bacterial products and dietary antigens which trigger an immune response causing the release of pro-inflammatory chemicals. This in turn contributes to the condition of systemic inflammation which is tied into neuroinflammation, and the potential development of a number of disease states. The gut microbiome appears to be a significant factor contributing to the maintenance or the breakdown of the IEB and the gut microbiome is influenced and modified by a number of factors including stress and drugs, in particular NSAIDs and opioids. Leaky gut syndrome is believed to be associated with many pathological states, especially stress-related disorders including IBS, inflammatory bowel disease (Crohn’s and ulcerative colitis), fibromyalgia, depression, headaches and other chronic pain-related conditions.

See: Leaky Gut (soon)

Glial cells participate in inflammation not only directly, but also in to response to molecular mediators produced by other immune system-derived cells, both blood-borne (dendritic cells, lymphocytes, neutrophils), and tissue-resident (mast cells). Mast cell are an important signaling link between the peripheral immune system and the brain in an inflammatory setting. Due to their widespread tissue presence near blood vessels and surfaces exposed to the environment, mast cells function as environmental “sensors” to communicate physiological and/or immune responses. Mast cells detect and respond to changes in environmental temperature and barometric pressure and are believed to play a role in the increased perception of pain associated with changes in weather.

Mast cells are found in tissues innervated by small caliber sensory nerve fibers (A-delta and C-fibers responsible for pain transmission that extend from the periphery to the spinal cord and brain), in meninges, and apposing cerebral blood vessels. Mast cell’s key role in the inflammatory process, when activated, is to rapidly release granules (degranulation) of bioactive chemicals, pro-inflammatory mediators such as cytokines and others into the surrounding tissues. Degranulation is triggered by direct injury (physical or chemical), stimulation of immune receptors (such as IgE in allergies) or by activated complement proteins. More than 50 mediators are known and their expression by mast cells is complex and determined to a large extent by tissue location. Additionally, mast cell-derived chemoattractants recruit other immune cells including eosinophils, monocytes, and neutrophils, and can induce T cell activation, proliferation, and cytokine secretion.

As such, it is clear that glial cells and mast cells play major roles in neuroinflammatiom through their release of chemically active protein mediators that impact tissues and stimulate pain, acutely and chronically. Current research is focusing on medications and other agents that can stabilize glial cells and mast cells, suppress their release of mediators and thereby reduce the development and/or maintenance of chronic pain.

Neuroinflammation and Oligodendrocytes

Oligodendrocytes, the myelin-producing cells of the central nervous system (CNS), may also participate in the pain process. In addition to their production of myelin, oligodendrocytes support nerve function and long-term integrity. Oligodendrocyte damage/dysfunction leads to spinal nerve axon pathology and the induction/maintenance of increased pain sensitivity. Also, like glial cells and mast cells, they produce and respond to chemokines/cytokines that modulate CNS immune responses and interact with microglia.   In the case of multiple sclerosis (MS), for example, autoimmune inflammation driven by invading peripheral immune cells leads to injury/degeneration of oligodendrocytes and neurons, and contributes to the neuropathic pain often experienced by MS patients.