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Back: Neuroinflammation as a Cause of Chronic Pain

“Neuroinflammation as a Cause of Chronic Pain"

Jeff Unger Picture

 Jeff Unger, MD
   PCMG Steering Committee Member
   Charlotte, North Carolina 
   The Unger Primary Care Medical Center
   Associate Director for Metabolic Studies
   Catalina Research Institute
   Chino, Californina

Fred is a 48 year old patient with type 2 diabetes, of 8 years duration.  His A1C is 8.7 %. On his most recent visit to his primary care physician (PCP), Fred is more concerned about the “constant buzzing and tingling in his hands and feet” than he is about getting his blood glucose levels treated to target. Fred says that his symptoms are worse at rest and decrease with activity. He has difficulty with balance and is falling on occasion. He claims that he has experienced pain daily for the past month, rates the pain as 4 on a scale of 10 and the pain is present 6 hours each day. His PCP performs a neurological examination and determines that Fred has lost vibration sense over the dorsum of his hallux, has diminished hot-cold sensation over the dorsum of his feet and has lost his ankle reflexes bilaterally. After diagnosing him with diabetic peripheral neuropathic pain, Dr. Jones explains to Fred that he must:

1) get his blood glucose levels controlled,
2) improve his lipids,
3) stop smoking,
4) lose 7 lbs and
5) begin medication to help with his pain.

Dr. Jones initiates therapy with a tricyclic antidepressant, but Fred calls the office after 3 days, complaining of dry mouth, blurry vision, orthostasis, and difficulty urinating. Dr. Jones apologizes that the drug was hard to tolerate and prescribes an opioid for Fred who is experiencing so much pain at rest that he cannot sleep.

For a few days after taking the hydrocodone, Fred begins to experience some relief. However, by day 7, the pain returns and appears to become even more intense than it was initially. He asks Dr. Jones if he can “double the dose” for a week to see if he can get some additional relief. Dr. Jones reassures Fred that he can do so safely. After doubling the dose, Fred’s pain intensifies once again. Now, Fred is experiencing not only pain in his hands and feet, but also headaches and diffuse myalgias. Not wanting to bother Dr. Jones, Fred simply calls for an early refill of the hydrocodone and continues to take up to 8 tabs per day until his next visit in 4 months.  By the time Fred is seen again by Dr. Jones, his pain is daily, has an intensity of 8 on a scale of 10, and is present 24 hours each day.

Physicians should be aware of a neurological process, known as neuroinflammation, seen in many patients with chronic pain who are started on  opioid therapy. In order to understand this process, let us examine how peripheral nerves become targets of immune activation.

Peripheral neurons are the origin of neuropathic pain. Two organelles help to stabilize multiple segments of each neuron. The astrocyte works with the neuron to transport ions in and out of neuronal segments. If a neuron requires sodium, the astrocyte will locate and transport sodium into a given segment of the neuron allowing the neuron to function normally. The microglial cells lie outside of each neuronal segment. Their purpose is to protect a given neuronal segment against any form of inflammation or destruction. The microglial cells perform this function by secreting a cytokine known as Interleukin-10. Most cytokines are proinflammatory in nature. However, Il-10 protects against inflammation. As long as Il-10 is produced by microglial cells, the neuronal segment is protected. However, “activation” of microglial cells can change the production of Il-10 to the proinflammatory production of interleukin-6 and glutamine. Glutamine is known to lower the threshold of central pain receptors whereas Il-6 is converted by the liver into C-reactive protein (CRP). The CRP then returns to a given segment of the neuron resulting in an inflammatory  or neuropathic response. Two known risk factors for neuronal and microglial activation are: use of opioids and stress (physical or emotional).

Clinically, susceptible patients who are initiated on opioids will initially note a slight improvement in their pain. However, as microglial cells become activated and switch production from Il-10 to Il-6, neurons become inflamed. Neurotoxicity develops and patients experience an exacerbation of their pain. Pain can become more diffuse as well. Some individuals will begin to experience headaches and myalgias as they develop peripheral and central sensitization to pain. Patients may begin to request early refills on their opioids. Their pain will continue to worsen despite the use of opioids.

Patients who experience neuroinflammation should have their opioids discontinued. If possible, these patients should be placed on FDA-approved medications for diabetic peripheral neuropathic pain, such as duloxetine or pregabalin. Tricyclic antidepressants should be avoided, especially in patients over age 60 due to the potential for cardiotoxicity and arrhythmias.

Share your thoughts on our Blog! Please share any interesting patients who may experience neuroinflammation with our membership. These are complicated pain management issues. I encourage other members to offer their expertise and pain management strategies.

Jeff Unger, MD

Further reading
1. Watkins L, et al. Glial activation: a driving force for pathologic pain. Trends Neurosci. 24:450-455. 2001.

2. Unger J, Cole BE. Recognition and Management of Diabetic Neuropathy. In Primary Care Clinics In Office Practice. Jeff Unger, MD-Ed. 34 (4) (2007) 887–913.