Regulation of Pain in Fibromyalgia by Selective Serotonin and Serotonin Norepinephrine Reuptake Inhibition

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Fibromyalgia is a chronic pain processing disorder primarily affecting the musculoskeletal system. Fibromyalgia is often accompanied by chronic fatigue, dyscognition and altered sleep architecture. One mechanism widely recognized as contributing to chronic pain in fibromyalgia involves musculoskeletal tenderness in response to innocuous mechanical stimuli also known as allodynia. However, the recently performed re-analysis of the clinical criteria for the diagnosis of fibromyalgia proposed that physicians should also take into account a patient’s overall symptoms deemphasizing the tender point count. It is generally agreed that the cellular basis for the chronic musculoskeletal pain of fibromyalgia involves abnormalities in ascending and descending pain pathways resulting from heightened central nervous system sensitization.

What are SSRIs & SNRIs?

Serotonin and norepinephrine are both neurotransmitters chemicals in the brain that transmit messages from one neuron (brain cell) to another. Each deals with multiple functions.


Serotonin’s functions include pain processing and the wakeful part of the sleep cycle. Your brain uses serotonin to create melatonin, which helps you get to sleep.  


Norephinephrine is involved with the body’s stress response, alertness, and memory. Your brain uses norepinephrine to create the neurotransmitter dopamine which deals with mental focus, motivation, and coordination.

 Abnormalities in serotonin and norepinephrine

Abnormalities in serotonin and norepinephrine are believed to be related to some cases of FMS and ME/CFS. SSRIs/SNRIs make more of them available by slowing down reuptake, which is when they’re absorbed after use so they can be recycled.

What Is Reuptake?

First, a little bit about how your brain works: Your brain cells (neurons) are separated by little gaps. When your brain transmits messages from one neuron to another, it bridges those gaps by releasing specialized chemicals called neurotransmitters to carry the message. After a while, the space between the cells basically gets cluttered with a lot of used neurotransmitters.

It’s kind of like opening your mail and ending up with a pile of empty envelope the envelopes were important for getting the mail to you, but you no longer need them. Your brain cleans up the mess by reabsorbing the neurotransmitters so they can be recycled. The medical term for that is reuptake.

Now let’s simplify it and go a step further: Imagine a spider perched on the back of a dining-room chair. He wants to get to the table, so he shoots a strand of web across the gap. He shouldn’t have a problem getting to his destination, but an oscillating fan across the room keeps turning that direction and blowing the web away before the spider can complete the journey.

Now, imagine that someone changes the speed on the fan so that it oscillates more slowly. That gives the spider enough time to cross the gap before the web is blown away. The spider is the message, the web is the neurotransmitter, and the fan is reuptake. When you slow reuptake, the message has enough neurotransmitter to get where it’s going. Reuptake inhibitors don’t increase the total amount of neurotransmitter in your brain, but they do increase the amount of time it’s available. That helps messages get where they’re going.

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Selective-serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibition have now been added to antidepressant medicines and pregabalin as clinically efficacious drugs for fibromyalgia. It is now thought that antidepressants such as amitryptiline and pregabalin act via high-voltage activated Ca2+ channels and the Kv1 family of K+ channels and/or by modifying defective serotonergic circuitry exemplified by abnormalities in serotonergic receptor-mediated events.

Selectiveserotonin and serotonin/norepinephrine reuptake inhibitors such as duloxetine and milnacipran, respectively, act through a G-protein-coupled mechanism involving the 5-hydroxytryptamine/5-hydroxytryptamine-(2A) receptor which leads to activation of cyclic AMP-dependent protein kinase A and Ca2+/calmodulin kinase IV. However, more recent evidence indicated that this drug class also activates Janus kinase-3, extracellular signal-regulated kinase 1/2 and the Src/Phosphatidylinositide-3-kinase (PI3K)/Akt/Glycogen Synthase Kinase-3/mammalian target of rapamycin signaling pathway.

The Risks: Serotonin Syndrome

SSRIs, SNRIs, and other medications that increase serotonin can lead to a potentially deadly condition called serotonin syndrome. The risk increases when you take more than one serotonin-increasing substance, which can include prescription medications, recreational drugs and even certain supplements. To lower your risk of serotonin syndrome, it’s important for you to tell your doctor and pharmacist about everything you’re taking.

Neurotransmitter dysregulation

Researchers theorize that the brains of people with fibromyalgia, chronic fatigue syndrome, and many other neurological illnesses either have low levels of certain neurotransmitters or don’t use their neurotransmitters properly. That’s called neurotransmitter dysregulation, and it’s believed to be responsible for many of our symptoms, including brain fog and pain amplification.

Research shows that slowing reuptake helps alleviate symptoms in a significant number of people with these illnesses. Older reuptake inhibitors slowed the process for all neurotransmitters, which led to a lot of unwanted effects. Modern reuptake inhibitors selectively target specific neurotransmitters especially serotonin and norepinephrine. They’re called Selective serotonin reuptake inhibitors (SSRIs) and Serotonin-norepinephrine reuptake inhibitors (SNRIs). While these drugs cause fewer problems than the older medications, they still have a long list of side effects.

Part of the problem is that we don’t have neurotransmitter deficiencies in every area of the brain, so the medication may improve transmission in one area while disrupting it in another.

The Risks: Suicide

SSRIs, SNRIs, and all other antidepressants are mandated by the FDA to carry a black-box warning the agency’s most serious alert about an increased risk of suicide or suicidal thoughts and behaviors. It’s important for anyone taking these drugs to be aware of the risk, and it’s also important for friends and family members to know about it. They may be the ones who spot the warning signs.

If you find yourself having suicidal thoughts, get help right away. From anywhere in the United States, you can call 1-800-273-8255. That’s a VA hotline, but anyone is welcome to call. You should also talk to your doctor about these thoughts and whether you should stop taking the medication.

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Research Reference:

  • Regulation of Pain in Fibromyalgia by Selective Serotonin and Serotonin Norepinephrine Reuptake Inhibition. International Journal of Physical Medicine & Rehabilitation 01(05). DOI: 10.4172/2329-9096.1000144

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