Why it hurts in Fibromyalgia, part 2: Amplified and unprovoked pain

You can find the video after the text

In this video, I will talk about the most likely explanations for the pain phenomena amplified and unprovoked pain in fibromyalgia.

My name is Andreas Persson and I am a physiotherapist and specialist in pain and pain rehabilitation. 

I will describe so that anyone can understand, what the most likely explanations are for the pain people with fibromyalgia experience. 

The description contains a link to what I say in a text with references to the scientific articles it is based on.

If you have not seen part 1, watch it first. Much of what I will talk about is based on the first part. The link to the video is in the description and now above on the screen. 

In the first part, I said that there are five different pain phenomena in fibromyalgia. We took a closer look at the first of them, lowered pain threshold.

This video will be about two of the other pain phenomena. Amplified and unprovoked pain. We start with amplified pain.

Amplified pain

People with fibromyalgia experience more pain than others when they are exposed to something painful. It can be something brief such as taking a blood test, or due to an injury caused by osteoarthritis in the knee.(1)

The cause of amplified pain in fibromyalgia is increased central sensitization in the spinal cord.(2) So what is Central sensitization? In the previous video, we looked at a model of the pain system with peripheral pain nerves in the body and spinal pain nerves in the spinal cord.

When something threatens to hurt us or if an injury already exists, the peripheral pain nerves are activated. A signal is sent thru the nerve fibers that connect to the spinal pain nerves in the spinal cord, which pass the signal on further up to the brain stem and the brain.

Central sensitization occurs when pain signaling from peripheral pain nerves persists over time. It does not have to be a long time, only tens of seconds.(2) The phenomenon means that the spinal pain nerves respond more strongly to the signal coming from the peripheral pain nerves.

There is thus amplification of the pain signal in the spinal cord. To better understand how this occurs, we need to zoom in.

When a signal is sent through the peripheral pain nerve, it causes small containers of neurotransmitters to travel to the cell membrane and be released. In this case, they contain the neurotransmitter glutamate. Glutamate binds to AMPA receptors on the spinal nerve, which causes the receptors to let sodium ions into the cell.

If enough sodium ions are let in, a new signal starts in the spinal pain nerve and the pain signal travels further up towards the brain stem and the brain so that the experience of pain is created.

If the peripheral pain nerve sends signals that are strong or for a long enough duration, another receptor called NMDA also becomes active. It is normally blocked by a magnesium atom, but the blockage goes out when repeated or strong signals are sent through the nerve.

When the NMDA receptor is activated, calcium ions also enter the nerve cell. The calcium ions initiate different processes that make the nerve more sensitive to incoming signals. One of the things that happen is that AMPA receptors that are stored inside the cell travel to the cell membrane. When the receiving nerve cell has more AMPA receptors, the spinal nerve becomes more activated as a result of a given stimulation from the peripheral pain nerve. The signal is amplified.(2)

This means that a relatively weak pain signal from the body can be amplified and experienced as intense pain.

In experiments, it has been shown that this amplification is stronger in fibromyalgia.(3 Here is a figure that shows what happens if you repeatedly expose a person with fibromyalgia and a normally pain-free person to painful stimulation with a certain intensity. 

As you can see, the pain in a person with fibromyalgia increases faster.(3,4)

This is the reason why people with fibromyalgia often get more pain from an injury in the body, from a medical procedure such as taking a blood sample, or from having osteoarthritis in a joint.

If you give people with fibromyalgia a drug that blocks the NMDA receptors, they get less pain.(5,6) The problem with taking this medication is that the NMDA receptors and a process similar to that of central sensitization are involved in the creation of memories. A serious side effect of the medicine is consequently impaired memory.(7,8)

So what is the reason central sensitization and amplification between peripheral and spinal pain nerves are increased in fibromyalgia? 

 The most likely causes are altered function in the descending pain-modulating pathways (9-11) and elevated levels of inflammatory cytokines.(12-14) 

These processes are probably also the causes of the increased sensitivity in the spinal pain nerve and the transmission from the sensory nerves to the spinal pain nerves which cause lowered pain threshold which we talked about in the previous video.(15)

We will take a closer look at the mechanisms of altered function in the descending pain-modulating pathways as well as the elevated levels of inflammatory cytokines when talking about the next pain phenomenon, unprovoked pain.

Before we move on, I just want to take the opportunity to explain why I am making this video.

Although I have worked clinically with people who have chronic pain for over ten years and have trained as a specialist in pain and pain rehabilitation, there is much that I do not know about the causes of chronic pain and fibromyalgia and the other symptoms associated with the pain. I also do not know everything about how to treat and manage the pain.

Making this video and hopefully more videos allows me to dive deeper into the research and learn more, and hopefully you will also learn things that you find interesting.

However, the ambition is not only that the videos shall be interesting, but also useful for those who have chronic pain, for those who are relatives, and for those who work with people who have chronic pain. I hope you want to be part of a journey where we learn more about the causes, and how to best treat and manage chronic pain.

If you want to be a part of this journey, click the like button. Subscribe to the channel and share the videos you like on social media. It improves the chance for me to continue making similar videos, and for you and others to see them. 

I don’t see the videos as one-way communication. I would like to have a conversation on the subjects with you. 

Write in the comments what you think and feel about what I am talking about, if there is something in the video that you think can be improved, if there is something you think is good, and if there is something else that you want me to make a video about.

Next, we will talk about unprovoked pain. 

Many people with fibromyalgia are in pain even when they do not load the body or expose it to stimulation such as pressure, cold, or heat. It can manifest as having back pain despite being in a completely unloaded position or as pain in a foot even though the foot is not in any way loaded or sensory stimulated at the moment.

Unprovoked pain can occur due to injury. For example, when a person has sprained an ankle or been hit by a weight on the arm. The pain after such injuries is caused by the inflammatory substances released in the injured area that makes peripheral pain nerves more sensitive. In this case, so sensitive that pain signals are sent spontaneously even without loading or touching the injured area.

In fibromyalgia, unprovoked pain can occur without any damage or inflammation in the body.(11,16) It can occur as a result of having done some activity, which we will talk more about in the next video on the phenomena after-pain. Sometimes, however, it hurts without any activity that has triggered the pain.

The cause of unprovoked pain in fibromyalgia, when there is no damage or local inflammation in the body, is that pain signaling starts in the spinal nerve without incoming signals from the peripheral pain nerve or the sensory nerves. Thus, the spinal pain nerves begin to send pain signals to the brain spontaneously.

What, then, is the reason for this?

The causes of unprovoked pain in fibromyalgia are probably the same as for lowered pain threshold and stronger central sensitization in amplified pain. Altered function in descending pain-modulating pathways (9-11) and elevated levels of inflammatory cytokines.(12-14) So now that these processes have been mentioned a few times, it’s time for us to take a closer look at them. We start with the changes in the descending pain-modulating pathways.

Several different nerve pathways originate in the brainstem and descend into the spinal cord with the ability to change the pain signaling. There are both those that can amplify pain signals and those that can attenuate them. People with fibromyalgia have altered function in the descending pain modulation. The changes consist of both increased function in the amplifying pathways and reduced function in the inhibitory pathways.(9,10)

The studies that show this are mainly based on pain-stimulated modulation, which means that a person is exposed to pain in one part of the body, and pain thresholds are measured in another part.(4) 

Here we can see a picture that describes how this can be done. The foot is immersed in ice water so that the person experiences pain. Pain thresholds are measured on the arm on the other side of the body. In this case, the pain threshold for heat. 

Exposing the body to pain, thus activates parts of the descending modulating pathways so that the activity in the pathways can be measured. For people that normally are pain-free, this type of experiment leads to increased pain thresholds but people with fibromyalgia experience lowered thresholds. 

The other probable cause of unprovoked pain, lowered pain threshold and amplified pain in fibromyalgia are elevated levels of inflammatory cytokines in the spinal cord. 

Several studies show that people with fibromyalgia have elevated levels of inflammatory cytokines in the spinal fluid, the fluid that circulates in and around the brain, and the spinal cord, which can be seen in blue-green here.(12,13) 

Cytokines are signaling molecules that are used for communication between different actors in the immune system, both in the body and in the central nervous system.

Research on mice has shown that if inflammatory cytokines are added to the spinal cord, it leads to the spinal pain nerves becoming more sensitive to incoming signals from peripheral pain nerves and sensory nerves, and also that they spontaneously start to send pain signals to the brain.(15) Studies have shown that the inflammatory cytokines also inhibit the activity of pain inhibitory nerve cells in the spinal cord.(15)

This means that elevated levels of inflammatory cytokines are a likely cause of pain in fibromyalgia.

The next video will address the most likely causes of after-pain- the pain that comes after physically strenuous activity or sensory stimulation and widespread pain – that the pain is present in the whole or large parts of the body.

If you liked this video, press the like button and share it on social media. If you want to see more similar videos, subscribe to the channel. Write in the comments what you think and feel about what I have been talking about, if there is something that you think can be improved, if there is something you think is good, or if there is something else that you want me to make a video about


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2. Latremoliere A, Woolf CJ. Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity. J Pain. 2009;10(9):895-926.

3. Staud R, Cannon RC, Mauderli AP, Robinson ME, Price DD, Vierck Jr CJ. Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain. 2003;102(1-2):87-95. 

4. Arendt-Nielsen L. Central Sensitization in Humans: Assessment and Pharmacology. Handb Exp Pharmacol. 2015;227:79-102. 

5. Sandkühler J. Models and Mechanisms of Hyperalgesia and Allodynia. Physiol Rev. 2009;89(2):707-58. 

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7. Orhurhu VJ, Vashisht R, Cohen SP. Ketamine Toxicity. StatPearls [Internet]. Treasure Island(FL): StatPearls Publishing;  2021. 2020. 

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9. Potvin S, Marchand S. Pain facilitation and pain inhibition during conditioned pain modulation in fibromyalgia and in healthy controls. Pain. 2016;157(8):1704-10.  

10. Harper DE, Ichesco E, Schrepf A, Hampson JP, Clauw DJ, Schmidt-Wilcke T, et al. Resting Functional Connectivity of the Periaqueductal Gray Is Associated With Normal Inhibition and Pathological Facilitation in Conditioned Pain Modulation. J Pain. 2018;19(6):635.e1-e15. 

11.  Harte SE, Harris RE, Clauw DJ. The neurobiology of central sensitization. J Appl Biobehav Res. 2018;23(2):e12137. 

12. Bjurstrom MF, Giron SE, Griffis CA. Cerebrospinal Fluid Cytokines and Neurotrophic Factors in Human Chronic Pain Populations: A Comprehensive Review. Pain Pract. 2016;16(2):183-203. 

13. Bäckryd E, Tanum L, Lind AL, Larsson A, Gordh T. Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. J Pain Res. 2017;10:515-25.

14. Nijs J, Loggia ML, Polli A, Moens M, Huysmans E, Goudman L, et al. Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients? Expert Opin Ther Targets. 2017;21(8):817-26.

15. Ji RR, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology. 2018;129(2):343-66. 

16. Hawkins R. Fibromyalgia: A Clinical Update. J Am Osteopath Assoc. 2013;113(9):680-9. 

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