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 Understanding Pain and Pain Amplification

Robert Bennett MD

Pain is the defining symptom a fibromyalgia diagnosis. However, all fibromyalgia patients experience other symptoms, which are sometimes more distressing than pain itself - see Spectrum of Fibromyalgia Symptoms. In order to understand your pain and the various ways in which medicines work, it is useful to have some understanding of the anatomy and physiology of pain pathways.

Pain Pathways

A major advance in the understanding of fibromyalgia has been the recognition that fibromyalgia patients have changes in the working of their central nervous system (i.e. brain and spinal cord) that leads to an amplified experience of pain. The basic connections as shown in the following figure:

 Pain impulses arising in the periphery (e.g. an injured muscle) travel in a peripheral nerve to a part of the spinal cord called the dorsal horn. At this point they have to be transferred to a second nerve that travels up the spinal cord to a part of the brain called the thalamus. From the thalamus projections go to a part of the brain that localizes pain and records pain severity (the somato-sensory cortex). Other projections go to those parts of the brain that are involved in the emotional response to pain (the limbic system). Pain amplification refers to an enhanced transmission of nerve impulses from the periphery (e.g. muscle or skin) to the brain; it is sometimes referred to as "central sensitization".



The major site of pain amplification is in the spinal cord, at the chemical junction (called a "synapse") between the incoming nerve from the periphery the outgoing nerve to the brain. The major chemicals released at this site are glutamate and substance P (these are referred to as "neurotransmitters").  When glutamate attaches to its receptor on the second nerve it stimulates a nerve impulse that travels to the brain.



Importantly, the activity of this spinal synapse is modified by descending nerve impulses originating in the brainstem that project down to the synapse in the spinal cord  - see figure below:

This descending system modulates (mainly inhibits) the transmission of the nerve impulse from the periphery to the brain. Several of the medications used in the treatment of fibromyalgia pain act at the level of this spinal cord synapse. Antidepressant medications (e.g. amitriptyline, duloxetine) reduce pain by increasing inhibitory activity of the descending pain system. Anti-epileptic medications (e.g. gabapentin, pregabalin) reduce pain by limiting the release of the glutamate neurotransmitter from the peripheral nerve ending in the spinal cord. Psychological factors may influence pain amplification either positively or negatively by modulating activity in the descending pain projections from the brainstem. 

Chronic pain from the periphery (e.g. arthritis, injuries, triggernpoints, spinal stenosis, endometriosis) is a potent stimulus to long-term pain amplification.   Sources of external pain are often referred to as "peripheral pain generators".  The effective management of peripheral pain generators is an essential component of a structured fibromyalgia treatment program, as their persistence will maintain an aggravate a state of central sensitization.

Central sensitization

As described above, the term "central sensitization" is a commonly used term that denotes amplification of pain impulses within the spinal cord and brain.  At a physiological level central sensitization denotes a critically important concept in the understanding of pain transmission. That is that the central nervous system is not "hardwired".  In other words the actual experience of pain is not always proportional to the pain stimulus. Central sensitization has been demonstrated in fibromyalgia patients in a number of ways.  The most obvious manifestation of this phenomenon in fibromyalgia patients is the fact that they are more tender to a given pressure than healthy individuals. Indeed, this forms the basis of the tender point examination and hence the diagnosis of fibromyalgia. Central sensitization is not unique to fibromyalgia; it also occurs in other painful conditions such as irritable bowel syndrome, overactive bladder, TMJ syndrome, idiopathic low back pain, vulvodynia, multiple chemical sensitivity. Central sensitization in fibromyalgia can be experimentally validated in several ways.  The easiest methodology to understand is the direct imaging of the brain either at rest or shortly after the application of painful stimulus.

For instance a recent study entitled "99mTc-ECD brain perfusion SPECT in hyperalgesic fibromyalgia" reported that FM patients had increased activity in some areas of the brain while they were resting (somatosensory cortex) and reduced activity in other areas (the frontal, cingulate, medial temporal and cerebellar cortices). The scans are shown below (orange/yellow areas have increased activity compared to healthy individuals and the blue areas represent decreased brain activity):

    Reproduced from Guedj et al Eur J Nucl Med Mol Imaging (2007) 34:130–134

Fibromyalgia patients have also been demonstrated to have increased brain activity in some areas (e.g. somatosensory cortex) when they are exposed to a pressure pain stimulus. In the study shown below fibromyalgia patients and healthy controls were subject to a pressure stimulus of 2.7 kg/cm2 applied to the thumb.  Only the FM patients experienced any pain and this was associated with increased activity in 12 areas of the brain that were not activated in the healthy controls. See below:

     Reproduced from Gracely et al Arthritis & Rheumatism 46: 333–1343, 2002

A more technical but comprehensive review of the literature that supports the concept of central sensitization in fibromyalgia patients can be found  at the following link:

    In depth explanation of pain pathways

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