Descending inhibition uses three brain chemicals—dopamine, serotonin, and norepinephrine. Interestingly, Dr. Jon Russell noted the metabolites of these chemicals (meaning the chemicals themselves) appeared to be present in lower concentrations in FMS patients way back in 1992. A group of Japanese researchers have found that if they gave laboratory rats a chemical called reserpine they could create an animal model of FMS. The animals displayed signs of depression, pain out of proportion to normal, increases in levels of muscle pain, and they responded to two medications used in FMS syndrome - pregabalin (Lyrica®) and duloxetine (Cymbalta®). Reserpine causes a reduction in dopamine, serotonin, and norepinephrine and simulates the reduction seen in humans with FMS. We’ll talk more about these medications in later short reports.

Descending pathways that will ultimately modify spinal pain signals originate in several different parts of the brain; especially notable areas are the frontal lobe (where you do your conscious thinking and make decisions), the hypothalamus, and the amygdala. They are relayed to the periaqueductal gray (PAG) and rostral ventral medulla (RVM). You may recognize some of these names from the structures mentioned in the short reports on the radiological imaging studies on FMS. 

The hypothalamus regulates autonomic responses to pain, such as heart rate and blood pressure, and the amygdala is involved in emotional feelings such as fear, anxiety, or depression.  These regions are also the interface between the hypothalamic-pituitary-adrenal (HPA) axis which receives connections from the PAG, amygdala, thalamus, and hypothalamus. Remembering the short report on cytokines you would recognize the term, “HPA axis.” If you have been an avid reader of all of the short reports published on this web site you may begin to see how everything is starting to fall into place and each of the topics are not independent but build on the other. Stay reading and you’ll end up knowing more about FMS than many health care providers. 

You probably should know how the descending inhibition system functions. It seems to be one of the areas where the body’s natural endorphins were designed to work—the enkephalins, endorphins, and dynorphins. Here, the endorphins and enkephalins are most important. Endogenous opioids in the PAG are recruited by the DNIC system and trigger the release of the neurotransmitter serotonin from neurons who live in the part of the brain called the medulla (which is right at the top of the spinal cord and is the transition between the midbrain and the spinal cord). These neurons stretch down into the spinal cord. The serotonin acts at the level of the dorsal horn to provide pain relief by inhibiting the peripheral C-fiber pain nerves before they interact with the WDRNs. They do this in a very elegant way that still preserves the sensory-discriminative A-fiber pain sensations.

The serotonin containing nerve cells are actually very interesting nerve cells. They are either  “ON-cells,” which play a role in descending facilitation of pain perception, “OFF-cells,” involved in descending inhibition of pain perception, or “neutral cells,” which can be recruited for either role. Fascinating. The balance between ON-OFF cells can be shifted by the RVM. This was evolutionarily designed. Why do you think there would ever be a need for this to be the case? Here is an example – the level at which pain can be experienced can be raised as animals become hungrier: OFF-cells active. Conversely, injury results in the level at which pain being is experienced being lowered: ON-cells active. An animal with an injured limb needs to be reminded that the limb is injured to help it heal so the limb is made more sensitive to pain by the brain. OFF-cells are continuously active under the influence of opioid pain medications. 

The observation that the DNIC was lacking in FMS patients was noted by researchers in 1997.  The FMS researcher we have mentioned in other short reports, Dr. Staud and his group published a report in 2002 the results of which indicated in their model of experimental windup pain that FMS patients appeared to lack a DNIC mechanism completely. In 2005 another group of researchers reported similar findings. 

Dr. Ge, who has done tremendous work with myofascial trigger points and tender points, pointed out in a recent 2011 review that active myofascial trigger points are one of the major contributors to impaired descending inhibition in chronic musculoskeletal pain which leads to increased sensitivity of muscle tissue. Because trigger points are all over the body, this leads to a generalized lowering of whole-body pressure pain thresholds, i.e. the whole body is sensitive to touch. They have shown in 2011 there is a shift from descending inhibition to descending facilitation due to muscle nociception. Remember, the descending system has “ON-cells” that the body would use to make areas more sensitive to pain. The authors postulated that the increased peripheral mechanical sensitivity resulting from the muscle characteristics of FMS syndrome effectively counterbalanced the effects of descending inhibition.   

Behavioural states are influential. Dr. Barcellos de Souza and his group demonstrated that FMS patients with comorbid depressive symptoms had more pronounced deficits in DNIC compared to FMS patients without such symptoms. Have you ever wondered where the “placebo response” comes from? In normal people, expectations of receiving a medication that provides pain relief  (the ‘placebo response’) activates brain regions that are transmitted through the descending inhibitory systems to reduce the intensity of pain signals at the first stages of pain processing in the spinal cord. 

In healthy people, if the normal DNIC analgesic response is blocked then the placebo response doesn’t happen.  In fact, in healthy people the DNIC can markedly alter the effects of a pharmacologically active agent given the information provided to the person. For example, some people will say a medication has stimulant effects even though they were given a depressant medication if they were told the medication was a stimulant; this is the “contra-placebo response.”  

Dr. Goffaux and his team explored the descending system in FMS patients and came up with fascinating findings.  FMS patients are capable of having a placebo response even though their descending inhibitory circuits are impaired. How can this be? FMS patients expected and experienced pain relief in Dr. Goffaux’s experiments but rather than showing spinal inhibition they paradoxically showed evidence of spinal hyperexcitability. This should not be happening. The placebo response in normal people works by shutting down the spinal cord—by inhibiting it and making it hypoexcited. Yet, in FMS, patients were reporting a placebo response while their spinal cords were hyperexcited?

 In other words, the FMS patients, like normal people, reported less pain when they were expecting pain relief (the placebo response) however their spinal cord did not show the inhibition that was seen in normal people, it was still reacting to the pain stimulus and demonstrating hyperexcitability. In normal people the spinal cord would have been suppressed by the DNIC. FMS patients could not activate their DNIC to suppress the activity of the spinal cord yet they expressed the same subjective pain relief. The authors concluded that “cognitive re-appraisal” of the ascending signals must have occurred to allow the experience of subjective pain relief. In other words FMS were “thinking” their placebo response in a different manner.

This was the first study that showed that expectations can produce pain relief in the absence of spinal inhibitory circuits and that the spinal cord and the brains of FMS were “disconnected!!” It also demonstrated a pathophysiology unique to FMS patients not found in normal people—spinal hyperexcitability persists despite subjective feelings of pain relief, which the authors interpreted to now mean “Fibromyalgia patients can no longer be subsumed under the rubric of somatoform or pseudoneurological disoders… because patients suffering from a pseudoneurological disorder should not demonstrate spinal hyperexcitability, much less when analgesia (pain relief) is expected and reported.”

In other words, even the mechanisms of the placebo response are different in FMS patients! This was an amazing study!! 

Remember, we spoke about windup and exercise and how exercise does not cause a reduction in windup in FMS as it does in normal people. Well, strange things also occur in the DNIC system with exercise in FMS. In 2010 it was reported that FMS patients were not able to activate their DNIC systems during exercise and, compared to normal individuals, reported a paradoxical greater pain sensitivity following exercise. Increased pain sensitivity was seen at distant, non-exercised, rested muscles which again implicates central pain facilitatory mechanisms. The distant sites could be connected only in the central nervous system and here only by the A-beta nerve fibers – the ones that go to the muscle cells. It is a characteristic feature of central sensitization that one of the final steps is involvement of A-beta nerve fibers. These fibers also connect to the WDRNs and because of the changes that have occurred to make the WDRNs more sensitive, the signals from the A-beta fibers will now be interpreted as being painful. Near the end of Part 2 there was a rather poetic description of what happens when the input from A-beta fibers that is relaying mechanical information is misinterpreted as painful information.   

There are two situations in which DNIC effects can be disrupted, one is fragmented sleep. FMS researchers evaluated how altered sleep can affect the DNIC system by comparing the effects of sleep deprivation to eight forced awakenings (one per hour) in healthy individuals. The group who underwent forced awakenings experienced a significant loss of DNIC mediated pain inhibition as well as an increase in spontaneous pain manifested as headaches and backaches; effects not seen with sleep deprivation. 

The second condition is hormonal changes. DNIC provides greater pain inhibition with high estrogen and low progesterone levels (ovulatory phase) and lower pain inhibition with lower estrogen levels (menstrual and luteal phases). Given that the menstrual and luteal phases correspond to approximately 75% of the cycle, even normal females have less DNIC pain inhibition than men for the majority of the month.  

It is now evident that central sensitization is a common denominator of a number of medical conditions that overlap with FMS.  Tension type headaches are thought to represent central sensitization due to prolonged painful inputs from myofascial tissues concentrated around the skull and neck. As was described in the section on radiologic imaging, just as in FMS syndrome, there are also losses of brain matter seen in seen in patients with chronic tension type headache. Central sensitization is a recognized phenomenon complicating migraine headaches. There is evidence for widespread hypersensitivity and DNIC dysfunction in irritable bowel syndrome and interstitial cystitis.   

Drs. Russell  and Larson, in their 2009 review on the pathology of FMS, say that “It is no longer acceptable to state that FMS is poorly understood, that the cause of symptoms is unknown, or that there is nothing wrong with these patients.”  The above discussion on the neurobiology of the pain should provide evidence for FMS supporting their statement. The imaging studies that were discussed in other short reports may have resulted in a paradigm shift in viewing FMS. FMS is a regional pain syndrome with a central component that also has manifestations of fatigue, sleep disturbances, and cognition – far greater than just the outward manifestations. It also has an overlap with other regional pain syndromes such as irritable bowel syndrome, migraines, interstitial cystitis, and tension type headaches that appear to share the same pathophysiology – a central pain amplification component resulting in diffuse pain and dysfunction within the descending inhibitory pain systems. There is also a dysfunction of the HPA axis, cytokine irregularities, and autonomic nervous system dysregulation.

That pretty much sums up what is known about the pain in the brain for FMS as of 2011. It’s a rather technical area both medically and also from a research perspective. After reading these three short reports it should be apparent that FMS is a far more complex pain syndrome that what first meets the eye. A 2009 editorial in the Journal of Rheumatology was entitled, “Should Rheumatologists Retain Ownership of Fibromyalgia?,” and made the statement that, “Fibromyalgia can no longer be categorized as a rheumatic disease process, but rather is a pain syndrome centered in the nervous system.” Hopefully these short reports have helped you understand the reason the editorial made that statement. All the more reason physicians whose training has been in pain medicine should be strongly considered for providing care to a FMS patient.

The next set of short reports are going to discuss what FMS is and is not – conditions that may be confused with FMS such as Lyme disease, and arthritic  diseases that frequently accompany FMS as well as what our friends the psychiatrists have to say. Then we’re going to look at the common medications used in FMS one by one, over 20 of them, so you understand what’s good, bad and ugly about each. Finally, what may be the most fascinating and enlightening short reports of all – the Integrative Management of FMS—where everything you have read about in the past is combined into treatment suggestions. 

Here you’ll find out just what is truly meant by integrative pain management and what you can expect to receive at the hands of a pain clinic that uses a multi-modal approach to pain management – guaranteed to open your awareness to the most current pain management methods in use today. So—keep checking back.