Windup is abnormal in FMS patients, it is more enhanced. Windup pain can be induced experimentally in both healthy patients and FMS patients. If this is done in healthy people and FMS patients, both the pain that is perceived and the intensity of windup will be greater for FMS patients compared to the normal folks. The WDRNs of FMS patients, once they become activated, require more time to settle down — up to twice as long. (if you haven’t read Part 1, you won’t know what WDRN means — so you’ll have to go back) The longer the WDRNs are activated, the more intense the sensation of pain and the more the nervous system is pushed towards changing towards the condition of central sensitization.
Now we can talk a little bit about what starts and maintains windup. Remember, it is the pain nerves, the C-fibers and the A-delta nerves that are activating the WDRNs after they get stimulated in the periphery of the body. What stimulates the pain nerves? If the first thing that comes to your mind is muscle tissue, you’re right. If you’ve read the short report on Tender Points you may recall some of the abnormalities in muscle tissue that were described: ragged red fibers, changes in energy chemicals, increases in cytokines, and changes called glycation end products. If you remember from Part 1 of this series of reports one of the roles of substance P is to activate “silent” connections in the spinal cord that the body keeps in reserve for emergencies. Well, the body uses this same tactic in the periphery as well. Instead of connections they are actual pain nerve cells kept in reserve and only excited with continued inflammatory conditions. They’re called "silent nociceptors," where "nociceptors" is a fancy term for “pain sensor.” When these nerve fibers are activated the WDRNs are barraged by even more pain signals from the body. It is the A-delta and C-fiber stimulus from muscles that produces the non-localized aching sensation noted by FMS patients.
A group of FMS researchers demonstrated for the first time in 2009 that the central sensitization we have been eluding to so far in FMS patients was maintained by pain nerves coming from the muscles. They did this by injecting the tender points in the trapezius, or shoulder muscle, and then measuring how much pain could be felt in the forearm, which is neurologically connected to the trapezius muscle only in the central nervous system. So, if there was a change, it would have to have occurred in the central nervous system and reflect some aspect of central sensitization. Sure enough, injecting the shoulder trigger points with the anesthetic chemical lidocaine affected not only the trapezius but also reduced the discomfort that was felt at the forearm. This suggested that the trapezius tender points were, at least partly, maintaining the secondary pain at the distant site in the forearm. The authors interpreted these findings as suggesting that the primary pain nerves from deep muscles helped to maintain symptoms at distant body locations.
Even greater effects may be had with exercise. Normally, after exercising windup is reduced in normal healthy individuals, but studies in FMS indicate the opposite. After exercising as much as they could, one study has shown that windup was increased in FMS patients. Several additional studies have also shown that exercise increases sensitivity to pain in FMS patients. The same group of researchers mentioned in the above paragraph demonstrated, for the first time, in 2010, that exercise consistently increases FMS pain and fatigue through painful input coming in from the muscles but this could be reduced by rest. Exactly how they did it was through a rather complex experimental design that is a little too much to describe here, but what matters is the fact that they obtained the results.
Another group of researchers in 2009 used a technique called surface EMG to investigate the differences in muscle fatigue of FMS patients. Surface EMG can examine the electrical activation patterns of muscles and ascertain abnormalities that may originate from the central commands coming down from the brain or unusual patterns that may be taking place in how different sections of the muscle begin to fire when told to do so by the brain. They found that the muscle symptoms were generated by pathological alterations in central nervous system motor recruitment strategies — the brain was just not telling the muscles to fire in a coordinated pattern.
The studies with FMS are now getting rather precise and beginning to include genetic markers. A very recent study in 2011 has found in FMS differences in certain genes that affect sensory fatigue and muscle pain. Compared to normal people, individuals with FMS had increases in products made from particular genes. These products are called immune cytokine IL-10 and two specific sensory molecule receptors named P2X4 and TRPV1. Laboratory studies using animals suggest these genes have a role in situations where noxious levels of muscle-produced metabolites are made. Interestingly, more of the TRPV1 receptor is made when NGF levels increase. (Are you beginning to see how everything is connected?) The authors hypothesize that if these receptors are increased in sensory neurons the neurons may be more sensitive to muscle metabolites, even those produced during normal exercise, which would result in widespread increases in muscle pain.
If you have read the sections on the radiologic imaging studies of FMS you know how powerful those studies have been in showing differences between the brains of FMS patients and normal individuals without FMS. Imaging evidence showing that trigger points in the muscles cause an abnormal central response was provided by researchers in 2008 showing that compared to non-trigger point sites, abnormally increased myofascial pain resulted in significantly enhanced activity in both the sensory-discriminative pain regions as well as in the affective-motivational processing regions in the brain. Remember from the radiologic imaging short reports, there are two components to the pain processing systems – one that localizes and provides quantitative aspects to pain (the S-D region) and another that provides an emotional character to pain (the A-M region).
In 2010 the first study was published that demonstrated latent myofascial trigger points could both contribute to central sensitization. This study also indicated a role for muscle cramps in the generation of local and referred pain. Central sensitization has also been shown to be affected by peripheral nociceptive input from myofascial trigger points in two studies involving whiplash and one study concerning migraine. You can refer to the short report on Tender Points to review the difference between latent and active trigger points. Briefly, latent trigger points are just like active trigger points except they are not spontaneously painful and need something to stimulate them.
The recent work of Dr. Ge and his colleagues has also demonstrated that mechanical stimulation of both active and latent myofascial trigger points can induce central sensitization in FMS patients. They have demonstrated that active myofascial trigger points contribute to both local and referred pain in FMS patients and latent myofascial points contribute to muscle cramps; both sources of peripheral pain input to the spinal cord. They found that painful stimulation of latent myofascial trigger points in a shoulder muscle was found to result in increased spontaneous activity of myofascial trigger points in a wrist muscle which indicated that there is some type of communication within the nervous system. This work is important because it suggests that latent myofascial trigger points, which were previously not thought to be sources of pain, have now been shown to be significant pain generators, even though people do not feel them. In a sense, they are “silent” pain generators.
Back in 1998, it was hypothesized that perhaps the C-fiber pain nerves could be bidirectional, meaning they could transmit signals backwards, from the spinal cord to the periphery of the body. Sure enough, bidirectionality was shown in a 2010 study in which increased activity at a latent myofascial trigger point was seen after painful stimulation of a second latent myofascial trigger point – the information was carried by the C-fiber pain nerves. To get the second myofascial trigger point stimulated a message had to be sent by the first trigger point to the spinal cord and then from the spinal cord down to the second trigger point.
When the C-fiber is activated in the periphery it releases nearly the same irritating substances and neurotransmitters as it would in the spinal cord. This causes neighboring nerves to be irritated and sets up a chain reaction where those nerves irritated send a message back to the spinal cord which irritates other nerve cells who send a message back to the skin or muscles, causing the release of additional irritating substances, which irritate more nerves, etc., etc. For example, it has been found that substance P is just as potent in the periphery of the body as it is centrally.
For FMS patients, once central sensitization is established it requires minimal pain input to be maintained. FMS researchers Dr. Staud and his group have shown that windup could be maintained in FMS patients by frequencies as low as 0.16 Hz and 0.08 Hz which was not possible in healthy people. As central sensitization progresses over time, the nervous system becomes so sensitive that the need for a peripheral stimulus diminishes until sensory symptoms could conceivably be elicited without any, or just with minimal peripheral triggers. Evidence for this in FMS patients has been presented in a 2011 study that compared 1,623 patients with painful diabetic neuropathy (PDN) and 1,434 patients with FMS recruited from 450 treatment centers throughout Germany.
The pain from diabetic neuropathy has usually resulted from a number of effects from the diabetes - injury to the nerves because of the damage to the small blood vessels that are supplying nourishment and the direct effects on the nerves and their membranes as a result of the diabetes. Once this occurs, the pain can occur without any outside painful stimulation, it is “internal” to the nervous system. Both FMS patients and those with PDN used similar descriptors to characterize the quality of their pain, notably burning pain, prickling, and touch-evoked allodynia (allodynia means pain from something that should not be painful). Of the five symptom subgroups identified, two profiles were found frequently (20% - 35%) in both groups of patients suggesting to the authors these profiles in both FMS and PDN were brought about without any peripheral stimulus.
From the perspective of a FMS patient, Drs. Russell and Larson have quite eloquently framed the concept of A-beta nerve stimulation, the messages coming from the muscles regarding where they are in space and what is pressing on them and the pain or allodynia this is initiating. Remember, the A-beta fibers send messages to the WDRN. However, rather than being interpreted as mechanical information about the muscles, the WDRNs have become so sensitized that this mechanical information is misinterpreted as being information that is conveying painful sensations. This is another hallmark of central sensitization. Information that is sent to the WDRN that is actually position sense about a muscle or some other aspect that deals with mechanical information ends up being interpreted as pain. Here’s what Drs. Russell and Larson had to say:
"Peripheral pain generators can include body contact with a hard chair or a firm mattress, a weighted ligament can begin to ache, a tendon under tension can become distractingly uncomfortable, a muscle that has been used beyond its readiness can complain about each active movement, a well-meaning hug can be dreaded, or even the pounding of shower water on the chest can be painful. A grand-mother may not want her grandchildren to sit on her lap because the pressures from their little elbows and knees may cause pain that may persist for hours to days."
A rather poetic summary.
The signals from the WDRNs in the spinal cord are carried into the brain by a number of nerve pathways. They have rather fancy names and each tends to connect, or “project” to specific regions of the brain. For example, the “ventral spinothalamic tract” projects directly to the region known as the lateral complex of the thalamus and plays a role in the sensory-discriminative aspects of pain. The “paleospinothalamic” or “dorsal spinothalamic tract” projects to the posterior medial and intralaminar thalamic nuclei and ends in the ventroposterolateral thalamus. It is involved in the affective-motivational components of pain. The recently discovered “spinoparabrachio-amygdaloid” pathway from laminae I and II is a unique pain pathway that ultimately projects to the amygdala and serves as a direct connection between the spinal cord and the brain pain processing centers involved in the emotional processing of pain. It is in these areas of the brain that the final alterations that will manifest as central sensitization will take place.
This pretty much sums up the concept of central sensitization. It begins in the spinal cord with windup. Windup is both a term describing what is occurring in the WDRNs and a process that leads to the overall effect of central sensitization. After having read this section you can see that it is a rather elaborate process that all begins with peripheral nerves being overstimulated resulting in the WDRNs becoming over-activated. Their over-activation is transmitted to the brain where the “central” sensitization responses are generated. Central sensitization is best thought of as an amplification response where-by pain signals are taken in from the periphery and amplified, so that what may have been a stimulus that would have been ignored in the past, or is an innocuous stimulus to someone else, is downright painful to a patient with FMS and painful stimuli are even more painful.
As mentioned in Part 1 of this series there is another component to the pain of FMS — that which is called descending inhibition. That is the topic of Part 3.