Introduction 1 2 3 5 6 7 8 9 10 10 11 12 12 13 14 15 16 17 18 19 20 21 The goal of this article is to provide a rational basis for future investigations. First, the concept of central sensitisation as a cause of chronic pain will be explained. This theoretical background will then be applied to FM and an overview of the evidence for central sensitization in FM will follow. Finally, based on the theoretical background and the findings in FM, the hypothesis concerning central sensitization in CFS will be unfolded, supported with the present knowledge on CFS. Central sensitization Introduction 22 23 22 22 24 25 26 25 27 22 28 29 25 30 33 Temporal summation or wind-up 34 35 N d 36 37 38 39 24 40 Endogenous pain modulatory systems 41 42 43 42 44 45 46 44 47 48 44 41 44 41 49 52 47 Evidence in FM 53 54 55 56 57 Pain measurements 55 58 63 61 55 61 60 55 59 64 55 24 25 61 60 61 61 65 66 66 67 68 69 66 67 34 Measurements of excitability 57 Cognitive emotional sensitization 34 70 71 72 73 75 74 76 Central abnormalities in FM 17 77 79 77 78 79 80 81 80 82 20 80 83 84 85 Central sensitization in CFS? Direct evidence supporting the central sensitization hypothesis in CFS patients is currently lacking. But the present knowledge concerning CFS is suggestive of a central process similar to that seen in FM, given the great overlap between the two diseases and the observed similarities. 86 87 88 68 89 90 91 21 2 12 21 6 92 93 94 95 96 97 99 44 49 52 17 18 19 56 80 Conclusion Chronic widespread pain can be the consequence of central sensitization. Central sensitization is known as an increased central neuronal responsiveness and causes hyperalgesia, allodynia, and referred pain and hyperalgesia across multiple spinal segments, leading to chronic widespread pain. Possible triggers for sensitization of the spinal cord have extensively been discussed, such as wind-up or temporal summation, dysregulated descending inhibitory pathways, and upregulated facilitatory modulation. Wind-up or temporal summation is the result of repetitive noxious stimuli, leading to an increase in electrical discharges in the dorsal horn. Inhibitory modulation can be impaired by abnormalities in the central nervous system and the facilitatory pain pathways can be stimulated by certain behavioral and cognitive factors. This theoretical background can be applied to FM. In FM, studies already provided evidence for central sensitization as the cause of chronic pain. Temporal summation was found to be more facilitated, and the inhibitory pain modulation seemed impaired in FM patients. These findings can explain the chronic spontaneous pain in FM. Furthermore, some central abnormalities could be examined/objectified in FM: 1) hyperexcitability of the spinal cord, 2) decreased perfusion of pain-related brain structures, and 3) high levels of substance P in CSF. In addition, FM patients often present with pain hypervigilance, maladaptive coping strategies, and catastrophic thoughts, leading to cognitive central sensitization. Based on the knowledge on central sensitization, on FM and on CFS, it is suggested that chronic widespread pain in CFS is the consequence of central sensitization. There are arguments and probable mechanisms that could explain this phenomenon in CFS. Also, in other chronic pain populations, central sensitization may play a key role. In fact, there are many similarities between CFS patients and other chronic pain populations such as patients with chronic low-back pain, whiplash, FM, etc. The psychosocial factors, for example, have been proved to contribute to pain perception in these different pain populations. But the specific nature of CFS such as the immunological abnormalities, elevated NO amounts, preceding infections etc., invites further research, in particular, on the possible contributory role of these abnormalities to pain processing in CFS. 88 57