Discussion
In ME/CFS patients sub grouped by the presence or absence of fibromyalgia (FM), we studied pressure pain thresholds (PPT) and the effects of orthostatic stress testing on PPT. First, in the supine position, PPT of the shoulder of ME/CFS patients with and without FM were all significantly lower than of the pre-HUT PPT of HC. The pre-HUT PPT of the finger of ME/CFS patients without FM were not different from that of HC, while that of patients with FM were lower that of HC. Second, post-HUT PPT declined significantly in ME/CFS patients with and without FM, whereas it did not change in HC. Third, the temporal summation (windup), defined by the slopes of the pain severity versus the number of stimuli and also defined by the difference in pain sensation between the first and tenth stimulus, were all higher in ME/CFS patients than in HC (all p<0.0001). Comparing pre- and post-HUT slopes, there were no significant differences in both the two patient groups and in HC, nor was there a difference in pre- and post-HUT windup defined by the delta pain sensation of the first and tenth stimulus.
Baseline PPT: the PPT pre-HUT findings in our study of 164 ME/CFS patients with FM confirm and extend previous reports showing that FM patients have lower PPT values than HC(18, 36-38). In two ME/CFS studies a lower baseline PPT was found compared to HC(26, 39). ME/CFS patients with FM had a lower PPT than ME/CFS patients without FM(40).
In our study the ME/CFS patients without FM had a similar baseline PPT on the finger compared to HC, and a lower baseline PPT on the shoulder compared to HC. A recent study in HC by Park et al. showed higher PPT on hands and fingers compared to the PPT of muscular parts, indicating the finger to be relatively less sensitive to pain(41). Despite the absence of a difference in PPT of the finger in patients without FM, PPT of the shoulder were significantly lower than that of HC. This could be explained by a high prevalence of muscle pain in even in patients without FM: in our study 70% of the ME/CFS patients without FM reported muscle pain and 17% of patients without FM used neuropathic pain medication. Also, NRS pain scores of patients without FM were higher than the NRS pain scores of HC. Taken together, our data on PPT and NRS pain scores and the data of Geisser et al.(40) indicate that pain is a very common phenomenon in adults with ME/CFS, with the pain spectrum ranging from no pain to severe pain/fibromyalgia. Therefore, not only the presence or absence of FM should be taken into account in pain management, but also the PPT values of the patients, irrespective of the diagnose of FM. This approach of using PPT measurements warrants further study.
PPT post-stressor: Earlier studies of the response of PPT to a physiologic stressor among HC have primarily used exercise as the intervention. Studies in HC invariably show that PPT is higher after exercise, indicating hypoalgesia (see for a review Koltyn)(42). In FM patients the data on PPT post-exercise are conflicting: in 2 studies an unchanged PPT in the non-exercised muscle groups were found after isometric contraction exercise(36, 43). In contrast, in two other studies an increased PT in the non-exercised muscle group was found in FM patients(37, 38). In ME/CFS patients a different pattern was seen: post-exercise PPT increased in HC in contrast to a decrease in ME/CFS patients(11, 26). In the present study, PPT in HC after the orthostatic stressor were unchanged, whereas in both ME/CFS patient groups PPT were significantly lower compared to values pre-HUT (both p<0.0001).
In a recent study we showed that during HUT, adults with ME/CFS reported increased fatigue, decreased concentration, increased dizziness/light-headedness, and the provocation or worsening of pain(NCP2019). Moreover, those with ME/CFS experienced a significant decrease of cerebral blood flow compared to HC, and that there was an inverse linear relation between the number of symptoms reported during HUT and the reduction in cerebral blood flow. In other studies, it was shown that working memory function, as assessed by the n-back test, decreased during HUT(44, 45). We therefore hypothesize, that the pain perception increase, as demonstrated by a PPT decrease, may be related to reduction in cerebral blood flow. The pathophysiology of the increased pain sensation after orthostatic stress (possibly related to increased catecholamines, metabolic changes, or inflammatory changes) needs to be addressed in future studies. On the other hand prolonged standing as a physiologic stressor in ME/CFS patients, might also be responsible for the increase in PPT. Future interventions during HUT, like application of a lower body compression could address the question whether the PPT decrease is due to cerebral blood flow reduction or due to prolonged standing(46).
Baseline windup: a recent meta-analysis comparing FM patients with HC showed that windup was significantly higher in FM patients compared to HC (test for overall effect: p=0.0005)(28). This meta-analysis analyzed 14 studies, including 298 healthy controls and 318 FM patients. In an ME/CFS study windup in ME/CFS patients (n=48) with a high pain rating score, a non-significant difference compared to HC (n=39) was found(47). Our results show, both in ME/CFS patients with and without FM, a highly significantly increased windup in ME/CFS patients (both p<0.0001) compared to HC. The differences between our study and of Collin et al.(47) are unexplained but may be due to different inclusion criteria.
Windup post-stressor: in a study using thermal stimulation, a differential effect of exercise was shown in HC (n=10) vs FM patients (n=10)(48). Following a maximal exercise stress test in FM patients, windup was higher than pre-exercise data, whereas in HC windup was lower post-exercise. In the study of Malfliet et al. post submaximal exercise windup between 20 HC and 20 ME/CFS patients no significant differences were observed(49). In the present study pre-HUT windup of HC was significantly lower than windup of ME/CFS patients with and without FM. Post-HUT data did not change in HC and in the two patient groups. A review of Staud et al. without pointing out any number of patients involved, indicated that part of the windup is related to abnormal pain processing in the spinal cord(2). Possibly, differences in flow reduction of the spinal cord vs central cortical and subcortical areas or different sensitivities to flow reduction may explain the observed differences in PPT and windup, but needs to be studied further.