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.