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Focus
Pain
DOI 10.1007/s00482-016-0150-5
© Deutsche Schmerzgesellschaft
Published by Springer-Verlag Berlin Heidelberg
- all rights reserved 2016
Even primitive peoples were aware
of the pain-relieving effect of the
known as baroreceptor stimulation:
Using mechanical pressure to stretch
the arterial wall of the carotid sinus,
baroreceptors are stimulated and the
nucleus tractus solitarii reflex arches
are activated. Chemical and physical
stimuli are
t o pain-inhibiting neurons of the
central pain network. This
mechanism, known from
neurophysiology, enables a new
approach
for chronification and therapy
of chronic pain in a subgroup of pain
patients.
Baroreflex sensitivity -
anatomy and physiology
Baroreceptors serve as sensors in the
control circuit of mean arterial blood
pressure. They are located in
of the wall of the large thoracic and
cervical arteries, especially in the aortic
arch and carotid sinus, as well as in the
heart. They can register information
about the mean arterial pressure, the
magnitude of the pressure amplitude,
the steepness of the pressure increase
and the heart rate and transmit it to the
circulatory center in the medulla
oblongata. If the mean arterial blood
pressure rises, the receptors are excited
by the change in the dilation of the
vessel walls. They project via afferent
innervations of the glossopharyngeal
T. Meller1 - F. Stiehm1,2 - R. Malinowski1 - K. Thieme1
1
Institute of Medical Psychology, Faculty of Medicine, Philipps University Marburg, Marburg, Germany
e.V. 2
Vitanas Clinic for Geriatrics, Geesthacht, Germany
Baroreflex sensitivity and
chronic pain
Pathogenetic significance and clinical
implications
dorsomedial nucleus tractus solitarii
(dmNTS) in the lower brainstem, where
the first synapse in the baroreceptor
reflex is located.
The dmNTS projects to other
brainstem areas such as the nucleus
ambiguus and the rostral (RVLM) and
caudal ventrolateral medulla (CVLM).
The dmNTS is connected to the CVLM
via excitatory glutamatergic fibers.
When activated via GABAergic fibers,
this has an inhibitory influence on the
RVLM, which, as the control core of the
sympathetic nervous system, sends
excitatory fibers to preganglionic
neurons of the spinal cord. The dmNTS
is connected via excitatory fibers to the
nucleus ambiguus, which also has a
cardioinhibitory effect as
parasympathetic regulatory unit (O Fig.
1). All neurons of the baroreflex (BR)
are subject to regulation by the
brainstem, hypothalamus and limbic
system.
"
nerve (carotid artery) and vagus nerve
(aorta) to the
tractility of the heart as well as a
decrease in peripheral resistance and an
increase in volume in the capacitance
vessels. In this way, phasic changes in
blood pressure can be compensated [6,
8].
The function of the BR is measured
as baroreflex sensitivity (BRS) and
expresses the inverse change in heart
rate in relation to changes in blood
pressure. Various methods of
measuring the BRS and other functional
parameters of the BR are summarized
in a review article by Duschek et al [8].
Baroreflex sensitivity and the
central nervous system
a The baroreceptor system also modulates
activity in the central nervous system
beyond the brain stem. The "central
nervous" branch of the BR connects the
cardiovascular system via the NTS.
centers of the brain stem with higher
The baroreceptor reflex is an
important control mechanism of
cardiovascular activity
The BR functions as a negative feed-back
loop and thus represents an important
control mechanism of cardiovascular
activity: An increase in the mean arterial
pressure ensures an inhibition of
sympathetic activity and an increase in
parasympathetic activity. There is a
counter-regulatory decrease in heart rate
The pain
 Focus
and con- brain areas. These include the
thalamus, hypothalamus, amygdala,
insula, the rostral and anterior
cingulate cortex (ACC), the
periaqueductal gray (PAG), the
somatosensory cortex (SI, SII) and
parts of the prefrontal cortex (PFC; [5,
6, 22]). Various studies report on the
inhibitory effect of BR activation: At
the spinal level, a weakening of motor
reflexes is shown [22]. Baroreceptor
stimulation leads to a reduction in
cortical excitability, particularly in
frontocentral and parietal areas,
quantified

The pain
 Focus
Fig. 1 8 Simplified schematic representation of the baroreflex-mediated mechanisms of blood pressure regulation.
CVLM caudal ventrolateral medulla; NA nucleus ambiguus; NTS nucleus tractus solitarii; RVLM rostral ventrolateral
medulla. (According to [3, 5, 8, 16, 22])
via event-related potentials and other
parameters of the electroencephalogram
(EEG; [8, 22]). The activation of BR has
an anxiety- and pain-relieving effect as
well as inducing trance [11] and
shortens sleep latency [22].
" Baroreflex sensitivity is
modulated by internal and
external influences
The BRS is modulated by internal and
external influences. Firstly, a
natural fluctuation in the activation of
the BR can be observed over the course
of the cardiac cycle: Like blood
pressure, it is highest in the systolic
range and lowest in the diastolic range.
In addition to manipula-
tions of the baroreceptors, e.g. through
vasopressor drugs or physical pressure
application, this is a suitable
operationalization to investigate the
influences of BR on cognitive and
sensory performance.
to investigate. Based on the
a reduction in the reaction time to
visual, auditory and tactile stimuli is
found across the cardiac cycle, parallel
to the course of BR activation [19]. The
BRS is shown to be a robust predictor of
performance and speed in such tasks,
with the relationship being inverse.
Confrontation with more complex
cognitive tasks is also associated with a
reduction in BRS. Various studies have
shown this correlation for mental
arithmetic tasks, visual
attention tests or visual working
memory tasks - but also for affective
stress such as increased anxiety and
worry (overview in [8]).
In summary, various types of mental
stress appear to be associated with a
R-Zacken BRS reduction. A
The explanatory model is that the
reduction of the BRS enables the stress-
induced increase in heart rate and blood
pressure and improves the energetic and
metabolic supply of the organism,
including cerebral blood flow [8]. This
top-down regulation is also associated
with the network of ACC, insula,
amygdala and PAG [5].
The pain
 Focus
Baroreflex and pain
sensitivity
The involvement of the cardiovascular
system in the modulation of pain
perception was first demonstrated in
the context of hypalgesia in patients
with hypertension (blood pressure
>140/90 mmHg).
investigated: During experimental
electrical stimulation of the dental pulp,
hypertensive patients in various age
ranges showed significantly increased
sensory thresholds and pain thresholds
in the dental pulp.
compared to normotensive control
subjects. Even within the normotensive
control group, there was a linear,
inverse correlation between resting
blood pressure and pain intensity.
sensitivity [30].
This was replicated with different
parameters. The relationship between
the resting blood pressure level and
subjective ratings of electrical, thermal
and mechanical pain stimulation, but
also reflex reactions to pain stimuli (no-
ciceptive flexor reflex [NFR]) has been
demonstrated [10]. The natural
variation in blood pressure within the
cardiac cycle also has an influence on
pain sensitivity: for example, in
normotensive, healthy subjects, the
threshold for reflex responses (NFR) to
pain stimuli applied shortly after the R
wave (systolic range) is higher than
when the NFR is applied shortly after the
R wave (systolic range).
these stimuli in the diastolic range
of the cardiac cycle [10]. The changes in
blood pressure are accompanied by
corresponding changes in BRS.
Compared to the normotonic and
hypertensive blood pressure range,
various studies show that a chronically
low blood pressure - <90/60-110/65
mmHg, depending on the source - can
be achieved at
healthy subjects with an increased
pain sensitivity [7]. Ex- perimental
findings show that the relationship
between BRS and pain sensitivity is
significantly less pronounced in this
hypotonic subgroup [6]. It is reasonable
to conclude that these relationships
between arterial blood pressure and
nociception are mediated via the BR.
The pain
Summary - Abstract
SchmerzDOI 10.1007/s00482-016-0150-5
© Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag Berlin Heidelberg - all rights
reserved 2016
T. Meller - F. Stiehm - R. Malinowski - K. Thieme
Baroreflex sensitivity and chronic pain. Pathogenetic significance
and clinical implications
Summary
The interaction of cardiovascular dynamics and pain perception baroreflex
sensitivity in a subgroup of patients can
reduce the activity of the dmNTS and thus represents a significant component of intrinsic
pain regulation . This leads to a reduction in the
autonomic pain stimulus regulation capacity and to a lack of increased sympathetic
arousal, an intrinsic pain inhibition. At the same
time, the function of the baroreflex itself arterial
c o g n i t i v e and affective processes
blood pressure. Arterial barore-
register such phasic modulated . In this paper, the blood pressure changes
and project the role of the baroreflex as a possible this
information to the dorsomedial important factor in the development and nucleus
tractus solitarii (dmNTS) in the lower brain. Maintenance of chronic pain
brain stem. Through connections in further are shown. The following are also taken into
account
brainstem areas, but also in higher-relevant learning processes. Building on cortical
areas, this ultimately results i n a mechanism-based
individual regulation of blood pressure, but also the treatment approaches for pain patients
modulation of sleep, anxiety and pain with hypertonic stress reactivity is critical. In
.
healthy people, there is therefore discussion
an inverse relationship between blood pressure and
Pain sensitivity, this connection Keywords
Blood pressure - Hemodynamics - Dorsomedial It is discussed that, due toNucleus tractus
solitarii - Chronic stress and pain behavior, classicalPain - Psychological pain therapy
and operant conditioning processes
Baroreflex sensitivity and chronic pain. Pathogenetic significance
and clinical implications
Abstract
The interaction of cardiovascular dynamicsmechanisms reduce baroreflex sensitivity
and pain perception is an important (BRS) and dmNTS activity in a subgroup of
component of intrinsic pain regulation. Inpatients . This leads to a decrease of autonomic
healthy subjects acute pain stimuli causeregulatory function as well as reduced pain increased
sympathetic arousal and increasedinhibition . Importantly, baroreflex function mean
arterial pressure. Arterial baroreceptorscan be modulated by cognitive and affective
sense phasic blood pressure changes andprocesses . This article reviews the role of the relay the
information to the lower brainstembaroreflex arc as a possible crucial factor in via the
dorsomedial nucleus tractus solitariusthe development and maintenance
of chronic (dmNTS). Projections in the brainstem andpain . The importance of learning
mechanisms also higher cortical areas result in elevationis described. Mechanism-based
individualized of blood pressure as part of the autonomictreatment approaches for
patients with nervous system as well as modulation ofhypertensive stress reactivity are also
critically sleep, anxiety and pain. In healthy subjectsdiscussed .
there is an inverse relationship between
blood pressure and pain sensitivity but Keywords
this relationship is impaired in chronic painBlood pressure - Hemodynamics - Nucleus
patients. Persistent stress, pain behaviortractus solitarii, dorsomedial -
Chronic pain - and classical and operant conditioningPain therapy, psychological
 The underlying model is formulated
as follows: As a reflex reaction to a pain
stimulus, the sympathetic arousal
increases and with it the blood pressure.
This stimulates the baroreceptors and,
as a result, a descending pain-inhibiting
activity, mediated via the NTS and its
direct (PAG, nucleus raphe magnus,
locus cae- ruleus) and indirect
projections (insula, ACC, SI, SII) in
corresponding central areas. The
descending pain-inhibiting activity
helps to downregulate sympathetic
activation [3]. Baroreceptors appear to
be primarily sensitive to changes in
systolic blood pressure and less sensitive
to changes in diastolic blood pressure
[3, 21].
Experimental data confirm the
model: an inverse relationship is found
between BRS and the level of rating of
sensory and affective dimensions of
experimentally experienced pain, for
example in the "cold pressor test" [6]. In
support of this, various studies have
shown that direct electrical,
pharmacological or physical stimulation
of the baroreceptors or their afferents
induces antinociception [3], as does
direct stimulation of the dm- NTS [1].
Surgical denervation of baroreceptor
afferents eliminates hypalgesia in the
hypertensive animal model and
produces hyperalgesia in the
normotensive animal model [3]. Other
mechanisms, such as opioid and
noradrenergic systems, are probably
also involved in mediating the
relationship between BRS and pain
sensitivity. However, this will not be
discussed here. For a detailed overview,
please refer to Duschek et al [3].
Reduction of baroreflex
sensitivity in chronic pain
To understand the functionality and
relevance of the described mechanism,
imagine its implications at the
behavioral level [3]: A short-term pain
stimulus, warning signal for a potential
attack or
an injury, generates a systemic arousal.
In the course of this, the BR is activated
and induces a de-sensitizing pain
inhibition that facilitates coping with
the potentially dangerous situation by
fight or flight [16, 20]. Subsequently, the
salience of the pain stimulus is
increased by switching to pain-
reinforcing activity in order to promote
protection and healing [16, 20]. If the
pain stimulus persists beyond this
point, a healthy mechanism in turn
shows more descending inhibitory
activity to facilitate the resumption of
vital activities [20]. The effect of BR on
pain perception is therefore also
modulated by the length of the pain
stimulus [3].
However, this process requires a
functioning BR. At the same time, it
appears to have a protective effect in
relation to various diseases. For
example, a pronounced BRS is
associated with lower cardiac mortality
after myocardial infarction and heart
failure [23]. With regard to pain
disorders, there is an inverse correlation
between systolic blood pressure and the
risk of postoperative pain [21], tension
headaches and migraines
[28] and chronic low back pain (CLBP;
[14]). These relationships are
presumably modulated via the BRS.
Conversely, a disruption of precisely
this protective mechanism is also
evident for various diseases outside the
cardiovascular area. For example, a
reduced BRS is found in the context of
[8, 24] 4 sleep apnea,
4 Restless legs syndrome,
4 Parkinson's syndrome,
4 Diabetes type 1 and 2,
4 Bronchial asthma,
4 Depression,
4 Anxiety disorders,
4 Schizophrenia,
4 chronic fatigue syndrome,
4 Burnout syndrome and
4 chronic pain.
Different causes of the BRS disorder are
identified for these diseases.
However, it is conceivable that reduced
inhibition processes play an important
role in the maintenance of the diseases.
Further research is urgently needed.
In the context of pain disorders, the
data on fibromyalgia (FM) and BRS
reduction is the most extensive.
Compared to healthy individuals, FM
patients not only show lower pain and
tolerance thresholds to experimental
pain stimuli, but also a reduced BRS
[25]. In patients with FM,
heterogeneous psychophysiological
subgroups have also been identified that
differ in their response to stressors [26].
Based on the above studies on the
relationship between blood pressure
and BR in pain-free subjects, it is
assumed that a disturbance of BR is
particularly relevant for the
development and maintenance of the
disease in the subgroup characterized
by hypertonic stress reactivity. Here, the
inverse relationship between blood
pressure and pain in healthy subjects is
disturbed [25]: the higher the blood
pressure, the stronger the pain.
There are also comparable findings
for other pain disorders: patients with
temporomandibular dysfunction show
impaired autonomic function
parameters compared to healthy
controls, which indicate a reduction in
BRS [17]. CLBP also shows a disturbed
correlation between BRS and pain
sensitivity [4]. Such dysregulation has
also been demonstrated in patients with
complex regional pain syndrome [15]
and cluster headache [2].
Reduced BRS appears to be a
common feature found in various
chronic pain and other diseases [17]. It
can be seen as a significant physiological
explanation of why stress and illness
behavior lead to the development and
chronification of disease. Chronic pain
appears to be associated with a
dysfunction of the overlapping systems
of pain regulation and blood pressure
modu- lation.
The pain
 Focus
lation [4]. In the clinical picture, this
dysfunction manifests itself in the fact
that the inverse relationship between
blood pressure and pain sensitivity that
exists in healthy individuals is abolished
or even reversed, so that increased blood
pressure is accompanied by increased
pain sensitivity [3]. It is conceivable that
this phenomenon entails more
comprehensive changes in endogenous
systems of pain regulation, the
disruption of which has been reported
in chronic pain disorders [3].
Significance of baroreflex
sensitivity for chronification
processes
Cognitive, affective and behavioral
influences are known to play a critical
role in the development and
maintenance of chronic pain [12, 29].
At this point, however, the significance
of a reduced BRS for chronification
processes should be discussed. This can
be illustrated using the example of
"learned hypertension" according to
Dworkin [9]. Particularly in individuals
with increased stress levels, the BR
mediates operant conditioning of blood
pressure increases.
tions: An increase in blood pressure, e.g. in the
stress-mediated arousal, stimulates the
baroreceptors, which reflexively inhibits
the perception of and reaction to
aversive stimuli [11]. As a result, the
subjective perception of stress is
reduced in the short term. Blood
pressure drops. In the long term, the
organism learns to react to stress with
hypertension [9]. This mechanism is
referred to as negative reinforcement of
blood pressure.
Elbert et al [11] showed that the
increase in blood pressure over 20
months can be predicted by the level of
the pain-reducing effect of baroreceptor
stimulation. According to this,
individuals with a strong correlation
between BRS and pain sensitivity are
particularly at risk of developing
hypertension [3]. To put this into
perspective, it should be noted that this
mechanism only explains part of the
pathophysiology of hypertonicity.
The pain
never represents. Other factors such as
diet, activity or humoral changes also
play a critical role. Classical and
operant conditioning processes are also
of immense importance for the
development and maintenance of
chronic pain [12]. Thieme et al [27]
showed that chronic pain patients with
hypertonic stress reactivity exhibit
more pain behaviour, increased
catastrophizing and greatly reduced
activity, which leads to higher pain
intensity via conditioning processes.
Turk et al [29] refer to these behaviors
as dysfunctional illness processing.
Once this process h a s started, the
typically reduced physical activity and
avoidance behavior in various areas of
life for this subgroup lead to an
increasing reduction in BRS. Similar to
the mechanism of hypertension
described above, this occurs via
negatively reinforcing conditioning
processes, which in the long term lead
to an increase in blood pressure and a
reduction in blood pressure variability
[9, 25]. Such a progressive decrease in
BRS over the course of the disease has
already been
shows [3]. In addition, preoperative BRS
correlates prospectively with early and
long-term postoperative pain levels [21].
The reduced BRS results in a reduction
in NTS activation, which prevents the
inhibition of chronic pain via direct and
indirect projections of the NTS [3].
Since the BR or its dysfunction appears
to be involved in the development and
maintenance of chronic pain disorders,
it could also enable a new treatment
approach.
Therapeutic implications
There are already various approaches to
training the BR mechanism, particularly
in the context of cardiovascular diseases,
but there have only been a few studies
to date on pain disorders. It s h o w s ,
that BR can indeed be influenced by
different methods: Physical endurance
training increases BRS in patients after
myocardial infarction and is associated
with lower mortality within a study
period of 10 years [23]. Biofeedback of
heart rate variability increased BRS i n
FM patients, accompanied by reduced
depression [13]. It appears that short-
term pain-reducing effects of yoga are
achieved via certain breathing
techniques that increase BRS [18].
In line with the inverse relationship
between BRS and stress [8], it is also
conceivable that stress-reducing
interventions have a positive effect on
BRS. A treatment approach aimed
directly at increasing BRS therefore
appears to make sense. The medium to
high effect sizes of psychologic pain
therapy indicate that a combination of
psychologic pain therapy and targeted
baroreceptor training could modulate
cortical and sub-cortical areas of the
pain network and thus achieve
descending pain inhibition and long-
term pain remission [24, 25].
case of chronic back pain
Conclusion for practice
4 Baroreceptors modulate the
processing of pain stimuli via NTS
projections to central areas of
descending pain inhibition.
4 Phasic increases in blood pressure
represent an adaptive stress
response in healthy individuals due
to the inverse relationship between
blood pressure and pain.
4 In chronic pain, this process
becomes maladaptive and disease-
promoting due to negative
reinforcement of the increase in
blood pressure.
4 In addition to disease-specific
explanatory models, the reduced
BRS could explain the connection
between stress, illness behavior and
chronic illness.
4 The role of BRS in the development,
maintenance and treatment of
chronic pain is important for

a subgroup with hypertonic stress
reactivity is particularly relevant.
4 To treat chronic pain effectively i n
the long term by restoring
endogenous pain inhibition,
psychological pain therapy should be
c o m b i n e d w i t h baroreceptor
training to address the pain
n e t w o r k even more effectively.
Correspondence address
T. Meller
Institute for Medical
Psychology, Faculty of
Medicine, Philipps University
Marburg
Karl-von-Frisch-Str. 4,
35032 Marburg, Germany
tina.meller@
staff.uni-marburg.de
Compliance with ethical
guidelines
Conflict of interest. T. Meller, F. Stiehm,R.Malinowski
and K. Thieme state that there is no conflict of interest.
This article does not include any studies
conducted by the authors on humans or animals.
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The pain