European Journal of Pain 13 (2009) 28–34

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European Journal of Pain

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Increased sensitivity to heat pain in chronic low blood pressure

Stefan Duschek a,*, Anja Dietel a, Rainer Schandry a, Gustavo A. Reyes del Paso b
a
Department Psychologie, Ludwig-Maximilians-Universität München, Leopoldstraße 13, 80802 Munich, Germany
b
Universidad de Jaén, Departamento de Psicología, Facultad de Humanidades y CCEE, 23071 Jaén, Spain

a r t i c l e i n f o a b s t r a c t

Article history: While in elevated blood pressure reduced sensitivity to acute pain has been well established, little is
Received 3 January 2008 known about possible alterations in pain perception within the lower range of blood pressure. In this
Received in revised form 6 February 2008 study, sensitivity to heat pain was assessed in 40 subjects with chronic hypotension (mean blood pressure
Accepted 20 February 2008
96.5/57.7 mmHg) and 40 normotensive control persons (mean blood pressure 121.8/77.2 mmHg).
Available online 18 April 2008
Employing a contact thermode, heat stimuli were applied to the forearm. Pain threshold and tolerance
were determined. Participants furthermore rated subjective intensities and unpleasantness of tonic heat
Keywords:
stimuli (45.5–47.5 °C) on visual analogue scales and in a questionnaire. Possible confounding of sensitivity
Pain
Blood pressure
to heat pain with skin temperature, temperature sensitivity and mood was controlled for. In addition to
Hypotension blood pressure, functional features of the arterial baroreceptor system were related to pain experience.
Baroreceptor Therefore, estimates for the input on the baroreceptors, as well as baroreflex sensitivity were obtained.
Hypotensive individuals exhibited markedly reduced pain threshold and pain tolerance, as well as
increased sensory and affective pain experience. The measures related to the baroreceptor system were
not associated with pain experience, suggesting that no significant modulation of heat pain occurs through
this system. The results of this study complete the findings on hypertension-related hypoalgesia and sug-
gest an inverse relationship between blood pressure and pain sensitivity across the whole blood pressure
spectrum. Furthermore, increased proneness of hypotensive individuals to clinical pain may be discussed.
Ó 2008 European Federation of Chapters of the International Association for the Study of Pain. Published
by Elsevier Ltd. All rights reserved.

1. Introduction 2008). The significance of this finding, however, is limited by the

Chronic low blood pressure is typically accompanied by symp-
toms such as fatigue, reduced drive, dizziness, headaches and cold
limbs, which can have a considerable impact on subjective well-
being and quality of life (e.g. Rosengren et al., 1993; Wessely
et al., 1990). In addition to these subjective complaints, reduced
cognitive performance, as well as diminished cerebral blood flow
and cortical activation have been documented in hypotension
(Duschek and Schandry, 2004, 2007; Duschek et al., 2006).
Associations between blood pressure and nociception are well
documented (Bruehl and Chung, 2004). Pain sensitivity has been
shown to be diminished in clinical hypertension, as well as in
healthy individuals with only moderately elevated blood pressure
(e.g. Myers et al., 2001; Zamir and Shuber, 1980). In the normoten-
sive population, an inverse linear relationship between blood pres-
sure and pain sensitivity has repeatedly been reported (Bruehl
et al., 1992; McCubbin and Bruehl, 1994).
In contrast, knowledge about pain perception in the low blood
pressure range is sparse. A preliminary study revealed increased
sensitivity to cold pressor pain in hypotension (Duschek et al.,
* Corresponding author. Tel.: +49 89 21805297; fax: +49 89 21805233.
E-mail address: duschek@psy.uni-muenchen.de (S. Duschek).
association between cold pain and peripheral blood flow. Reduced
perfusion in hypotension may imply more pronounced cooling of
the skin, as well as increased activity of vascular nociceptors
(Klement and Arndt, 1991). It therefore remains unknown whether
the conclusion of increased sensitivity is restricted to cold pain or
also applies to other sources of pain.
The clinical relevance of the blood pressure–pain association is
underlined by reports on an inverse relationship between blood
pressure and the prevalence of pain syndromes in the normoten-
sive and hypertensive ranges (e.g. Hagen et al., 2002, 2005). Taking
this into account and assuming an inverse relationship between
blood pressure and pain sensitivity across the entire blood pres-
sure spectrum, increased proneness of hypotensive individuals to
clinical pain may be hypothesized.
In addition to the association between hypotension and pain
experience, the present study investigated possible relationships
between functional features of the arterial baroreceptor system
and nociceptive responses. The baroreceptors form part of a nega-
tive feedback loop (‘‘baroreflex”) in which blood pressure fluctua-
tions are responded to by compensatory changes in heart rate
(Guyton and Hall, 2005). In addition, baroreceptor stimulation is
believed to attenuate pain experience (Bruehl and Chung, 2004).
It was hypothesized that stronger input on the baroreceptors

1090-3801/$34.00 Ó 2008 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejpain.2008.02.007
 S. Duschek et al. / European Journal of Pain 13 (2009) 28–34
Table 1
Means (M) and standard deviations (SD) of systolic blood pressure, diastolic blood pressure, age, skin temperature, scores on the Mood Scale and the time interval from the latest
period in both samples
Hypotensive group
M SD
Systolic blood pressure (mmHg) 96.5
Diastolic blood pressure (mmHg) 57.7
Age (years) 27.7
Skin temperature (°C) 31.5
Mood Scale 13.1
Time interval from latest period (days) 11.2
during periods of blood pressure increase is accompanied by
reduced pain sensitivity (Rau and Elbert, 2001). Furthermore, an
inverse association between the sensitivity of the baroreflex and
cold pain was observed, suggesting a dependence of pain percep-
tion on the degree of baroreflex activation (Duschek et al., 2007).
It should not, however, be overlooked that conflicting results
which challenge the baroreceptor hypothesis have also been re-
ported. In a number of human studies, the expected antinocicep-
tive effect of experimental baroreceptor stimulation failed to
appear or was restricted to particular sources of pain (Edwards
et al., 2003; Rau et al., 1994).
In this study, heat stimulation was applied to evaluate pain per-
ception in chronic hypotension. Pain threshold and tolerance, as
well as subjective pain intensities were assessed. Furthermore, a
possible dependence of the sensitivity to heat pain on the function
of the baroreceptor system was investigated. Based on former re-
search, both the impact on the arterial baroreceptors and barore-
flex sensitivity were hypothesized to be inversely associated with
pain intensity.
2. Methods
2.1. Participants
Forty hypotensive and 40 normotensive control subjects partici-
pated. The definition of the WHO (1978) was applied as the inclusion
criterion for the hypotensive sample. In this definition, hypotension
is diagnosed when systolic blood pressure falls below 100 mmHg in
women and 110 mmHg in men, regardless of the diastolic value. The
inclusion criterion for the control group was systolic blood pressure
between 115 and 140 mmHg. Criteria for exclusion comprised
relevant physical diseases, acute or chronic pain of any kind, psychi-
atric disorders, as well as the use of psychoactive drugs, analgesics or
medication affecting the cardiovascular system. Health status was
assessed using an anamnestic interview and a comprehensive med-
ical questionnaire. All subjects were right-handed according to the
Edinburgh Handedness Inventory (Oldfield, 1971).
The hypotensive and the control groups were matched accord-
ing to age and gender. Both samples consisted of 32 female and 8
male subjects. Table 1 includes information about blood pressure
recorded just before the experimental procedure, as well as age,
and skin temperature measured at the forearm. Furthermore, the
scores on the ‘‘Befindlichkeits-Skala” [Mood Scale] (Von Zerssen,
1976) are displayed. This is a 28-item self-rating scale widely used
in German speaking countries for the assessment of current emo-
tional state. The questionnaire includes positive and negative
adjectives, which are related to general aspects of well-being
(e.g. cheerful, relaxed), as well as to more specific emotions (e.g.
depressed, insecure). Higher values on the scale represent a more
adversely affected emotional state.
Fifteen women of the hypotensive and 20 of the control group
were using oral contraceptives. Five hypotensive and three control
subjects reported that they were having their period on the day of
29
Normotensive group
M SD
4.8 121.8 5.3
4.5 77.2 5.9
5.7 27.8 5.4
1.3 31.9 1.1
13.5 11.1 8.7
7.4 11.8 7.8
the experiment. For the remaining women, the time interval from
the end of the latest period is presented in Table 1.
Sixty-three of the participants were university students (31 in
the hypotensive sample and 32 in the control group). Of the
remaining subjects, ten were employees, four were self-employed
and three were unemployed.
2.2. Pain induction and quantification
Thermal stimulation was performed using a Thermal Sensory
Analyzer (TSA II, Medoc Advanced Medical Systems, Israel). A con-
tact thermode (surface 30  30 mm) was attached to the volar sur-
face of the left forearm. The thermode was digitally controlled
using the software WinTSA and CoVAS (Medoc, Israel).
In order to control for possible alterations in temperature sensi-
tivity in hypotension, warm and cold sensory thresholds were
determined. For this purpose, the temperature of the thermode
rose or fell at a rate of 1 °C/s, beginning at 32 °C. Subjects were in-
structed to press a response key as soon as they felt warmth or
coldness. The temperature returned to 32 °C at a rate of 10 °C/s
immediately after the keystroke. Five warm followed by five cold
stimuli were applied with inter-stimulus intervals randomly rang-
ing from 4 to 7 s.
Pain sensitivity and tolerance were quantified using a testing-
the-limits procedure. Once again, the temperature increased at
1 °C/s from a baseline of 32 °C. To determine pain threshold, partic-
ipants pressed the key when the sensation ‘‘started to become
painful”. In case of the assessment of pain tolerance, the key was
pressed when subjects could ‘‘no longer tolerate the pain”. Five tri-
als were performed for each condition (inter-stimulus interval 10 s,
return rate 10 °C/s). In order to obtain estimates for temperature
sensitivity, pain sensitivity and pain tolerance, the temperatures
at which the keystrokes took place were averaged across the five
trials of each condition.
Ratings on subjective pain intensity were obtained using tonic
heat stimulation. Therefore, five stimuli of temperatures ranging
from 45.5 to 47.5 °C were presented (pseudorandom sequence:
45.5, 46.5, 47, 46, 47.5 °C). Stimulus duration was 60 s1 with each
stimulus being preceded by a 60 s baseline of 32 °C (increasing and
return rate 7 °C/s). In order to prevent sensitization, the area of ther-
mal stimulation was changed slightly for each trial.
The participants’ subjective pain experience was quantified
using two 10 cm line visual analogue scales (VAS) referring to
the sensory and affective aspects of pain (‘‘How strong/unpleasant
was the pain?”). The anchor points of the scales were marked
‘‘not at all” and ‘‘extremely”. The VAS were presented immediately
after each stimulus. After the last stimulus, the overall pain
experience during tonic heat stimulation was rated on the
1
Relatively long lasting stimuli were chosen so that indices of baroreflex
sensitivity could be obtained during heat stimulation (see Data analysis). Sequence
analysis, which was applied for this purpose, requires recording periods of at least
60 s (Reyes del Paso, 1994).
30 S. Duschek et al. / European Journal of Pain 13 (2009) 28–34
‘‘Schmerzempfindungsskala” [Pain Sensation Scale] (Geissner,
1995). This is a self-rating questionnaire comprising a list of 24
adjectives related either to the sensory (e.g. pungent, biting) or
affective (e.g. horrible, unsupportable) dimension of pain. The util-
ity of the instrument in assessing experimentally induced pain has
been well established (Geissner, 1995).
2.3. Recording of hemodynamic data
Blood pressure was monitored continuously during a 5 min
resting phase, as well as during the presentation of the tonic heat
stimuli and the preceding baseline periods. To this end a Finometer
device (Model-2, Finapres Medical Systems, The Netherlands) was
used. The cuff of the Finometer was applied to the mid-phalanx of
the third finger of the right hand. In order to control for the influ-
ence of hydrostatic level errors, the height correction unit inte-
grated in the device was used. To enable periodical recalibration,
the ‘‘Physiocal” feature (Wesseling et al., 1995) was put into oper-
ation. The signal was digitized at a sample rate of 200 Hz.
3. Procedure
Assignment of subjects to the two study groups was carried out
on the basis of blood pressure readings taken in a screening session
which was conducted at least 1 week prior to the main experiment
and again at the beginning of the experimental session. Here, after
a rest period of 10 min, three sphygmomanometric blood pressure
measurements were taken in a sitting position. For this purpose, an
automatic inflation blood pressure monitor (MIT, TYP M CR15;
Omron, USA) was used. Readings were separated by 5 min rest
intervals. The mean value of the three measurements was used
for group assignment. The criterion for inclusion in the experimen-
tal or control group had to be fulfilled at both the screening and
experimental sessions.
The subjects gave informed consent prior to the experiment.
After the blood pressure readings, skin temperature was taken at
the forearm using a digital infrared thermometer (Bosotherm
Medical, Boso, Germany). For the purpose of hemodynamic record-
ing under resting conditions, participants were asked to sit still, not
to speak and to relax with their eyes open. Following this, pain
assessment was performed in the described manner. In order to
prevent experimenter effects, all instructions were presented to
the subjects in written form. All sessions were conducted by the
same female experimenter. Subjects were requested not to smoke
or drink either alcohol or beverages containing caffeine for 3 h
prior to the screening and experimental sessions.
4. Data analysis
4.1. Analysis of the hemodynamic data
The rate of change in blood pressure within the cardiac cycle
was applied as an estimate for the input on the baroreceptors. To
quantify this, the maximum slope of blood pressure rise during
the systolic upstroke (dp/dt) was computed using the software
Beatscope 1.1a (Finapres Medical Systems, The Netherlands). This
index was chosen because of the well-known high sensitivity of
arterial baroreceptors to rapid blood pressure changes. While the
receptors show a certain degree of habituation (‘‘resetting”) to
long-term alterations in blood pressure, they do not habituate to
short-term changes within the cardiac cycle (Dembowsky and
Seller, 1995; Rau and Elbert, 2001).
The sensitivity of the baroreflex was quantified in the time do-
main by analyzing the spontaneous covariation of systolic blood
pressure and pulse interval (Bertinieri et al., 1985; Parati et al.,
2000; Steptoe and Sawada, 1989; Steptoe and Vögele, 1990). In or-
der to achieve sufficient temporal resolution, the blood pressure
data was resampled at 1000 Hz by means of spline interpolation
using MATLAB software (The MathWorks, Inc., USA). For further
analysis, a software program developed by Reyes del Paso (1994)
was employed. The program locates sequences of three to six con-
secutive heart cycles (‘‘reflex sequences”) in which systolic blood
pressure increases are accompanied by increases in pulse interval,
and those in which blood pressure decreases are accompanied by
decreases in pulse interval. Since a time lag of one heartbeat is
known to produce the best estimates of baroreflex sensitivity
(Steptoe and Vögele, 1990), each systolic value was paired with
the pulse interval from the cycle immediately following. 1 mmHg
and 1 ms were applied as minimal criteria for changes in blood
pressure and pulse interval, respectively. Pulse interval was de-
fined as the interval between systolic points (‘‘intersystolic inter-
val”). When one of these reflex sequences was detected, the
regression line was computed across all cardiac cycles of the given
sequence. Baroreceptor sensitivity was expressed as the change in
pulse interval (in ms) per mmHg blood pressure change, measured
by the slope of the regression line. The validity of this index has
been well documented (Bertinieri et al., 1985; Duschek and Reyes
del Paso, 2007; Steptoe and Vögele, 1990).
4.2. Statistical analysis
Temperature and pain sensitivity were compared between the
hypotensive and control groups using multivariate analysis of var-
iance (MANOVA). Dependent variables comprised the indices for
warm and cold sensitivity, pain threshold and tolerance, as well
as the VAS ratings and scores on the Pain Sensation Scale.
In order to avoid redundancy and to enhance the reliability of
the measurement, a principal component analysis was computed
on the 10 VAS ratings (Basilevsky, 1994). The analysis revealed a
first factor with an eigenvalue of 6.36 explaining 63.55% of the total
variance. Factor loads of the 10 scales ranged between .65 and .91.
In light of the considerable shared variance, it seemed appropriate
to combine these variables. The individual factor values of the sub-
jects were included in the MANOVA.
The hypotensive and the control groups did not differ signifi-
cantly with respect to skin temperature (t = .43, p = .16) or scores
on the Mood Scale (t = .0.16, p = .88). The use of oral contracep-
tives among the female participants in the two groups did not dif-
fer (U = 432.0, p = .23) nor did the time interval from the latest
period (t = 0.26, p = .80). These parameters were therefore not ap-
plied as control variables in the MANOVA.
Possible effects of the input on the arterial baroreceptors and
baroreflex sensitivity on pain experience were determined using
multiple regression analysis performed across the entire sample.
Two regression models were computed with pain threshold and
tolerance as dependent variables, and dp/dt and baroreflex sensi-
tivity measured under resting conditions as predictors. Another
three models referred to subjective pain intensity, containing the
factor values revealed from the VAS and both parameters of the
Pain Sensation Scale as dependent variables. Here, the values for
dp/dt and baroreflex sensitivity averaged across the 5 periods of to-
nic heat stimulation served as predictors. In order to evaluate the
linear relationship between blood pressure and pain sensitivity,
systolic values were included as a further predictor in each of the
models.
5. Results
No significant differences between the hypotensive and normo-
tensive groups were found with respect to temperature sensitivity
 S. Duschek et al. / European Journal of Pain 13 (2009) 28–34 31

(warm sensitivity: hypotensives, M = 34.77, SD = 1.69, controls, VAS affective

M = 35.24, SD = 2.37, F[1/77] = 1.06, p = .31; cold sensitivity: 11
hypotensives, M = 31.10, SD = 0.34, controls, M = 31.13, SD = 0.37, 10 Hypotension
F[1/77] = 0.12, p = .73). As can be seen in Fig. 1, pain threshold 9 Control group
and pain tolerance were markedly lower in the hypotensive than 8
in the normotensive group. The MANOVA revealed a significant ef- 7
fect on both variables (pain threshold: F[1/77] = 4.20, p = .044; pain 6
tolerance: F[1/77] = 6.70, p = .012).
5
The VAS ratings of subjective pain experience were higher in
4
hypotensive than in normotensive subjects. This holds true for
3
the sensory and affective dimensions concerning each of the five
2
tonic heat stimuli (see Figs. 2 and 3). However, the group difference
in the factor values representing the aggregated VAS ratings 1
reached only the 10% significance level (hypotensives: M = 1.20, 0
45.5 ºC 46 ºC 46.5 ºC 47 ºC 47.5 ºC
SD = 1.00, controls: M = 1.20, SD = 1.00, F[1/77] = 3.07, p = .084).
The scores on both dimensions of the Pain Sensation Scale were Fig. 3. Ratings on the affective VAS dimension in hypotensive and control subjects
significantly higher in hypotensives than in normotensive controls (bars represent standard deviations).
(sensory: F[1/77] = 4.42, p = .039; affective: F[1/77] = 4.84, p = .031;
see Fig. 4).
The results of the multiple regression analyses are displayed in
Table 2. Significant Beta values were found for systolic blood pres- Pain Sensation Scale
sure in each of the models except for that on the VAS ratings sug-
gesting an inverse linear relationship between blood pressure and
pain sensitivity. The values for dp/dt and baroreflex sensitivity did
35 Hypotension *
not prove to predict any of the pain measures.
30
* Control group

25

20
Pain threshold and pain tolerance
52 15
Hypotension

50 Control group * 10
Temperature in ºC

Sensory Affective
48

46
* Fig. 4. Scores on the Pain Sensation Scale in hypotensive and control subjects ( for
p < .05, bars represent standard deviations).

44 6. Discussion

42 As main findings, the study revealed reduced threshold and tol-

erance to heat pain, as well as increased ratings in the question-
40 naire on sensory and affective pain experience in individuals
Pain threshold Pain tolerance with chronic low blood pressure. Regression analysis furthermore
documented an inverse linear association between blood pressure
Fig. 1. Pain threshold and pain tolerance in hypotensive and control subjects ( for
p < .05, bars represent standard deviations). and pain sensitivity across the hypotensive and normotensive
ranges.
The findings are in line with the increased sensitivity to cold
pain in low blood pressure (Duschek et al., 2008). In that study, just
VAS sensory
11 as in the present one, reduced pain thresholds and tolerance, as
10 Hypotension well as higher subjective pain intensities were observed in hypo-
9 tension. However, besides pain sensitivity, individual behavior
Control group during cold pressor testing depends to a certain degree on systemic
8
perfusion which is inevitably altered in hypotension (Fruhstorfer
7
and Lindblom, 1983; Klement and Arndt, 1991). However, these
6
two things are not confounded in the current study. A number of
5
further possible third variable effects were also controlled for.
4
Emotional state, which has been suggested to be negatively af-
3 fected by low blood pressure (Duschek and Schandry, 2007;
2 Wessely et al., 1990) did not differ between hypotensive and
1 control subjects. The same holds true for skin temperature and
0 temperature sensitivity which may potentially influence the
45.5 ºC 46 ºC 46.5 ºC 47 ºC 47.5 ºC
perception of heat pain.
Fig. 2. Ratings on the sensory VAS dimension in hypotensive and control subjects An inverse association between blood pressure and pain sensi-
(bars represent standard deviations). tivity has already been documented for the normotensive and
32 S. Duschek et al. / European Journal of Pain 13 (2009) 28–34
Table 2
Regression analyses for the prediction of pain experience from systolic blood
pressure, dp/dt and baroreflex sensitivity (Beta and R-values, significance levels of
Beta * for p < .05, ** for p < .01)
Systolic blood dp/dt Baroreflex
pressure sensitivity
Pain threshold .30* .01 .18
Pain tolerance .42** .14 .03
VAS (factor values) .25 .14 .07
Pain Sensation Scale .32* .10 .05
(sensory)
Pain Sensation Scale .35* .11 .10
(affective)
hypertensive ranges (Bruehl et al., 1992, 2002; Fillingim and Maix-
ner, 1996; France, 1999; Ghione, 1996; McCubbin and Bruehl,
1994; Myers et al., 2001; Zamir and Shuber, 1980). The present
finding suggests that this notion can be generalized to the com-
plete blood pressure spectrum. In this respect, the blood pres-
sure–pain relationship clearly differs from the relationships
between blood pressure and other behavioral and psychophysio-
logical factors which were found to be non-linear (for overview
see Duschek and Schandry, 2007). The association between blood
pressure and cognitive functioning, for instance, has an inverted
u-shape with a decline in performance at both ends of the spec-
trum (Duschek et al., 2003; Duschek et al., 2005; Qiu et al., 2005;
Waldstein et al., 2005). Also, cortical activation, as well as cerebral
blood flow have repeatedly been shown to be reduced both in indi-
viduals with elevated and low blood pressure (Baumbach and
Heistad, 1988; Duschek and Schandry, 2004; Duschek et al.,
2006; Hajdu and Baumbach, 1994; Stegagno et al., 2007; Weisz
et al., 2002).
As a secondary aim, the study investigated a possible link be-
tween the function of the arterial baroreceptor system and the per-
ception of heat pain. In the regression analyses, where blood
pressure proved to predict pain experience, however, neither the
impact on the baroreceptors, estimated by the slope of the blood
pressure increase within the cardiac cycle, nor baroreflex sensitiv-
ity did so. This is in contrast to the substantial inverse association
already shown between baroreflex sensitivity and the subjective
intensity of cold pain (Duschek et al., 2007). This association was
interpreted as reflecting the generally assumed pain-inhibiting ef-
fect of the baroreceptor system. Contrary to the present finding, in
that study increased activity of the reflex as a consequence of its
higher sensitivity was accompanied by reduced experience of cold
pain.
Such inconsistency, however, is also to be found in the literature
on the effects of experimental baroreceptor stimulation on noci-
ceptive responding. Most of these studies were based on stimula-
tion of the aortic baroreceptors by means of neck cuff
techniques, e.g. ‘‘phase-related neck suction” (PRES) (Rau et al.,
1992). Apart from a number of positive findings (Droste et al.,
1994; Kardos et al., 1994), the application of this technique also re-
vealed conflicting results. Edwards et al. (2003) failed to produce
reductions in pain through a PRES procedure where pain was elic-
ited by electrocutaneous nerve stimulation. al’Absi et al. (2005) re-
ported that both baroreceptor stimulation and inhibition evoked
by PRES led to lower pain ratings. Results also varied subject to
the methods of pain induction. In the present context, a study by
Rau et al. (1994) is of particular interest as it revealed increased
thresholds for mechanical, but not for heat pain during experimen-
tal baroreceptor stimulation. One may thus hypothesize that the
inhibitory effect of the baroreceptor system is differently pro-
nounced depending on the source of pain. In this regard, it is cer-
tainly a limitation of the present study that the protocol was
restricted to thermal pain, and did not include further methods
such as mechanical stimulation.
It has also been suggested that the baroreceptor system is in-
volved in mediating the association between hypotension and
R hyperalgesia (Duschek et al., 2007). This view is not, however, sup-
ported by the current data. Alternatively, mechanisms of action re-
.29 stricted to the central-nervous system may play a dominant role.
.37
.21
As neural interfaces between the cardiovascular and pain regula-
.28 tory systems, brain stem structures such as the nucleus of the sol-
itary tract and the rostral ventrolateral medulla have been
.28 considered (Bruehl and Chung, 2004). Both structures are heavily
involved in cardiovascular regulation, and their experimental stim-
ulation has been shown to modulate nociceptive responses (Aicher
and Randich, 1990; Randich and Maixner, 1984). This effect may be
mediated by direct and indirect projections from the brain stem to
regions including the periaqueductal grey, the nucleus raphe mag-
nus and the locus coeruleus which play a substantial role in noci-
ception (Bruehl and Chung, 2004; Burnett and Gebhart, 1991;
Millan, 2002).
Several neurochemical systems are also assumed to be involved
in the interaction between hemodynamic factors and nociception.
Animal studies have shown that endogenous opioid activity is nec-
essary for a full expression of the inverse relationship between
blood pressure and pain sensitivity (Maixner et al., 1982; Zamir
et al., 1980). However, human studies prove somewhat controver-
sial, suggesting that the blood pressure–pain relationship does
not completely disappear in the absence of functionally active opi-
oid systems (McCubbin and Bruehl, 1994; Schobel et al., 1998). Fur-
thermore, catecholaminergic mechanisms, in particular the central
noradrenaline system, participate in both blood pressure regulation
and descending pain inhibition (Carlson, 2004; Millan, 2002;
Randich and Maixner, 1984). The relevance of this system is under-
lined by the fact that each of the aforementioned brain stem struc-
tures, which are supposed to constitute structural interfaces
between cardiovascular and nociceptive regulation, contain norad-
renergic pathways (Bruehl and Chung, 2004; Ghione, 1996; Millan,
2002).
To conclude, possible clinical implications of the present finding
should be considered. Hypotension is commonly not viewed as a
medical condition that would require treatment (Duschek and
Schandry, 2007). Nonetheless, a number of studies documented
reduced subjective well-being and quality of life as a result of
the complaints associated with this state (Pilgrim et al., 1992;
Rosengren et al., 1993; Wessely et al., 1990). In the present context,
one may furthermore consider whether the increased sensitivity to
acute pain implies that hypotensive individuals are more prone to
clinical pain. Findings revealed by experimental pain induction can
certainly not be generalized directly to clinical conditions. A link
between laboratory and clinical pain is, however, suggested by
studies showing that patients suffering from chronic pain are more
sensitive to pain induced by thermal and electrical stimulation
(Arroyo and Cohen, 1993; Berglund et al., 2002; Maixner et al.,
1995; Petzke et al., 2003).
Evidence for the clinical relevance of the blood pressure–pain
relationship stems from reports of an inverse association between
blood pressure and the occurrence of pain syndromes in the
normotensive and hypertensive populations. Hagen et al. (2005)
documented a 10–60% lower prevalence of chronic musculoskele-
tal complaints in individuals with essential hypertension, as well
as an inverse linear relationship between blood pressure and
occurrence of such symptoms. A longitudinal study revealed
a 30% lower risk of development of non-migraine headache across
an 11 years follow-up interval in hypertension (Hagen et al., 2002).
In persons being assessed for coronary heart disease, chest pain
experienced during treadmill exercise was inversely associated
with blood pressure (Ditto et al., 2007). In patients recovering
 S. Duschek et al. / European Journal of Pain 13 (2009) 28–34
from prostatectomy, the degree of postsurgical pain was found to
correlate negatively with blood pressure (France and Katz, 1999).
Studies on the occurrence of pain syndromes in hypotension are
still lacking. However, in light of the inverse association between
blood pressure and clinical pain in the normal and high blood pres-
sure ranges, and considering the increased sensitivity to experi-
mental pain in case of reduced blood pressure, its seems
suggestive to assume an increased prevalence of clinical pain in
hypotension.
To sum up, the present study yielded evidence that chronic low
blood pressure is accompanied by reduced threshold and tolerance
to heat pain, as well as increased sensory and affective pain expe-
rience. Extending former findings, the study suggests that the con-
clusion of increased pain sensitivity is not restricted to cold pain,
but may be generalized to further sources of pain. The results pro-
vide further evidence for the notion that the inverse association be-
tween blood pressure and pain experience, which has previously
been documented for the normotensive and hypertensive ranges,
may be generalized to the complete blood pressure spectrum.
Acknowledgements
This study was funded by the German Research Foundation
(Project No. DU 447/1-1). The cooperation between the Universi-
ties of Munich and Jaén was supported by the German Academic
Exchange Service and the Spanish Ministry of Education and Sci-
ence. We are grateful to Ann-Kristin Adam and Magdalena Muc-
kenthaler for their help with subject acquisition. Annina
Neumann and Markus Seifert were a great help with the analysis
of the hemodynamic data.
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