From the Department of Clinical and Biological Sciences, University of
Pavia, II Faculty of Medicine, Varese, Italy.
Correspondence to Luigina Guasti, MD, Internal Medicine, Ospedale di Circolo, University Hospital, Viale Borri 57, 21100 Varese, Italy.
The aims of this study were to (1) investigate whether the
antihypertensive treatment with enalapril could modify the dental pain
threshold and tolerance in human hypertensive subjects and (2) find
whether changes in blood pressure levels during treatment could account
for possible variations in pain sensitivity.
In all subjects, dental pain perception was determined twice
(time interval, 6±2 months) by a pulpar test (performed by the same
operator who was blinded to the pressure level of the subjects). The
first evaluation (first assessment) was done without any
pharmacological treatment. It consisted of a pulpar test preceded by
automatic office blood pressure measurements (see "Baseline Blood
Pressure") and followed by 24-hour ambulatory monitoring. At the
second assessment, the hypertensive patients were receiving
angiotensin-converting enzyme (ACE) inhibitor
treatment (which was started after the first assessment) while the
normotensive subjects remained without any treatment. After a
tritiation period, all the hypertensive patients were given enalapril,
20 mg/d, at 7 AM, which was also given the day of the
second assessment. In addition to the pulpar test, automatic office
blood pressure measurements were repeated at the second assessment in
all subjects. Moreover, the hypertensive group underwent additional
ambulatory blood pressure monitoring, whereas the normotensive group
did not. All subjects were studied at the two assessments after an
overnight fast (in particular, the subjects were asked to avoid
coffees, teas, cola-containing drinks, alcoholic beverages, chocolate,
and smoking during the 12 hours preceding the tests).
Baseline Blood Pressure
Pain Perception Assessment
The subjects had been previously instructed to raise their right hand
at the occurrence of any pulp sensation (pain threshold, rU). At this
point the stimulation was interrupted. Pain tolerance (rU) was obtained
by reapplication of the test current immediately afterward and keeping
up the stimulation until the subjects asked for the test to be
stopped.14 27 The pulpar test was performed on
three healthy teeth (two upper incisors and one inferior
incisor, always in the same order). Mean values (of the three) of pain
threshold and tolerance were used in subsequent analysis.
Ambulatory Blood Pressure
Statistical Analysis
The percentage of change of both arterial pressures and
pain perception variables between the two assessments were obtained
by the following formula: First Assessment Value-Second Assessment
Value/First Assessment Valuex100 (%). The statistical
analysis was performed with the computerized Statistical
Package for the Social Sciences (SPSS). A value of P<.05
was considered significant.
The dental pain threshold was significantly higher in the 25
hypertensive patients than in the 14 normotensive subjects (29±6
versus 22±4 rU in hypertensives and normotensives, respectively,
P<.001). The pain tolerance also tended to be higher,
although not significantly, in the hypertensive group (48±18 versus
44±20 rU, NS).
Follow-up
On retesting of hypertensive patients during chronic treatment
with ACE inhibitors, a significant reduction was observed
in both 24-hour and baseline blood pressure values
(Table
A significant decrease of pain threshold and tolerance was found when
the dental pain sensitivity was retested during pharmacological
treatment (P<.001 and P<.005, respectively)
(Fig 1
As expected, the control group of normotensive subjects, who remained
untreated during follow-up, did not show any significant variation with
respect to baseline systolic and diastolic blood
pressures or baseline heart rate (first versus second assessment:
136±13/82±10 versus 139±15/83±11 mm Hg, NS; and 64±13 versus
65±11 bpm, NS).
Moreover, both pain threshold and tolerance remained unchanged at the
second evaluation (Fig 2
When pain threshold and tolerance of the normotensive subjects
were compared with those of hypertensive patients obtained during
treatment with enalapril, no significant difference (previously
observed between normotensives and untreated hypertensives) was found.
Baseline arterial systolic and
diastolic blood pressures were similar in normotensives and
enalapril-treated patients. However, although a reduction in 24-hour
pressure was observed in the treated hypertensive patients, the
ambulatory values remained higher than those recorded in
normotensive subjects at the first assessment (P<.05 for
24-hour systolic pressure; P<.005 for
diastolic pressure).
In the hypertensive group, the Spearman rank correlation showed no
significant relations between changes (arithmetic difference and
percent change) in pain threshold and tolerance and changes in 24-hour
blood pressure. However, the baseline systolic and
diastolic blood pressure variations were slightly, although
significantly, correlated with pain tolerance changes
(P<.05).
ACE Inhibitors and Pain Perception
Regarding the effect of ACE inhibitors on pain sensitivity,
controversial results have been found in animal studies. Both a
significant reduction of hypalgesic behavior and no diminished
responsiveness to noxious stimuli were reported in hypertensive animals
treated with ACE
inhibitors.39 40 41
Angiotensin II (Ang II) seems to antagonize morphine- and
electroacupuncture-induced analgesia.42 43 On
the other hand, other authors have reported that
intracerebroventricular
angiotensin produced a large analgesic effect that could be
blocked by naloxone.44 Moreover, the
dermorphin-induced antinociception was markedly reduced by
coadministration of captopril in mice.45 In
addition, Ang II was found to induce baroreflex resetting independently
of blood pressure levels46; thus this action on
baroreceptor function might affect the perception pattern. At a central
level, the activity of Ang II has been reported at the nucleus tractus
solitarii and area postrema, which are anatomic regions of primary
interest both in blood pressure regulation and pain
perception.47 48 Captopril acts as a kininasi II
inhibitor and reduces degradation of bradykinin. This
nonapeptide and its related kinins may induce pain, and the
facilitation to bradykinin may account for the enhancement of the
algesic effect of phenylbenzoquinone and formalin found in animals
pretreated with captopril.49 50 Thus, the actions
of ACE inhibitors may affect pain perception at various
levels. We tested only enalapril to avoid potential intraclass
differences on pain sensitivity.
In our study, the significant increase in pain sensitivity
observed during treatment with enalapril in the group of hypertensive
subjects led to a normalization of pain perception. Pain threshold and
tolerance in the treated patients decreased to levels similar to those
of normotensives, yet in the presence of 24-hour blood pressure values
higher than those of normotensives. However, some limitations of this
study have to be acknowledged: the patient population was relatively
small, and the investigation was not designed as a placebo-controlled
study.
The individual pattern of pain perception seems to be one relevant
factor in the determination of symptoms during myocardial
ischemia, and a generalized impaired pain sensitivity has been
associated with silent ischemia.15 16 17
Moreover, a role of hypertension in the development of silent
ischemia has been reported.51 52 These
results suggest that ACE inhibitors may facilitate the
perception of painful stimuli and, at least in hypertensive patients
with coronary artery disease, may possibly interfere with
silent episodes.
A recent study investigating pain threshold by hot-plate test in
normotensive Wistar-Kyoto and spontaneously hypertensive rats (SHR)
after ACE inhibitor treatment found a normalization of the
increased hot-plate latencies normally exhibited by SHR, whereas pain
sensitivity was unaffected by hydralazine, otherwise effective
in reducing blood pressure.41 In the same study,
the treatment with losartan, an angiotensin type 1
(AT1) receptor antagonist, had no
effect on blood pressure at the dose used, in the presence of markedly
reduced hot-plate latencies.41 Thus, the authors
favored the hypothesis of an interplay between
renin-angiotensin mechanisms and intrinsic analgesic
modulation in explaining the ACE inhibitor–induced changes
in pain sensitivity. Studying spinal nociceptive transmission in rats,
Randich and Robertson53 found that it was
significantly attenuated in SHR and that captopril treatment affected
the response properties of SHR neurons. However, the findings of that
study could not clarify whether this action was obtained by the
lowering of arterial pressure or by an influence of the
drug on facilitatory or inhibitory
systems.53 In the present study, we found a
mild, though significant, relationship between the changes in baseline
blood pressure values and pain tolerance reduction. Although the
24-hour blood pressure relates to pain sensitivity better than the
standard blood pressure,27 no significant
relation was found between variations of sustained blood pressure
induced by therapy and changes in pain perception. The normalization of
pain sensitivity found after treatment in the hypertensive group could
be related, at least in part, to the drug-induced lowering of blood
pressure. Alternatively, the central effects of ACE inhibition or
facilitation to bradykinin may account for the increased sensitivity to
pain observed after treatment. In our opinion, the increased pain
sensitivity may express both variations in mechanisms by which blood
pressure affects pain perception and the pharmacodynamic effects of the
ACE inhibitors.
Received September 18, 1997;
first decision October 13, 1997;
accepted December 8, 1997.
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© 1998 American Heart Association, Inc.
Scientific Contributions
Treatment With Enalapril Modifies the Pain Perception Pattern in Hypertensive Patients
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—The
cardiovascular system shares numerous anatomic and
functional pathways with the antinociceptive network. The aim of this
study was to investigate whether angiotensin-converting
enzyme (ACE) inhibitor treatment could affect
hypertension-related hypalgesia. Twenty-five untreated hypertensive
patients, together with a control group of 14 normotensive subjects,
underwent dental pain perception evaluation by means of a pulpar test
(graded increase of test current applied to healthy teeth). After the
evaluation of the dental pain threshold (occurrence of pulp sensation)
and tolerance (time when the subjects asked for the test to be
stopped), all the subjects underwent a 24-hour ambulatory blood
pressure monitoring. The hypertensive group then was treated with 20
mg/d enalapril, whereas the normotensive subjects remained without any
treatment. After a time interval of 6±2 months, the dental pain
sensitivity was retested in all the subjects, and ambulatory blood
pressure was recorded during treatment in the hypertensive
patients. At the first assessment, hypertensive patients showed a
higher pain threshold than normotensive subjects
(P<.001). On retesting of pain sensitivity in
hypertensive patients, a significant decrease of both pain threshold
and tolerance, leading to their normalization, was observed during
treatment (P<.001 and P<.005,
respectively), in the presence of reduced 24-hour and office blood
pressure values. A slight, though significant, correlation was observed
between variations in pain tolerance and baseline blood pressure
changes occurring during treatment. During follow-up, the normotensive
subjects did not show any significant pain perception or office blood
pressure changes. Hypertension-related hypalgesia was confirmed.
Mechanisms acting both through lowering of blood pressure and specific
pharmacodynamic properties may account for the normalization of pain
sensitivity observed in hypertensive patients during treatment with
ACE inhibitors.
Key Words: hypertension, essential • blood pressure monitoring • angiotensin-converting enzyme inhibitors • enalapril • pain threshold
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Complex mechanisms
and numerous pathways underlie the pathophysiology of pain
perception.1 The cardiovascular
control network shares with the antinociceptive system various central
and peripheral neurotransmitters, as well as anatomic
nuclei and projections.1 2 3 4 5 6 Experimental
studies have also demonstrated a link between the baroreceptor function
and pain perception.7 8 9 10 11 Modulatory interactions
between pain sensitivity and the cardiovascular system
have been reported both in physiological conditions
and in patients with various cardiovascular syndromes.
Alterations in pain sensitivity and circulating ß-endorphin, an
endogenous opioid-like peptide, were found in hypertensive
subjects, patients with shock and heart failure, and subjects with
silent myocardial ischemia.12 13 14 15 16 17 18 19 Both in
animal and human studies, hypertension has been associated with a
reduced perception of painful stimuli.12 However,
the effect of cardiovascular-acting agents on pain
perception has been poorly investigated. Antihypertensive drugs could
influence pain sensitivity through blood pressure reduction and/or by
specific pharmacodynamic mechanisms. In patients with hypertension, no
significant change in pain sensitivity was reported after the use of
diuretics or ß-blockers, whereas ketanserin tended to
decrease or reverse the reduced pain perception associated with high
blood pressure values.20 21 Moreover,
interactions between ß-endorphins, pain sensitivity, and central
2-stimulating agents have been
reported.22 23 24 25 26
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Thirty-nine consecutive subjects (mean age, 43±4 years) with
the following characteristics were enrolled in the study: male sex, age
between 30 and 50 years, no pharmacological treatment or washout of an
antihypertensive therapy for at least 3 weeks, no concomitant diseases
(diabetes, neuropathies, cardiac or lung diseases, obesity, stroke, or
psychiatric disturbances), dental formula suitable for the
pulpar test (see below) as indicated by a previous dental checkup
(subjects with tooth fractures, abrasions, caries lesions, fillings,
and marked periodontal diseases were excluded), and informed consent to
the study. Twenty-five of 39 subjects were hypertensives who were
either sent from the general practitioner for blood
pressure evaluation or followed up by our center because of a history
of hypertension. The 14 healthy normotensive subjects were studied
during a general clinical checkup of Italian post office employees and
were considered as the control group. A routine diagnostic
workup excluded secondary forms of hypertension in all the subjects.
Normotensive and hypertensive subjects were similar regarding mean age
(44±5 and 43±4 years in normotensive and hypertensive subjects,
respectively), smoking habits (2 mild smokers in the normotensive
group, 4 mild smokers in the hypertensive group), and body mass index
(24.6±1.9 versus 24.7±1.7 kg/m2 in normotensives and hypertensives,
respectively). The study was approved by the ethics committee of
our department.
In the morning, between 9 and 11 AM, the subjects
were kept at rest in a supine and comfortable position for a 30-minute
period. Blood pressures were automatically measured by a
Hewlett-Packard 78352A recorder every 3 minutes. The blood pressure
value of the measurement preceding the pulpar test was defined as
baseline blood pressure. If the value differed >5 mm Hg from the
previous measurement, another measure was taken until two were
close.
After the 30-minute rest, dental pain perception was
investigated by means of a pulpar tester. The method has been
previously described.14 27 Briefly, the pulp
stimulator (Medi-tester, Medic-Al) allows the delivery of automatic
intermittent bursts of electrical stimuli, with negative polarity at
linearly increasing intensity from 0 to 0.03 mA (maximal tension, 6500
mV; burst frequency, 5 Hz). The stimulator was applied to the enamel
surface of the tooth through a metal cylinder. The switching on and off
occurred automatically when the contact with the tooth was made or
excluded, respectively. The hand of the operator in contact with the
lips of the subject closed the circuit. As the test current increased
from 0 to 0.03 mA, a number from 0 to 80 (relative units [rU]) was
displayed on a digital reader of the instrument (not visible to the
subject under examination).
After pain perception evaluation, ambulatory blood
pressure was recorded by means of a Takeda TM 2421 (A&D Co) set to
take a measurement every 15 minutes for a period of 24 hours. In two
subjects, the quality of the monitoring was not sufficient (valid
measurements <80%) and was repeated successfully the following day.
The reading, editing, and analysis of the data were performed
by a software system as previously
described.14 27 The following
parameters were taken into consideration in subsequent
analysis: 24-hour systolic and diastolic
pressures, 24-hour heart rate, and daytime (7 AM to 10
PM) and nighttime (10 PM to 7 AM)
systolic and diastolic pressures.
Data are presented as mean±SD. The qualitative
variable (smoking habit) was compared between normotensive and
hypertensive subjects by a 
2 test, and
possible variations of this variable between the first and second
assessment were tested by a McNemar test. Student's t test
was used to compare parametric variables between
normotensive and hypertensive subjects. A Mann-Whitney U
test was performed to compare pain threshold and tolerance between the
normotensive and hypertensive groups. Hemodynamic data
obtained at the time of the two assessments were compared by a paired
t test. A Wilcoxon rank test was used to compare the
results of pain perception evaluation at baseline and during follow-up.
Possible relations between blood pressure variations and pain
sensitivity changes occurring during follow-up were tested by Spearman
rank correlation analysis.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
The 24-hour blood pressure was 141±11/93±11 and
123±12/74±6 mm Hg in hypertensive and normotensive subjects,
respectively (P<.001).
No difference was found in smoking habits and body mass index
between subjects at the first and second assessment. 
).
View this table:
[in a new window]
Table 1. Hemodynamic Variables in Hypertensive
Patients Before and During ACE Inhibitor Treatment ).
View larger version (19K):
[in a new window]
Figure 1. Pain sensitivity changes in hypertensive patients
during ACE inhibitor treatment. The pain threshold (top)
and tolerance (bottom), expressed in relative units (rU), are shown
before and during treatment with enalapril. A significant reduction of
both pain threshold and tolerance was observed during treatment
(P<.001 and P<.005,
respectively). ).
View larger version (17K):
[in a new window]
Figure 2. Pain sensitivity measured in normotensive
untreated subjects at two assessments. No significant difference was
observed during the follow-up in pain threshold (top) and tolerance
(bottom), expressed in relative units (rU).
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Hypalgesia in Hypertension
Hypertension and reduced pain perception have been repeatedly
associated in animals and in humans. In humans, various experimental
techniques have been used to identify the pain threshold, with similar
results. Hypertensive patients show a reduced sensitivity to pain that
is independent of the method used to provoke the painful
stimuli.12 13 20 27 28 29 30 The pulpar test may evoke
painful pulpal sensations as the test current applied to the tooth
under examination gradually increases. Since only A
and C fibers are
thought to be contained in the pulp, superficial sensations cannot
interact with the stimulation of the pain perception
pathway.31 32 A fair short-term and long-term
reproducibility has been reported regarding the pulpar test results in
normotensive and hypertensive subjects when they were studied at rest
and in a baseline condition.20 33 34 In this
study, pain threshold was significantly higher in hypertensive than
normotensive subjects, thus confirming a reduced pain sensitivity in
patients with high blood pressure levels. The pain tolerance was also
higher in hypertensive patients, although the difference did not reach
statistical significance. It is a matter of discussion whether
hypalgesia is triggered by mechanisms related to increased
arterial pressure or it is a feature of hypertension
related to the complex alterations of central functions associated with
hypertension.12 However, at least in part, the
high pressure values per se seem to have a role in hypalgesia.
Hypalgesic behaviors have been associated with various forms of
experimental hypertension independently of the method used to induce
blood pressure elevation.35 36 On reduction of
blood pressure, after the removal of the constricted kidney, a
normalization of pain threshold was reported in renal hypertensive
rats, although occurring with a delayed pattern with respect to blood
pressure changes.37 The lowering of blood
pressure in rats by peripherally acting ganglionic blockers
reversed hypalgesia in the hypertensive strain and induced hyperalgesia
in the control rats.38
Only a few studies have investigated the possible
interactions between antihypertensive agents and pain perception in
humans. In this study, the treatment with the ACE inhibitor
enalapril was associated with a change in both pain threshold and
tolerance, with pain sensitivity being higher during treatment. When
the dental pain perception and blood pressure values were retested
during follow-up, the control group of untreated normotensive subjects
showed unchanged results.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Fields HL. Neurophysiology of pain and pain
modulation. Am J Med. 1984;77:2–8.2-adrenergic stimulation increases
neurointermediate lobe immunoreactive ß-endorphin in spontaneously
hypertensive rats. Hypertension. 1987;9:566–570.
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