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JH-D-20-00007
Review
Blood pressure-related hypoalgesia: a systematicreview andmeta-analysis
Elena Makovaca, Giuseppina Porciellob,c, Daniela Palombad, Barbara Basilec,e,and Cristina Ottavianib,c
Journal of Hypertension 2020, 38:000–000aCentre for Neuroimaging Science, Kings College London, London, UK, bDepartment
Objective: Spontaneous or experimentally induced highblood pressure (BP) is associated with reduced painperception, known as BP-related hypoalgesia. Despite itsclinical implications, such as the interference with earlydetection of myocardial infarction in ‘at risk’ groups, the sizeof the association between high BP and pain has not yetbeen quantified. Moreover, the distinct association betweenhigh BP and physiological or psychological components ofpain has not yet been considered so far. The aim of thisstudy was to overcome this gap by performing separatemeta-analyses on nociceptive response versus quantifiableperceptual measures of pain in relation to high BP.
Methods: PubMed and Web of Knowledge databaseswere searched for English language studies conducted inhumans. Fifty-nine studies were eligible for the analyses.Pooled effect sizes (Hedges’ g) were compared. Randomeffect models were used. Results show that higher BP issignificantly associated with lower nociceptive response(g¼ 0.38; k¼6) and reduced pain perception, assessed byquantifiable measures (g¼0.48; k¼ 59).Results: The association between BP and pain perception,derived from highly heterogeneous studies, wascharacterized by significant publication bias. BP assessment,pain assessment, site of pain stimulation, percentage offemale participants in the sample, and control for potentialconfounders were significant moderators.
Conclusion: Current meta-analytic results confirm thepresence of BP-related hypoalgesia and point towards theneed for a better understanding of its underlying mechanisms.
Keywords: blood pressure, hypertension, hypoalgesia,meta-analysis, pain
Abbreviations: BP, blood pressure; CI, confidence interval;EEG, electroencephalogram; g, Hedges’ g; NFR, nociceptiveflexion reflex; NRS, Numeric Rating Scale; PRISMA, PreferredReporting Items for Systematic Reviews and Meta-Analyses;VAS, Visual-Analog Scale; VRS, Verbal Rating Scale
of Psychology, Sapienza University of Rome, Rome, cIRCCS Santa Lucia Foundation,Rome, dDepartment of General Psychology, University of Padua, Padua and eSchool ofCognitive Psychotherapy (SPC) S.r.l, Rome, Italy
Correspondence to Cristina Ottaviani, PhD, Department of Psychology, Sapienza
INTRODUCTION
University of Rome, Via dei Marsi 78, 00185 Rome, Italy. Tel: +39 6 49917632;fax: +39 6 49917711; e-mail: cristina.ottaviani@uniroma1.it
Received 2 January 2020 Revised 30 January 2020 Accepted 17 February 2020
J Hypertens 38:000–000 Copyright � 2020 Wolters Kluwer Health, Inc. All rightsreserved.
DOI:10.1097/HJH.0000000000002427
Numerous studies suggest that blood pressure (BP)elevation is associated with decreased pain percep-tion, leading to the concept of BP-related hypo-
algesia. This phenomenon has been first observed inpreclinical studies, which suggested that it was possible to
Journal of Hypertension
induce hypoalgesia in rats by experimentally (e.g. pharma-cologically) increasing their BP [1,2]. In humans, a reductionin pain perception has been reported in normotensivesduring spontaneous [3] or experimentally induced high BP[4] as well as in unmedicated hypertensive patients [5] andindividuals with a family history of hypertension [6]. Consid-ering that pain is a warning signal in several medical con-ditions, and vital in the case of cardioischemic disease onset(e.g. heart pain), BP-related hypoalgesia makes the ‘at risk’group of hypertensive patients less aware of initial warningsymptoms. Reducedpainperception interfereswith the earlydetection of the so-called silent (asymptomatic) myocardialischemia and infarction [7], conditions that are nearly twice ascommon in hypertensive patients than in normotensives[7,8]. Indeed, in patients with coronary diseases, an inverserelation between chest pain and BP both at rest [9,10] andduring physical activity [11] has been documented. More-over, longitudinal studies suggest a pathophysiological linkbetween BP-related hypoalgesia and hypertension [12], indi-cating that reduced pain perception may be a contributingfactor rather than a consequenceof elevated BP, thus leadingto the development of hypertension [13]. The theory oflearned hypertension postulates that BP-mediated hypoal-gesia is a causal factor in the development of clinical hyper-tension via a reward mechanism [14]. Here, pain reductionfollowing phasic BP increases might act as a negative rein-forcement of this ‘coping mechanism’, which on a long runmight result in the stabilization of high tonic BP [15,16].
Despite such accumulating evidence on the relationbetween high BP and diminished pain perception, the sizeof such association has not yet been systematically quanti-fied. To date, only narrative and systematic reviews havebeen conducted on the topic, all highlighting the hetero-geneity of included studies and the impossibility to drawconclusive evidence [5,13,17–20]. In fact, not all studies
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Makovac et al.
were able to reproduce BP-related hypoalgesia neither inanimals nor in humans [21–23]. To make the picture evenmore complicated, the relationship between hypertensionand pain becomes completely reversed in patients withchronic pain [24–28].
To overcome these gaps, we conducted a meta-analysisto provide estimates of the magnitude and generalizabilityof BP-related hypoalgesia, the association between BP andnociceptive or quantifiable perceptual components of thepain response. In recent years, enough data on the associa-tion between BP and pain perception has been accumu-lated to urge the identification of sources of variation (i.e.heterogeneity) and potential moderators so that a more in-depth understanding of BP-related hypoalgesia as a riskfactor for health can be reached.
The identification of potential moderators of the BP–painassociation is particularly needed considering that themechanisms underlying BP-related hypoalgesia have notyet been fully clarified. Data point to the role of arterialbaroreceptors, the mechanoreceptors located in the aorticarch and carotid sinus that are involved in the regulation ofBP [13]. First, carotid baroreceptors stimulation results in areduction of pain perception in both hypertensive patientsand normotensives [29]. Second, stimulation of barorecep-tors by natural increases in BP during the systolic phase ofthe cardiac cycle is associated with dampened nociception[30–32]. Third, preclinical studies confirm that the associa-tion between BP and pain disappears when baroreceptoractivity is suppressed by pharmacological denervation [1].Interestingly, shared brain areas (periaqueductal gray,amygdala, and insula) exist for the regulation of bothbaroreceptor functioning and pain [33], pointing towardsthe possibility that both BP elevations and pain modulationdepend on a common central mechanism. The nucleusraphe magnus in the rostral medulla, for example, is acrucial hub of the endogenous opioid system [34], whichalso receives afferent baroreceptor information [35]. Fur-ther, the activity of the nociception-suppressive and noci-ception-facilitative cells on the nucleus raphe magnus (theso-called ON and OFF cells) is temporally associated tospontaneous fluctuations of BP [36]. Stimulation on suchcells in rats (via the vagal nerve) has shown to have an effecton both nociception and BP [37]. Lastly, alterations of theafferent sensory pathway cannot be excluded as a contrib-uting factor to dampened pain perception, mostly inpatients with persistent hypertension [38].
Given that hypertension is a leading cause of deathworldwide, and that meta-analyses have enormous poten-tial value for the development of guidelines for futureresearch or clinical trials, here we quantified existing evi-dence supporting the association between high BP andpain. The role of potential moderators of such associationwas examined by considering both the features of thesample and the methodology used to assess BP and pain.
METHODS
Literature search and studies selectionTwo search strategies were used to systematically collectempirical studies of the effects of BP on pain perception.First, PubMed (http://www.pubmed.com) and Web of
2 www.jhypertension.com
Knowledge (http://apps.webofknowledge.com) databaseswere searched for English-language publications through 7January 2019. The following keywords have been used:Blood pressure AND (Hypoalgesia OR Pain stimul� (stimu-lation, stimulus, stimuli) OR Pain threshold OR Pain toler-ance) NOT Animal.
Second, the reference lists of previous systematicreviews were searched for relevant studies.
The search was limited to English-language publicationsand human samples. Inclusion criteria for our analysis wereas follows: BP assessment; painful stimuli administration;pain assessment; and a design suitable for calculating aneffect size. Reasons for exclusion were review articles; casereports; conference proceedings, abstracts, and books;studies conducted only on clinical populations with disor-ders affecting the cardiovascular system (e.g. diabetes,coronary disease) or with chronic pain syndromes (e.g.fibromyalgia).
A total of 5179 results were retrieved. Comparison of theretrieved titles identified 1781 studies that were duplicates,thus leaving 3398 abstracts for further evaluation (see Fig. 1for the literature search flowchart). The current meta-anal-ysis is based on data extracted from 63 studies that met theinclusion criteria (see Table 1) and had pain perception asoutcome (6 for the meta-analysis on nociceptive responseand 61 for the meta-analysis on quantifiable perceptualmeasures of pain). Among the 61 studies having quantifi-able perceptual measures of pain as outcome, additionaldata (not published in the reviewed article but needed tocalculate effect sizes or to run moderator analyses) werereceived for 7 studies [6,25,39–43].
CodingA standardized data coding form was developed to extractthe following information from each study: authors andpublication year; study design; characteristics of the studysample (age, percent women, size, subgroups); methodthat has been used to induce pain (type, site of stimulation,and its duration); BP assessment (type of device and pro-tocol); pain assessment (nociceptive response, quantifiableperceptual measures, and exact method); adjusted cova-riates; and brief results. Each study (and each participant)was included only once in one of our meta-analyses [44].
Each research article was read and analysed by at leasttwo members of the research team (E.M., C.O.). Disagree-ments were resolved through group discussion. Intercoderreliabilities were established for 20% of the studies withsatisfactory results: Cohen’s k ¼ 0.96; r> 0.99.
When studies had more than one measure of pain and/orBP, a hierarchical inclusion method was implemented toprevent conflation of effect size estimates. Our choiceswere motivated by both theoretical assumptions and theneed to reduce heterogeneity, therefore, opting for themost frequently used option. Considering that almost allstudies had more than one measure of pain perception, thehierarchical inclusion rule was as follows: for nociceptiveresponse, flexion reflex (NFR), then wind-up, and lastlyEEG responses; for quantifiable perceptual measures, painthreshold, next pain tolerance, next Visual-Analog Scale(VAS) or Numeric Rating Scale (NRS), or Verbal Rating Scale(VRS) responses, or else the Mc Gill Pain Questionnaire (if
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FIGURE 1 Flow chart showing study selection for the meta-analysis.
Meta-analysis on BP-related hypoalgesia
only subscales, sensory first otherwise total score). Whenstudies assessed both pain intensity and pain unpleasant-ness, pain intensity was the preferred choice.
When studies had more than one type of pain stimulus,the hierarchical inclusion rule was based on the mostfrequently used: electrical (intracutaneous first, thenextracutaneous), ischemic, CPT, thermal (heat), other(i.e. Forgione–Barber finger pressure, muscle pain, toothextraction, puncture, surgical operation).
In line with the current guidelines for the assessment ofBP [45], which consider 24 h the golden standard, whenstudies had more than one type of BP assessment (i.e.resting BP and BP reactivity to a task), resting BP has beenchosen, with 24-h BP as a preferred choice compared withlaboratory BP.
When an article reported overall pain and pain peak [46],overall pain was used in the analysis.
When studies had experimental manipulations, such aspharmacological manipulations [4,47,48], transcutaneouselectrical nerve stimulation [49], administration of pain indetermined phases of the cardiac cycle [30] or duringbaroreceptors manipulation, such as neck suction [50,51],only the control/placebo condition or – when reported –the result irrespective of the cardiac phase were included inthe analysis. When no difference emerged between theseconditions, we first contacted the authors to obtain data for
Journal of Hypertension
the control/placebo condition, then, if such data was notavailable, we used the average of the two conditionsreported in the article [47].
For studies reporting on medically ill samples (i.e. with adiagnosis of diabetes, coronary disease, psychopathologi-cal disorder, chronic pain, etc.), we included only datarelated to the healthy controls, when it was possible toobtain it either from the article or by contacting the authors[52,53].
Data analysisTwo separate meta-analyses were conducted on nocicep-tive response and quantifiable perceptual measures of pain,respectively. Calculation of effect sizes and pooled effectsizes were obtained using ProMeta Version 2.0 (Internovi).All the analyses were performed using random-effectsmodels as they account for the amount of variance causedby differences between associations as well as differencesamong participants within associations. For each study (orsubsample of a study), we calculated a Hedges’ g effect size,and considered g equal to 0.20, 0.50, and 0.80 as small,medium, and large effects, respectively [54]. Effect sizesindicating lower pain perception associated with higher BPgot a positive sign [55]. Calculation of effect sizes was basedon means, standard deviations, P values, and sample sizesof the groups. Whenever studies did not provide raw data to
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TA
BLE
1.
Stu
die
sin
clu
ded
inth
em
eta
-an
aly
sis
an
dco
nd
itio
ns/
com
pari
son
su
sed
tod
eri
ve
eff
ect
size
s
Stu
die
s(a
uth
or
gro
up
,year
[ref.
no
.])
nPerc
en
tw
om
en
Ag
eExp
.g
rou
pPain
typ
e
Sti
mu
lus
du
rati
on
(ms)
Sit
eo
fst
imu
lati
on
Pain
ass
ess
men
tB
Pd
evic
eB
Pp
roto
col
Co
vari
ate
sC
on
trast
MA
(Hed
ges’
g)
Al’A
bsi
etal
.,2006
[47]
99
40.4
19.5
1A
trisk
Elec
t(e
xtra
)17
2Su
ralner
veTo
lera
nce
Auto
mat
icRes
tY
es3
Corr
elat
ion
bet
wee
nBP
and
pai
nto
lera
nce
irre
spec
tive
of
dru
gco
nditio
n
Pain
per
ception
(0.5
1)4
Angrilli
etal
.,1997
[50]
39
025.3
Hyp
oEl
ect
(intr
a)10
Han
dTh
resh
old
5A
uto
mat
icRes
tN
oC
orr
elat
ion
bet
wee
nBP
and
senso
ryth
resh
old
5Pa
inper
ception
(0.5
4)6
Bru
ehlet
al.,
2002
[25]
29
60.8
32.7
Norm
oIs
chem
300
000
7A
rmN
RS
Auto
mat
icRes
tY
es9
Mea
nin
trat
ask
NRS
for
the
hig
han
dlo
wre
stin
gBP
tert
iles
inpai
nfr
eesu
bsa
mple
Pain
per
ception
(0.4
8)
Bru
ehlet
al.,
2010
[39]
79
50.6
27.5
Norm
o10
Isch
em300
000
7A
rmV
AS
Auto
mat
icRes
tY
es11
Corr
elat
ion
bet
wee
nBP
and
VA
Sin
tensi
ty12
Pain
per
ception
(�0.1
9)
Bru
ehlet
al.,
2010
[73]
55
65.5
17.1
Norm
oH
eat
1000
13
Arm
Thre
shold
Auto
mat
icRes
tN
oC
orr
elat
ion
bet
wee
nSB
Pan
dac
ute
pai
nth
resh
old
Pain
per
ception
(1.0
8)
Cam
pbel
lan
dD
itto
2002
[49]
45
022
At
risk
Elec
t(e
xtra
)5
Arm
VA
SA
uto
mat
icRes
tN
oC
orr
elat
ion
bet
wee
nca
sual
BP
and
pai
nin
the
entire
sam
ple
Pain
per
ception
(1.2
9)
Cam
pbel
let
al.,
2003
[12]
110
022
14
Norm
o15
Oth
er16
180
000
7H
and
Tole
rance
Auto
mat
ic24h
No
Corr
elat
ion
bet
wee
npai
nto
lera
nce
atag
e14
and
SBP
atag
e22
Pain
per
ception
(0.7
9)
Cam
pbel
let
al.,
2004
[74]
135
43.7
33.4
1N
orm
oIs
chem
5000
17
Arm
VRS
Auto
mat
ic24h
No
Corr
elat
ion
bet
wee
nSB
Pan
din
tensi
tyPa
inper
ception
(0.4
7)
Chal
aye
etal
.,2013
[75]
26
50
26
Norm
oH
eat
–18
Arm
Thre
shold
Bea
t-to
-bea
tRes
tY
es19
Corr
elat
ion
bet
wee
npai
nth
resh
old
and
SBP
Pain
per
ception
(0.2
6)
Chung
and
Bru
ehl,
2008
[76]
30
46.7
35
Norm
oH
eat2
015
Arm
Win
dup
Bea
t-to
-bea
tRes
tY
es21
Ass
oci
atio
nbet
wee
nre
stin
gBP
and
ther
mal
win
d-u
pN
oci
ception
(0.7
7)
Cook
etal
.,2004
[77]
34
100
19
1A
trisk
Oth
er22
–23
Leg
NRS
Bea
t-to
-bea
tRes
tY
es24
Pain
inte
nsi
tyduring
max
imal
exer
cise
inFHþ
vers
us
FH-
Pain
per
ception
(0.1
6)
Cott
on
etal
.,2018
[40]
15
25
–/
Norm
oTh
erm
al6000
Leg
VA
SBea
t-to
-bea
tRes
tY
es26
Corr
elat
ion
bet
wee
nSB
Pat
bas
elin
ean
dpai
nin
tensi
tyra
tings2
7
Pain
per
ception
(1.2
1)
de
laC
oba
etal
.,2018
[78]
27
100
51.4
Norm
o28
Oth
er29
5000
Finger
Thre
shold
Bea
t-to
-bea
tRes
tN
o30
Corr
elat
ion
bet
wee
nSB
Pan
dpai
nth
resh
old
Pain
per
ception
(1.1
8)
de
laC
oba
etal
.,2018
[79]
99
58.6
20.7
Norm
o31
Ther
mal
–A
rmTh
resh
old
Auto
mat
icRes
tN
o32
Corr
elat
ion
bet
wee
nSB
Pan
dpai
nth
resh
old
Pain
per
ception
(0.4
9)
Des
chau
mes
etal
.,2014
[80]
293
46.1
42
Norm
o33
Oth
er34
–M
outh
VA
SA
uto
mat
icRes
tN
oC
orr
elat
ion
bet
wee
nSB
Pbef
ore
surg
ery
and
post
oper
ativ
epai
n35
Pain
per
ception
(0.0
5)
Dev
oiz
eet
al.,
2016
[81]
26
50
26
Norm
oC
PT300
000
7H
and
VA
SBea
t-to
-bea
tRea
ctY
es36
Corr
elat
ion
bet
wee
nth
eBP
variat
ion
and
aver
age
pai
nse
nsa
tion
Pain
per
ception
(�0.1
0)
Ditto
etal
.,1997
[82]
24
37
100
19.3
At
risk
Elec
t(e
xtra
)38
1A
rmV
AS
Bea
t-to
-bea
tRea
ctY
es39
Max
imum
pai
nre
port
ed(v
ideo
gam
eday
)by
FHþ
vers
us
FH�
hig
hM
AP
reac
tors
Pain
per
ception
(1.4
8)
Ditto
etal
.,2009
[41]
40
030.1
1A
trisk
Ther
mal
1000
40
Arm
41
VA
SA
uto
mat
ic24h
No
Pain
unple
asan
tnes
sra
ting
inhyp
erte
nsi
vepat
ients
and
norm
ote
nsi
ves
Pain
per
ception
(0.4
7)
Dro
uin
and
McG
rath
2013
[83]
307
43.3
12.4
1N
orm
o42
Oth
er43
/H
and
VA
SA
uto
mat
icRes
tY
es44
Corr
elat
ion
bet
wee
npai
nra
tings
and
SBP
Pain
per
ception
(0.3
0)
Dusc
hek
etal
.,2007
[84]
60
53.3
25
Norm
oC
PT60
000
Han
dV
AS
Bea
t-to
-bea
tRes
tY
es45
Corr
elat
ion
bet
wee
npai
nin
tensi
tyan
dSB
PPa
inper
ception
(0.5
8)
Dusc
hek
etal
.,2008
[85]
60
100
24.5
1H
ypo
CPT
180
000
7H
and
VA
SBea
t-to
-bea
tRea
ctY
es46
Corr
elat
ion
bet
wee
npai
nth
resh
old
and
SBP4
7Pa
inper
ception
(0.5
3)
Makovac et al.
4 www.jhypertension.com Volume 38 � Number 1 � Month 2020
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JH-D-20-00007
TA
BLE
1(C
on
tin
ued
)
Stu
die
s(a
uth
or
gro
up
,year
[ref.
no
.])
nPerc
en
tw
om
en
Ag
eExp
.g
rou
pPain
typ
e
Sti
mu
lus
du
rati
on
(ms)
Sit
eo
fst
imu
lati
on
Pain
ass
ess
men
tB
Pd
evic
eB
Pp
roto
col
Co
vari
ate
sC
on
trast
MA
(Hed
ges’
g)
Dusc
hek
etal
.,2009
[86]
80
80
27.8
1H
ypo
Ther
mal
60
000
Arm
Thre
shold
Auto
mat
icRes
tY
es48
Pain
thre
shold
inhyp
ote
nsi
vepat
ients
vers
us
contr
ols
Pain
per
ception
(0.4
5)
Edw
ards
etal
.,2002
[30]
36
44.4
23.3
Norm
oEl
ect
(ext
ra)
149
Sura
lner
veN
FR,
NRS
Auto
mat
icRes
tY
es50
Corr
elat
ion
bet
wee
nSB
Pan
dN
FRan
dN
RS
Noci
ception
(0.0
0);
Pain
per
ception
(0.0
0)
Fech
iret
al.,
2012
[87]
14
28.6
24.3
Norm
oEl
ect
(intr
a)0.5
Leg
VA
SBea
t-to
-bea
tRea
ctY
es51
Corr
elat
ion
bet
wee
nSB
Pan
dan
alges
iaPa
inper
ception
(0.6
2)
Filli
ngim
etal
.,1998
[88]
21
100
23
Norm
oTh
erm
al/5
2A
rm53
Thre
shold
Auto
mat
icRes
tN
oPa
inonse
tin
hig
han
dlo
wBP
gro
ups5
4Pa
inper
ception
(0.6
9)
Fran
cean
dSt
uar
t,1995
[89]
80
019.7
At
risk
Isch
emic
300
000
Han
dN
RS
Bea
t-to
-bea
tRea
ctN
oC
orr
elat
ion
bet
wee
nto
talpai
nra
ting
index
score
san
dpar
enta
lhis
tory
Pain
per
ception
(0.4
9)
Fran
cean
dSu
chow
ieck
i,2001
[90]
113
52.2
18.9
At
risk
Elec
t(e
xtra
)55
12
Sura
lner
veN
FRA
uto
mat
icRes
tY
es56
Inte
nsi
tyof
stim
ula
tion
nee
ded
toel
icit
NFR
inFHþ
and
FH�
Noci
ception
(0.5
8)
Fran
ceet
al.,
1991
[51]
45
022
1A
trisk
Isch
emic
60
000
7Le
gTh
resh
old
Auto
mat
icRes
tN
oPa
inth
resh
old
for
FHþ
and
FH�
Pain
per
ception
(1.8
5)
Fran
ceet
al.,
2002
[91]
102
46.1
19.1
1A
trisk
Elec
t(e
xtra
)1
2Su
ralner
veN
FR,
thre
shold
Auto
mat
icRes
tY
es57
NFR
thre
shold
inFHþ
and
FH-
acro
ssper
iods;
pai
nth
resh
old
inFHþ
and
FH�
during
the
initia
lpre
mat
has
sess
men
t
Noci
ception
(0.5
8);
Pain
per
ception
(0.6
2)
Fran
ceet
al.,
2005
[4]
158
46.2
19.3
At
risk
Elec
t(e
xtra
)1
2Su
ralner
veN
FR,
NRS
Auto
mat
icRes
tY
es58
NFR
thre
shold
and
elec
trocu
taneo
us
pai
nth
resh
old
inFHþ
vers
us
FH-5
9
Noci
ception
(0.0
0);
Pain
per
ception
(0.2
6)
Frew
and
Dru
mm
ond,
2009
[52]
17
54.5
135.8
1N
orm
o60
CPT
61
240
000
Foot
VRS
Auto
mat
icRea
ctY
es62
Corr
elat
ion
bet
wee
npai
nto
lera
nce
and
SBP
during
the
firs
tC
PTin
contr
ols
Pain
per
ception
(1.1
3)
Ghio
ne
etal
.,1988
[92]
156
32.1
32.4
1H
yper
Elec
t(in
tra)
–To
oth
Thre
shold
Auto
mat
icRes
tN
oC
orr
elat
ion
bet
wee
nm
ean
MA
Pan
dpai
nth
resh
old
Pain
per
ception
(0.5
6)
Girdle
ret
al.,
1998
[53]
14
100
24.4
Norm
o63
Isch
emic
64
2000
65
Arm
Thre
shold
Auto
mat
icRea
ctY
es66
Corr
elat
ion
bet
wee
nm
ean
task
SBP
and
pai
nth
resh
old
Pain
per
ception
(0.1
3)
Guas
tiet
al.,
1995
[93]
67
042
Hyp
erEl
ect
(intr
a)200
67
Tooth
Thre
shold
Auto
mat
ic24h
Yes
68
Corr
elat
ion
bet
wee
n24
hSB
Pan
dpai
nth
resh
old
Pain
per
ception
(0.7
4)
Guas
tiet
al.,
1996
[94]
72
042.5
1H
yper
Elec
t(in
tra)
200
67
Tooth
Thre
shold
Auto
mat
ic24h
Yes
68
Corr
elat
ion
bet
wee
n24
hSB
Pan
dpai
nth
resh
old
Pain
per
ception
(0.7
9)
Guas
tiet
al.,
1998
[95]
39
043
Hyp
erEl
ect
(intr
a)200
67
Tooth
Thre
shold
Auto
mat
ic24h
Yes
68
Pain
thre
shold
inhyp
erve
rsus
norm
oPa
inper
ception
(0.8
0)
Guas
tiet
al.,
1999
[96]
146
041.5
1H
yper
Elec
t(in
tra)
200
67
Tooth
Thre
shold
Auto
mat
ic24h
Yes
68
Pain
thre
shold
inhyp
erve
rsus
norm
oPa
inper
ception
(0.4
6)
Guas
tiet
al.,
1999
[97]
181
042.5
1H
yper
Elec
t(in
tra)
200
67
Tooth
Thre
shold
Auto
mat
ic24h
Yes
68
Corr
elat
ion
bet
wee
n24
hSB
Pan
dpai
nth
resh
old
Pain
per
ception
(0.6
5)
Guas
tiet
al.,
2002
[98]
73
040.5
1H
yper
Elec
t(in
tra)
200
67
Tooth
Thre
shold
Auto
mat
ic24h
Yes
68
Pain
thre
shold
inhyp
erve
rsus
norm
oPa
inper
ception
(0.4
7)
Horing
etal
.,2016
[99]
33
63.6
20.1
Norm
oTh
erm
al69
60
000
70
Han
dV
AS
Auto
mat
icRes
tY
es71
Corr
elat
ion
bet
wee
nre
stin
gSB
Pan
dpai
nra
ting
during
the
firs
ttr
ialof
the
firs
tse
quen
ce
Pain
per
ception
(0.7
5)
Keo
gh
and
Witt,
2001
[100]
50
50
24.2
Norm
oC
PT120
000
7H
and
Thre
shold
Auto
mat
icRes
tY
es72
Corr
elat
ion
bet
wee
nch
anges
inSB
Pan
din
pai
nto
lera
nce
afte
rca
ffei
ne
73
Pain
per
ception
(0.5
5)
Meta-analysis on BP-related hypoalgesia
Journal of Hypertension www.jhypertension.com 5
CE: Tripti; JH-D-20-00007; Total nos of Pages: 16;
JH-D-20-00007
TA
BLE
1(C
on
tin
ued
)
Stu
die
s(a
uth
or
gro
up
,year
[ref.
no
.])
nPerc
en
tw
om
en
Ag
eExp
.g
rou
pPain
typ
e
Sti
mu
lus
du
rati
on
(ms)
Sit
eo
fst
imu
lati
on
Pain
ass
ess
men
tB
Pd
evic
eB
Pp
roto
col
Co
vari
ate
sC
on
trast
MA
(Hed
ges’
g)
Kin
get
al.,
2012
[101]
60
64
46
Norm
o74
Oth
er29
–To
oth
VA
SA
uto
mat
icRes
tY
es75
Corr
elat
ion
bet
wee
npre
oper
ativ
eSB
Pan
dpai
non
the
firs
tpost
oper
ativ
eday
Pain
per
ception
(0.4
9)
Koen
iget
al.,
2017
[42]
30
100
15.2
7N
orm
o76
CPT
24
000
7H
and
Thre
shold
Man
ual
Res
tY
es77
Corr
elat
ion
bet
wee
nbas
elin
eSB
Pan
dpai
nth
resh
old
Pain
per
ception
(0.0
0)
Luo
etal
.,2013
[102]
60
51.7
55.6
Hyp
er78
Oth
er79
–A
bdom
enV
RS
Man
ual
Res
tN
oPa
inin
tensi
tysc
ore
sin
hyp
erte
nsi
vepat
ients
vers
us
norm
ote
nsi
ves
Pain
per
ception
(1.0
6)
McC
ubbin
etal
.,2006
[103]
125
60.8
19.5
1A
trisk
CPT
120
000
7H
and
MPQ
Auto
mat
icRes
tY
es80
Corr
elat
ion
bet
wee
nth
eto
tal
score
on
the
MPQ
and
rest
ing
SBP
on
the
pla
cebo
day
Pain
per
ception
(0.4
3)
Mye
rset
al.,
2001
[104]
104
48.1
22.4
Norm
oC
PT300
000
7H
and
Thre
shold
Auto
mat
icRes
tY
es81
Corr
elat
ion
bet
wee
npai
nth
resh
old
and
rest
ing
SBP
Pain
per
ception
(0.4
5)
Nah
man
-Ave
rbuch
etal
.,2016
[43]
40
50
26.4
5N
orm
oTh
erm
al–8
2A
rmTh
resh
old
Man
ual
Res
tY
es83
Corr
elat
ion
bet
wee
nSB
Pan
dpai
nth
resh
old
sat
bas
elin
ePa
inper
ception
(0.2
4)
Nyk
licek
etal
.,1999
[105]
63
46.6
144.1
1H
yper
Elec
t(e
xtra
)160
000
7A
rmTh
resh
old
Auto
mat
icRes
tY
es84
Diffe
rence
sin
pai
nth
resh
old
inhyp
eran
dnorm
oPa
inper
ception
(0.2
1)
O’C
onnor
etal
.,2004
[23]
12
022.2
Norm
oO
ther
85
–86
Leg
VRS
Man
ual
Res
tY
es87
Corr
elat
ion
bet
wee
npre
exer
cise
SBP
and
mea
npai
nin
tensi
tyra
tings
inth
epla
cebo
conditio
n
Pain
per
ception
(�0.6
7)
Ols
enet
al.,
2013
[5]
6914
47.3
56.3
Hyp
er88
CPT
106
000
Han
dN
RS
Auto
mat
icRes
tN
o89
Corr
elat
ion
bet
wee
nSB
Pan
dac
ute
pai
nra
tings
inin
div
idual
sfr
eeof
chro
nic
pai
n
Pain
per
ception
(0.2
0)
Ott
avia
niet
al.,
2018
[106]
18
55.5
32.7
Norm
oEl
ect
(ext
ra)
5A
rmTh
resh
old
Auto
mat
ic24h
Yes
90
Corr
elat
ion
bet
wee
nhom
eSB
Pan
dpai
nth
resh
old
Pain
per
ception
(2.4
5)
Page
and
Fran
ce,
1997
[107]
116
48.3
19.4
1A
trisk
Elec
t(e
xtra
)1
2Su
ralner
veN
FR,
thre
shold
Auto
mat
icRes
tY
es91
Corr
elat
ion
bet
wee
nSB
Pan
dN
FRan
dpai
nth
resh
old
Noci
ception
(0.4
8);
Pain
per
ception
(0.2
4)
Papag
eorg
iou
etal
.,2017
[108]
40
52.5
51.2
Hyp
erC
PT–9
2H
and
Tole
rance
93
Auto
mat
ic24h
No
Tole
rance
inhyp
erve
rsus
norm
oPa
inper
ception
(0.6
1)
Nas
cim
ento
Reb
elat
toet
al.,
2017
[109]
72
55.5
71.4
Hyp
erO
ther
16
–94
Leg
95
Thre
shold
(PPT
)–9
6Res
tN
oD
iffe
rence
sin
pre
ssure
pai
nth
resh
old
bet
wee
nnorm
oe
hyp
er
Pain
per
ception
(0.4
3)
del
Paso
etal
.,2011
[110]
29
93.1
49.4
Norm
o97
CPT
180000
7H
and
98
Thre
shold
Bea
t-to
-bea
tRes
tY
es99
Corr
elat
ions
bet
wee
nbas
elin
eSB
Pan
dpai
nth
resh
old
inth
ehea
lthy
subgro
up
Pain
per
ception
(0.7
9)
Rin
get
al.,
2008
[46]
63
47.6
42.3
1H
yper
Elec
t(e
xtra
)1
2Su
ralner
veTh
resh
old
Auto
mat
ic24h
Yes
100
Pain
thre
shold
inhyp
erve
rsus
norm
oin
the
pla
cebo
conditio
n
Pain
per
ception
(0.1
7)
Scheu
ren
etal
.,2016
[111]
32
50
24.2
Norm
oTh
erm
al60
000
Han
dN
RS
Bea
t-to
-bea
tRes
tN
oC
orr
elat
ion
bet
wee
nbas
elin
eSB
Pan
dN
RS
senso
ryPa
inper
ception
(0.1
2)
Schobel
etal
.,1998
[48]
21
025
1A
trisk
Oth
er101
120
000
Han
d102
NRS
Bea
t-to
-bea
tRes
tN
oC
orr
elat
ion
bet
wee
nre
stin
gSB
Pan
dpai
nper
ception
Pain
per
ception
(1.3
7)
Shef
fiel
det
al.,
2000
[112]
51
49
38
Norm
oTh
erm
al5000
Arm
VA
SM
anual
Res
tN
oC
orr
elat
ion
bet
wee
nSB
Pan
dpai
nin
tensi
tyra
ting
Pain
per
ception
(0.6
0)
Stew
art
and
Fran
ce,
1996
[113]
82
019.7
At
risk
Isch
emic
103
420
000
7A
rmN
RS
Auto
mat
icRes
tN
o104
Rat
ings
of
inte
nsi
tyof
isch
emic
pai
nin
FHþ
vers
us
FH�
atm
inute
5
Pain
per
ception
(0.5
2)
Um
eda
etal
.,2009
[114]
23
100
20
Norm
oO
ther
105
120
000
7H
and
Thre
shold
Bea
t-to
-bea
tRes
tN
oC
orr
elat
ion
bet
wee
nre
stin
gSB
Pan
dpai
nth
resh
old
Pain
per
ception
(�0.1
4)
Makovac et al.
6 www.jhypertension.com Volume 38 � Number 1 � Month 2020
CE: Tripti; JH-D-20-00007; Total nos of Pages: 16;
JH-D-20-00007
TA
BLE
1(C
on
tin
ued
)
Stu
die
s(a
uth
or
gro
up
,year
[ref.
no
.])
nPerc
en
tw
om
en
Ag
eExp
.g
rou
pPain
typ
e
Sti
mu
lus
du
rati
on
(ms)
Sit
eo
fst
imu
lati
on
Pain
ass
ess
men
tB
Pd
evic
eB
Pp
roto
col
Co
vari
ate
sC
on
trast
MA
(Hed
ges’
g)
Um
eda
etal
.,2010
[115]
50
50
29
1N
orm
oO
ther
106
120
000
7H
and
Thre
shold
Bea
t-to
-bea
tRes
tY
esC
orr
elat
ion
bet
wee
nre
stin
gM
AP
and
thre
shold
acro
ssco
nditio
ns
Pain
per
ception
(0.0
0)
Vas
send
and
Knar
dah
l,2004
[116]
58
100
35.9
Norm
oEl
ectr
(ext
)107
50
108
Han
dTh
resh
old
Bea
t-to
-bea
tRea
ctY
es109
Corr
elat
ion
bet
wee
npai
n-
induce
dM
AP
and
mea
npai
nth
resh
old
Pain
per
ception
(0.7
6)
The
mea
sure
sre
port
edin
the
table
do
not
repre
sent
the
only
avai
lable
variab
les
inth
eex
amin
edst
udie
sbut
those
that
wer
euse
din
the
curr
ent
met
a-an
alys
isfo
rth
eco
mputa
tion
of
the
ESan
dfo
rm
oder
ator
anal
ysis
.1
Estim
ated
valu
e;2
dura
tion
of
each
stim
ula
tion
tria
lco
nsi
stin
gof
five
1-m
sre
ctan
gula
rpuls
esw
ith
a3-m
sin
terp
uls
ein
terv
al;
3co
ntr
olfo
rci
rcad
ian
rhyt
hm
and
men
stru
alcy
cle,
no
alco
holor
anal
ges
icm
edic
atio
nfo
r24
han
dnar
cotic
med
icat
ion
for
3day
s;4
the
study
incl
uded
anN
FRas
sess
men
t,but
the
pro
vided
dat
aw
asin
suff
icie
nt
toder
ive
the
ES;
5w
ithout
the
most
extr
eme
poin
t;6
the
study
incl
uded
aEE
Gm
easu
rebut
giv
enth
enee
dto
excl
ude
the
nec
ksu
ctio
nm
anip
ula
tion
conditio
n,
the
avai
lable
info
rmat
ion
wer
enot
suff
icie
nt
toal
low
the
com
puta
tion
of
the
ES;
7m
axim
um
dura
tion;
8fo
ris
chem
icpai
nth
ephar
mac
olo
gic
alm
anip
ula
tion
did
not
yiel
dan
yef
fect
,th
us,
we
hav
eco
nsi
der
edth
eav
erag
ean
dnot
only
the
pla
cebo
conditio
n;
9co
ntr
olfo
rci
rcad
ian
rhyt
hm
,no
anal
ges
icor
anti-inflam
mat
ory
med
icat
ions
for
24
hprior
tost
udy
par
tici
pat
ion;
10
his
tory
of
abdom
inal
pai
nduring
child
hood;
11
no
caff
eine
for
3h
prior
toth
eap
poin
tmen
t,an
alges
ics
or
med
icat
ions
pote
ntial
lyaf
fect
ing
blo
od
pre
ssure
(e.g
.pse
udoep
hed
rine)
for
12
hprior
toth
eap
poin
tmen
t;12
com
bin
esth
ose
who
wer
ehar
asse
dan
dth
ose
who
wer
enot;
13
tem
per
ature
incr
easi
ng
ata
ram
pra
teof
0.58C
/s;
14
sam
esu
bje
cts
test
edat
the
age
of
14
(longitudin
aldes
ign);
15
11
par
tici
pan
tshad
ahis
tory
of
hyp
erte
nsi
on
(at
risk
);16
Forg
ione
and
Bar
ber
’spre
ssure
;1710
min
of
BP
cuff
inflat
ion,
during
whic
hsu
bje
cts
contr
acte
dth
eir
han
dfo
r5
sev
ery
30
s;18
tem
per
ature
incr
easi
ng
ata
ram
pra
teof
0.38C
/s;
19
no
anal
ges
icor
anti-inflam
mat
ory
med
icat
ion
atle
ast
24
hprior
tote
stin
g;
20
also
isch
emic
;21
no
anal
ges
ics,
nonst
eroid
alan
ti-inflam
mat
ory
dru
gs,
or
any
med
icat
ions
pote
ntial
lyaf
fect
ing
BP
for
12
hprior
toan
dca
ffei
ne
3h
prior
tost
udy
par
tici
pat
ion;
22
musc
lepai
n(in
suff
icie
nt
dat
aon
CPT
toder
ive
the
ES);
23
afte
ra
4-m
inw
arm
-up
at25
W,
resi
stan
cein
crea
sed
up
to50W
and
then
ata
rate
of
24
W/
min
untilpar
tici
pan
tsre
ached
volit
ional
exhau
stio
n;
24
contr
olfo
rm
enst
rual
cycl
e;25
gro
up
of
yoga
pra
ctitio
ner
snot
incl
uded
inth
ean
alys
is;
26
refr
ain
from
exer
cisi
ng
or
consu
min
gca
ffei
nat
edpro
duct
sfo
r2
hbef
ore
test
ing,
and
refr
ain
from
drinki
ng
alco
holor
taki
ng
any
med
icat
ions
outs
ide
the
usu
alre
gim
enfo
r24
hprior.
Reg
ula
rly
cycl
ing
wom
en(in
cludin
gth
ose
usi
ng
horm
onal
contr
acep
tive
s)w
ere
alw
ays
test
edin
the
firs
t12
day
sof
thei
rm
enst
rual
cycl
e,unle
ssth
eyw
ere
on
monophas
ichorm
onal
contr
acep
tion;
27
aver
age
of
cert
ain
and
unce
rtai
nra
tings;
28
the
study
incl
uded
agro
up
of
pat
ients
with
fibro
mya
lgia
that
was
not
consi
der
edin
the
anal
ysis
;29
ora
lpost
surg
ical
pai
n;
30
med
icat
ion
use
(antidep
ress
ants
,an
xioly
tics
,an
alges
ics
and
opio
ids)
;31
The
gro
up
with
unre
solv
edch
ronic
pai
nw
asnot
consi
der
edin
the
anal
ysis
;32
no
anal
ges
icm
edic
atio
ns
for
12
hprior
toth
esc
hed
ule
dst
udy
sess
ion;
33
som
ehad
his
tory
of
card
iova
scula
rpro
ble
ms;
34
sponta
neo
us
pai
nduring
the
firs
t6
haf
ter
the
end
of
surg
ery
inth
ehosp
ital
;35
com
posi
tesc
ore
taki
ng
into
acco
unt
the
deg
ree
of
sponta
neo
us
pai
nre
port
edby
the
pat
ient
during
the
firs
t6
han
dth
eam
ount
of
anal
ges
icdru
gin
take
during
the
firs
t3
day
s;36
contr
olfo
rm
enst
rual
cycl
e,no
smoki
ng
and/o
rdrinki
ng
coff
ee1
hbef
ore
test
ing;
37
the
sam
ple
was
const
itute
dby
48
indiv
idual
sbut
only
hig
hM
AP
reac
tors
wer
ein
cluded
inth
ean
alys
is;
38
also
Cold
Pres
sure
Test
(CPT
,48C
).Both
task
sad
min
iste
red
afte
rper
form
ance
ata
video
gam
e;39
contr
olfo
rm
enst
rual
cycl
e;40
10
low
-hea
tan
d10
hig
hhea
tpre
sente
dat
30-s
inte
rval
;41
par
tici
pan
tste
sted
with
legs
up
and
legs
dow
nin
counte
rbal
ance
dord
er;
42
16%
of
par
ents
and
11.3
%of
bio
logic
alm
oth
ers
met
criter
iafo
rhyp
erte
nsi
on;
43
child
’snondom
inan
tring
finger
was
pie
rced
with
a21-g
auge
safe
tyla
nce
tfo
ra
stan
dar
diz
edblo
od
dra
w;
44
no
nonpre
scription
med
icat
ion
and
caff
eine
for
24
hprior
toth
ela
bora
tory
visi
t;45
no
alco
holor
bev
erag
esco
nta
inin
gca
ffei
ne
for
3h
prior
toex
per
imen
talse
ssio
n;
46
no
caff
eine
and
alco
hol;
47
contr
olli
ng
for
BM
I;48
no
smoki
ng,
alco
hol,
and
caff
eine
for
3h
prior
toth
esc
reen
ing
and
exper
imen
talse
ssio
ns;
49
five
rect
angula
r-w
ave
puls
esof
1-m
sdura
tion
follo
wed
by
a4-m
sin
ters
tim
ulu
sin
terv
al;
50
no
caff
eine,
alco
hol,
and
vigoro
us
exer
cise
for
2h,
and
anal
ges
icm
edic
atio
nfo
r24
hbef
ore
test
ing;
51
no
smoki
ng
and
drinki
ng
coff
eeon
the
day
of
inve
stig
atio
n;
52
stai
rcas
era
mp
of
0.5
Cev
ery
5s;
53
and
ipsi
late
ralch
eek;
54
ther
mal
pai
nonse
tin
8C,
hig
hve
rsus
low
BP
bas
edon
the
med
ian
split
;55
the
study
incl
uded
anis
chem
icco
nditio
n;
56
no
caff
eine,
nic
otine,
alco
hol,
pai
nm
edic
atio
n,
and
stre
nuous
exer
cise
for
atle
ast
4h
bef
ore
thei
rar
riva
lat
the
labora
tory
;57
refr
ain
from
caff
eine,
nic
otine,
alco
hol,
med
icat
ions,
and
stre
nuous
exer
cise
for
atle
ast
4h
bef
ore
thei
rar
riva
lat
the
labora
tory
;58
contr
olfo
rm
enst
rual
cycl
e,no
caff
eine,
nic
otine,
alco
hol,
and
stre
nuous
exer
cise
for
atle
ast
4h
bef
ore
thei
rar
riva
lat
the
labora
tory
,an
dfr
om
anal
ges
icm
edic
atio
nfo
r24
hprior
tote
stin
g;
59
incl
udes
anal
oxo
ne
conditio
nas
dat
aw
ere
not
pre
sente
dse
par
atel
y;60
the
study
incl
uded
asa
mple
of
MD
Dth
atw
asnot
consi
der
edin
the
anal
ysis
;61
the
study
incl
uded
anar
ithm
etic
task
with
elec
tric
shock
and
both
stre
ssors
are
per
form
edtw
ice;
62
smoke
rsex
cluded
,no
alco
holin
take
for
1w
eek,
no
alco
holic
or
caff
einat
edbev
erag
esfo
r12
h,
no
food
for
2h,
and
no
opia
tean
alges
ics
for
24
hbef
ore
the
exper
imen
t;63
the
study
incl
uded
asa
mple
with
bulim
ianer
vosa
that
was
not
incl
uded
inth
ean
alys
is;
64
han
dgrip
during
tourn
iquet
cuff
inflat
ion;
65
appro
xim
ate
tim
eat
whic
hpar
tici
pan
tshad
tosq
uee
zean
dre
leas
e(h
andgrip
exer
cise
);66
contr
olfo
rci
rcad
ian
variat
ions,
no
ove
r-th
e-co
unte
rm
edic
atio
ns,
incl
udin
gan
alges
ics
for
24
han
dca
ffei
ne
on
the
day
of
test
ing;
67
burs
tfr
equen
cyat
5H
z;68
contr
olfo
rci
rcad
ian
rhyt
hm
s,no
med
icat
ions
or
was
hout
3w
eeks
bef
ore
the
study,
no
smoki
ng,
caff
eine,
tea,
choco
late
,co
laor
alco
hol12
hbef
ore
the
exper
imen
t;69
han
dim
mer
sion
inhot
(478C
)w
ater
;70
5tr
ials
of
1-m
inim
mer
sion
tim
ean
d30-s
pau
se,
tota
ling
7.5
min
per
sequen
ce;
71
abst
inen
cefr
om
pai
nm
edic
atio
nan
dre
crea
tional
dru
gs
for
atle
ast
24
hbef
ore
the
lab
visi
t;72
no
alco
holan
dca
ffei
ne-
conta
inin
gpro
duct
sfo
r12
h,
and
food
and
or
cigar
ette
sfo
r2
h;
73
no
asso
ciat
ion
with
rest
ing
SBP
inth
epla
cebo
conditio
n;
74
endodontic
pat
ients
;75
no
anal
ges
ics
up
to6
hprior
tocl
inic
alas
sess
men
t;76
the
sam
ple
with
nonsu
icid
alse
lf-inju
ries
was
not
incl
uded
inth
ean
alys
is;
77
BM
I(c
ontinuous)
,use
of
med
icat
ion
(yes
/no),
use
of
contr
acep
tive
pill
(yes
/no),
num
ber
of
cigar
ette
ssm
oke
dper
day
(cat
egorica
l),al
coholco
nsu
mption
(yes
/no)
and
dru
gs
take
nduring
the
30
day
spre
cedin
gth
est
udy
(yes
/no);
78
som
epat
ients
had
dia
bet
esm
ellit
us,
fatt
yliv
er/h
epat
itis
B,
chole
cyst
itis
/chole
cyst
olit
hia
sis,
gas
tric
ulc
er,
pre
mat
ure
ventr
icula
rco
ntr
actions,
anem
ia;
79
maj
or
abdom
inal
surg
ery;
80
nonsm
oke
rs,
not
consu
min
gm
ore
than
thre
eal
coholic
bev
erag
esper
wee
k,not
curr
ently
taki
ng
any
opio
idor
nonopio
idpai
nm
edic
atio
n,
test
edif
men
stru
alcy
cle
phas
ehad
any
effe
cton
pai
nre
port
s;81
nonsm
oke
rs,
abst
ain
from
caff
eine
for
the
2h
bef
ore
thei
rap
poin
tmen
t;82
bas
elin
ete
mper
ature
was
set
at32.08C
and
was
incr
ease
dor
dec
reas
edat
ara
teof
18C
/s;
83
wom
enw
ho
wer
enot
on
contr
acep
tion
wer
ete
sted
during
the
folli
cula
rphas
e;th
ose
on
contr
acep
tion
wer
ete
sted
atday
s2
–20
afte
rm
enst
ruat
ion
end.
None
of
the
subje
cts
took
any
anal
ges
icm
edic
atio
nfo
r24
hbef
ore
the
test
ing;
84
refr
ain
from
usi
ng
alco
holon
the
day
of
the
exper
imen
t,fr
om
caff
eine
consu
mption
for
atle
ast
3h
and
from
smoki
ng
for
atle
ast
2h
prior
toth
ela
bora
tory
sess
ion;
85
musc
lepai
n;
86
exer
cise
bouts
;87
nonsm
oki
ng
and
low
-caf
fein
eco
nsu
mer
s;88
the
study
incl
uded
asa
mple
with
chro
nic
pai
nth
atw
asnot
consi
der
edin
the
anal
ysis
;89
no
caff
eine
consu
mption
for
1w
eek;
alco
holco
nsu
mption
for
24
h;
and
eating
and
exer
cisi
ng
for
12
hbef
ore
the
exper
imen
talte
stin
g;
90
par
tici
pan
tsw
ere
aske
dto
refr
ain
from
alco
holan
duse
of
anal
ges
icor
anti-inflam
mat
ory
med
icat
ions
for
24
hbef
ore
the
study
and
from
caff
eine,
alco
hol,
and
vigoro
us
exer
cise
for
2h
bef
ore
the
exper
imen
t.To
avoid
circ
adia
nin
fluen
ces,
allse
ssio
ns
wer
esc
hed
ule
din
the
afte
rnoon;
91
resu
lts
did
not
chan
ge
when
the
anal
ysis
was
re-d
one
contr
olli
ng
for
anal
ges
icor
antihyp
erte
nsi
vem
edic
atio
ns;
92
untilre
trac
ted;
93
the
study
incl
uded
anEE
Gas
sess
men
tth
atw
asnot
inco
rpora
ted
inth
em
eta-
anal
ysis
bec
ause
of
the
pau
city
of
studie
sw
ith
this
spec
ific
type
of
phys
iolo
gic
alm
easu
res;
94
untilth
epre
ssure
sensa
tion
chan
ged
into
pai
n;
95
seve
nan
atom
ical
poin
tsex
amin
ed,
the
left
tibia
was
chose
nas
itw
asth
em
ost
com
par
able
with
site
sfr
om
oth
erst
udie
s;96
doct
or
dia
gnosi
sof
hyp
erte
nsi
on;
97
gro
up
with
fibro
mya
lgia
not
incl
uded
;98
also
arm
;99
excl
uded
those
regula
rly
taki
ng
pre
scription
or
ove
r-th
e-co
unte
rm
edic
atio
ns;
contr
olfo
rci
rcad
ian
rhyt
hm
variat
ion;
no
caff
eine
and
nic
otine
for
atle
ast
2h
pre
cedin
gth
eir
arriva
lat
the
labora
tory
;100
tore
frai
nfr
om
caff
eine,
alco
hol,
and
vigoro
us
exer
cise
for
2h,
and
anal
ges
icm
edic
atio
nfo
r24
hprior
tote
stin
g;
101
noxi
ous
mec
han
o-s
tim
ula
tion:
skin
fold
pin
chin
g;
102
also
feet
and
lobe;
103
also
CPT
;104
only
refr
ain
from
smoki
ng
2h
bef
ore
the
sess
ion;
105
Forg
ione–
Bar
ber
pre
ssure
afte
ris
om
etric
exer
cise
;106
caff
eine
and
phys
ical
exer
cise
;107
also
pre
ssure
pai
n(n
ot
exam
ined
);108
four
puls
esper
seco
nd,
each
puls
ew
ith
adura
tion
of
50
ms;
109
refr
ain
from
vigoro
us
phys
ical
activi
ty,
drinki
ng
tea
or
coff
ee,
smoki
ng,
and
hav
ing
larg
em
eals
during
the
last
4h
bef
ore
.A
lcoholw
asnot
allo
wed
the
last
12
hbef
ore
the
exper
imen
t.C
PT,
Cold
Pres
sor
Task
;El
ect,
elec
trocu
taneo
us
stim
ula
tion;
ES,
effe
ctsi
ze;
Extr
a,ex
trac
uta
neo
us;
FH�
,w
ithout
afa
mily
his
tory
of
hyp
erte
nsi
on;
FHþ
,w
ith
afa
mily
his
tory
of
hyp
erte
nsi
on;
Hyp
er,
hyp
erte
nsi
vepat
ients
;H
ypo,
hyp
ote
nsi
vepat
ients
;In
tra,
intr
acuta
neo
us;
Isch
em,
isch
emic
;M
A,
met
a-an
alys
is;
MA
P,m
ean
arte
rial
pre
ssure
;M
PQ,
McG
illPa
inQ
ues
tionnai
re;
NFR
,N
oci
ceptive
Flex
ion
Ref
lex;
Norm
o,
norm
ote
nsi
ves;
NRS,
Num
eric
Rat
ing
Scal
e;Rea
ct,
Rea
ctiv
ity;
VA
S,V
isual
Anal
og
Scal
e,V
RS,
Ver
bal
Rat
ing
Scal
e.
Meta-analysis on BP-related hypoalgesia
Journal of Hypertension www.jhypertension.com 7
CE: Tripti; JH-D-20-00007; Total nos of Pages: 16;
JH-D-20-00007
Makovac et al.
calculate effect sizes and instead provided statistics (e.g. r,t), we applied transformation formulas to convert to g [56].When an article reported P less than 0.05 or nonsignificant,we relied on a highly conservative estimate of the effect sizeand computed Hedges’ g with P-values of 0.045 and 1 (one-tailed), respectively.
When the standard deviation (SD) of the changes wasnot provided, we imputed a change-from-baseline SD usinga correlation coefficient as indicated by Higgins and Green:SDchange¼H[SD2baselineþ SD2final� (2 �Corr � SDbaseline �SDfinal)] [57]. When only standard errors (SE) were pro-vided, standard deviations were obtained by applying thefollowing formula SD¼ SE �Hn [57].
Cochran’s Q and I2 statistics were used to assess hetero-geneity between studies. A statistically significant Q valuerejects the null hypothesis of homogeneity of findingsamong studies, indicating that systematic differencesmay potentially influence the results. I2 values of 25, 50,and 75% reflect low, moderate, and high heterogeneity,respectively.
The problem of publication bias or ‘file-drawer effect’(i.e. the existence of unpublished studies with null results)was estimated informally by inspecting the funnel plot ofeffect size against standard error for asymmetry and for-mally by using Begg and Mazumdar’s rank correlations, andEgger’s regression intercept test. We did not rely on thepopular failsafe N as it has been considered a problematicmethod to assess publication bias [58].
We first run the analyses including the entire set ofstudies and then subsequently re-run them without somepotential outliers, identified based on having statisticallysignificant standardized residuals [59]. Statistics reported inthe present meta-analysis conform to the Preferred Report-ing Items for Systematic Reviews and Meta-Analyses(PRISMA) statement (see supplemental material for PRISMAchecklist, http://links.lww.com/HJH/B298) [60].
Moderator analysisFor each outcome, we examined how the size of theassociation varied as a function of sex (% of women), meanage (years), experimental sample (hypertensive patients,normotensives, at risk), pain type (CPT; electrical, ischemic,thermal, other), painful stimulus duration (min), site ofstimulation (arm/hand, foot/leg, sural nerve, tooth/mouth),pain assessment (NFR, EEG, wind-up/threshold, tolerance,VAS/NRS/VRS, McGill Pain Questionnaire), device to assessBP (beat-to-beat versus noncontinuous), protocol to assessBP (rest, reactivity, 24 h), and adjustment for potentialconfounders (yes, no).
First, sex was examined as a moderator, in light ofreported prominent sex differences in the associationbetween pain and cardiovascular activity [61] and in theprevalence of BP-related hypoalgesia [62]. Moreover, prom-inent sex differences have been reported in pain percep-tion, namely compared with men, women report more painand have a lower pain threshold and tolerance to experi-mental pain stimuli [63–65].
BP-related hypoalgesia appears to be independent ofage, as there is evidence of reduced pain perception ofoffspring of hypertensive patients even in newborns [66].
8 www.jhypertension.com
However, age was examined as a moderator because of itsknown influence on pain perception [67,68].
Third, we wanted to test whether BP-related hypoalgesiais more pronounced in individuals at risk for hypertension(i.e. with borderline hypertension, or family history ofhypertension) or with a formal diagnosis of hypertensioncompared with normotensives. We did so because on onehand, hypoalgesia can be induced in normotensive indi-viduals by experimentally increasing BP [4], and on theother hand, because the putative mechanisms implicated inBP-related hypoalgesia are impaired both in hypertensiveindividuals and in those who are at risk to develop hyper-tension [69]. Importantly, all studies conducted on hyper-tensive individuals either required participants todiscontinue drug treatment for at least 2 weeks beforethe experimental session or recruited unmedicatedhypertensive individuals.
Fourth, we examined if specific types of pain inductionwould evoke more pronounced BP-hypoalgesia; for exam-ple, intracutaneous electrical stimulation is considered themost appropriate stimulus, as it is less likely to recruitnonpain fibers [70].
Fifth, painful stimulus duration was examined as apotential moderator of the association between BP andpain perception, given that longer versus brief painfulstimulus duration may differently stimulate endogenousopioid responses [71].
Similarly, whereas baroreceptor functioning is thoughtto play a role in the association between transient phasic BPincreases (spontaneous or induced) and hypoalgesia, otherkey variables may play a role in the association betweentonic BP and pain perception, such as neurovascular alter-ations impairing nociceptive transmission in stable hyper-tension [72]. Thus, to better understand thepathophysiological mechanism underlying BP-relatedhypoalgesia, the moderating role of BP assessment (i.e.24-h, tonic or phasic) was also considered.
Lastly, in order to inform future studies on the best wayto elicit BP-related hypoalgesia, body site of pain stimula-tion, pain assessment, and adjustment for potential con-founders were examined as covariates.
A minimum of five studies for each subgroup wasrequired for the moderation analysis. Stimulus duration(continuous moderator) was evaluated using meta-regres-sion, whereas categorical moderators (prevalence ofwomen, experimental sample, pain type, site of stimulation,pain assessment, device to assess BP, protocol to assess BP,and adjustment for potential confounders) were entered asgrouping variables in the effect size calculations.
RESULTSTable 1 discloses the specific contrasts that were used toextract effect sizes in the present meta-analyses. Studiesmarked with an asterisk in the table and figures indicatepotential outliers. Given the small number of studiesassessing DBP in association with pain sensitivity[25,47,50], the present meta-analyses focus on SBP only.For this reason, from now on, the acronym BP will be usedto refer to SBP.
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FIGURE 2 Forest plot for meta-analysis on the association between blood pressure and physiological nociceptive response.
Meta-analysis on BP-related hypoalgesia
Nociceptive responseThe meta-analysis of six studies (555 adults) between BP andphysiological nociceptive response yielded a statisticallysignificant negative association. As depicted in Fig. 2, theoverall effect size for all included studies was low, g¼ 0.38,95% confidence interval (95% CI 0.13–0.64), P¼ 0.003. Testsof homogeneity reflected relatively low heterogeneity,Q¼ 10.25, P¼ 0.069; I2¼ 51.2. Publication bias was notdetected by the funnel plot, Egger’s test (intercept¼ 1.17,t¼0.54, P¼ 0.062), or Kendall’s tau (Z¼ 0.56; P¼ 0.57).
Exclusion of a potential outlier [4] significantlyincreased the effect size (g¼ 0.51, 95% CI 0.31–0.71,P< 0.0001) and reduced heterogeneity (Q¼ 2.93,P¼ 0.57; I2¼ 0), without affecting the presence of publi-cation bias. Moderation analysis could not be performedbecause of the inadequate number of studies in this meta-analysis.
Quantifiable perceptual measures of painAnalysis of 61 studies (11 126 participants) showed a sig-nificant association between high BP and diminished painperception (g¼ 0.48, 95% CI 0.40–0.57, P< 0.0001), whichwas medium in size. Figure 3 shows the forest plot. Signifi-cant heterogeneity was shown by the Q and I2 statistics,Q (58)¼ 149.1, P< 0.0001; I2¼ 59.8. Evidence of publica-tion bias was detected by an asymmetrical funnel plot (seeFig. 4). The bias was confirmed by Egger’s regression test(intercept¼ 1.27, t¼5.90, P< 0.0001) but not by Kendall’stau (Z¼ 0.76; P¼ 0.45).
Exclusion of extreme outliers [39,51,106] neither changedthe effect size (g¼ 0.47, 95% CI 0.39–0.55, P< 0.0001) norheterogeneity, Q (55) ¼ 117.8; P< 0.0001; I2¼ 51.6.
Results of moderation analysis for quantifiableperceptual measures of painAs shown in Table 2, contrasting studies having a preva-lence of women (�60%) with studies having less than 60%of women in the sample yielded a significant difference,Q (1)¼ 4.89, P¼ 0.03, with the latter being more strongly
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associated with perceptual measures of pain (g¼ 0.55,k¼ 16, n¼ 715 versus g¼ 0.33, k¼ 28, n¼ 9239). Onlythe second set of studies presented significant heterogene-ity, Q (26)¼ 46.1, P¼ 0.01; I2¼ 43.6.
The type of BP assessment emerged as a marginallysignificant moderator, Q (2)¼ 5.40, P¼ 0.06, with studiesthat used 24-h BP assessment (g¼ 0.61, k¼ 12, n¼ 1049) orBP recorded during the painful stimulation (g¼ 0.58,k¼ 11, n¼ 442) being characterized by a stronger associa-tion compared with studies assessing resting BP (g¼ 0.41,k¼ 36, n¼ 9580). It has to be noted that only studiesassessing resting BP showed substantial heterogeneity,Q (35)¼ 90.1; P< 0.0001; I2¼ 61.2.
Studies assessing threshold or tolerance assessmentproduced a higher overall effect size (g¼ 0.56, k¼ 31,n¼ 2182) than studies using VAS, NRS, VRS, or McGill PainQuestionnaire (g¼ 0.38, k¼ 27, n¼ 8764; Q (1)¼ 3.89;P¼ 0.04, with both sets of studies being characterized bysignificant heterogeneity (Q (29)¼ 55.5; P¼ 0.002; I2¼ 47.7and Q (26)¼ 56.9; P< 0.0001; I2¼ 54.4, respectively).
Site of pain stimulation was a marginally significantmoderator of the association between BP and pain percep-tion (Q (3)¼ 8.20; P¼ 0.06), with studies targeting the suralnerve yielding a small effect size and no heterogeneity(g¼ 0.30, k¼ 6, n¼ 574; Q (4)¼ 4.99; P¼ 0.42; I2¼ 0),studies targeting the hand/foot having a small-to-mediumeffect size and moderate heterogeneity (g¼ 0.404, k¼ 21,n¼ 8155; Q (20)¼ 37.96; P¼ 0.01; I2¼ 47.3), and studiestargeting the arm/leg or the mouth/teeth showing mediumeffect size and significant heterogeneity (g¼ 0.56, k¼ 22,n¼ 1117; Q (21)¼ 53.4; P< 0.0001; I2¼ 60.7 and g¼ 0.53,k¼ 9, n¼ 1165; Q (8)¼ 19.9; P¼ 0.01; I2¼ 59.8).
Lastly, mean effect size was lower in studies that did notcontrol for potential confounders (g¼ 0.65, k¼ 21,n¼ 8209) compared with those that did control (g¼ 0.42,k¼ 38, n¼ 2862); Q (1)¼ 4.40; P¼ 0.03 with only the firstset of studies being characterized by significant heteroge-neity; Q (20)¼ 84.8; P< 0.0001; I2¼ 76.4.
Age, BP device, and pain type did not moderate theassociation between BP and pain perception. Meta-
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FIGURE 3 Forest plot for meta-analysis on the association between blood pressure and quantifiable perceptual measures of pain.
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regression analysis did not show any significant role ofpainful stimulus duration as moderator.
Overall, results did not change when extreme outliers[39,51,106] were excluded from the analysis, with the fol-lowingexceptions: after the exclusion, typeofBPassessmentbecamesignificant as amoderator of the associationbetweenBP and pain perception, Q (2)¼ 7.16; P¼ 0.03, whereasadjustment for potential confounders was no longer a signif-icant moderator of such association, Q (1)¼ 2.84; P¼ 0.092.
DISCUSSIONOver the past decades, many experimental studies, con-ducted both in animals and humans, have investigated thephenomenon of BP-related hypoalgesia. Most of these
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studies have shown a positive association, but some failedto replicate the effect. This is the first systematicmeta-analysisperformed on the topic, which also aimed at considering thedistinctive effects of high BP on nociceptive and perceptualcomponents of the pain response. Results confirmed theexistence of a significant association between BP and painperception in the expected direction, that is, diminished painperception in the presence of elevated BP. When the full setof studies was examined, the size of the effect was small fornociceptive response and becamemediumafter exclusionofpotential outliers. In the case of quantifiable perceptualmeasures of pain, the size of the effect was medium.
Despite measuring an inherently different phenomenon,both meta-analyses suggest a significant associationbetween BP and pain responses. However, the meta-
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FIGURE 4 Funnel plot for meta-analysis on the association between blood pressure and quantifiable perceptual measures of pain.
Meta-analysis on BP-related hypoalgesia
analysis conducted on quantifiable perceptual measures ofpain was characterized by significant heterogeneity and thepresence of publication bias, pointing to the possibility ofsystematic errors.
By performing additional moderation analysis, we alsotried to characterize the association between BP and painresponses by considering both the features of the sampleand the methodology used to assess BP and pain. Unfortu-nately, studies examining nociception did not meet therequirements to be included in subgroup analyses, as theywere quite limited (k¼ 6); instead, we were able to performmoderation analysis for studies examining quantifiableperceptual measures of pain. Results showed larger effectsin studies that had a prevalence of female individuals in thesample; assessed pain threshold or tolerance (comparedwith those using VAS, NRS, VRS, or McGill Pain Question-naire), assessed 24-h ambulatory BP (compared with rest-ing or pain-related BP increases in the laboratory), providedpainful stimuli over the arm/leg or the mouth/teeth (com-pared with the hand/foot or the sural nerve), and did notstatistically adjust for potential confounders.
As expected in light of existing studies detecting sexdifferences in BP-related hypoalgesia [61], the inverse asso-ciation between BP and perceptual measures of pain waslarger in studies that had a prevalence of women in thesample. It has to be noted, however, that this is not acompletely predictable result, as some studies arose doubtson the generalizability of BP-related hypoalgesia in women.For example, it has been observed that whereas in men atrisk for hypertension the pain sensation following the coldpressor task decreased more rapidly compared with menwithout a family history of hypertension, in women at riskthere was a tendency to report higher pain compared withwomen who did not carry a risk for hypertension [61].
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The best way to assess pain perception is a matter ofdebate and goes beyond the scope of the present work.However, pain threshold and tolerance (with the majorityassessing threshold) and measures of pain intensityappeared to be quantifiable ways to capture the perceptualcomponents of BP-related hypoalgesia compared with self-report on the unpleasantness of pain. Our result is consis-tent with previous work where higher self-reported painsensitivity was associated with higher anxiety but not withsubjects’ actual pain threshold or tolerance [117].
Studies using 24-h ambulatory BP assessment as well asstudies assessing BP responses in the laboratory, yieldedlarger BP–pain perception associations compared with stud-ies relying on resting BP. This result can be explained by thefact that whereas spontaneous or induced transient phasicBP increases are recognized to be linked with baroreceptorfunctioning, when tonic BP is examined, other key variablesmay play a role, for example, neurovascular alterationsimpairing nociceptive transmission in stable hypertension,particularly with comorbid diabetes [72].
Studies stimulating the sural nerveyielded the smallereffectsizes compared with studies stimulating other body regions,such as the arm/leg or the mouth/teeth. However, it has to benoted that only six studies stimulated the sural nerve, and thiswas the only set of studies that was not characterized bysignificant heterogeneity. For these reasons, this moderationanalysis does not provide conclusive evidence against the useof sural nerve stimulation in future studies.
Lastly, BP-related hypoalgesia appears to be less pro-nounced when factors that influence both pain and BP aretaken into account, such as nicotine, caffeine, analgesics,chocolate, alcohol, and strenuous physical exercise. How-ever, although effect sizes were larger in studies that did notcontrol for such covariates, a significant inverse relation
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TABLE 2. Association between blood pressure and quantifiable perceptual measures of pain in different subgroups
Random-effects model Heterogeneity Test of difference
k N g (95% CI) Q I2 Q
58 10 969 0.48 (0.39–0.57)�� 144.4�� 60.5
Percent of women 4.89�
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