bloodpressure-relatedhypoalgesia:asystematic reviewandmeta … · 2021. 2. 1. · ce: tripti;...

CE: Tripti; JH-D-20-00007; Total nos of Pages: 16;

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: [email protected]

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


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



JH-D-20-00007

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4 www.jhypertension.com Volume 38 � Number 1 � Month 2020


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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)


Journal of Hypertension www.jhypertension.com 5


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


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.


Journal of Hypertension www.jhypertension.com 7


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].


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.


http://links.lww.com/HJH/B298


JH-D-20-00007

FIGURE 2 Forest plot for meta-analysis on the association between blood pressure and physiological nociceptive response.


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


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.

Makovac et al.

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


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.


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].


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�

bloodpressure-relatedhypoalgesia:asystematic reviewandmeta … · 2021. 2. 1. · ce: tripti;...

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