Efficacy of hypertonic dextrose infiltrations for pain

THE OffiCiAL JOURnAL Of THE PORTUGUESE SOCiETY Of RHEUMATOLOGY

156

ORiGinAL ARTiCLESREViEw ARTiCLES

1. División Académica Multidisciplinaria de Comalcalco, Comalcalco,

Tabasco, México; Universidad Juárez Autónoma de Tabasco

2. Centro Médico Olympia, Cancún, México

3. Universidad Juárez Autónoma de Tabasco, División Académica

de Ciencias de la Salud, Villahermosa, Tabasco, México; División

Académica Multidisciplinaria de Jalpa de Méndez, Jalpa de

Méndez, Tabasco, México

4. Hospital General de Yajalón, Secretaría de Salud. Yajalón,

Chiapas, México

5. División Académica de Ciencias de la Salud, Villahermosa,

Tabasco, México; Universidad Juárez Autónoma de Tabasco;

6. Universidad Autónoma de Yucatán, Mérida Yucatán, México

rious adverse events were observed when HDI wereused. Conclusions. We found that HDI reduced long termpain in individuals with rotator cuff. HDI could be analternative to non-invasive treatments when no favor-able results can be achieved. However, due to the smallnumber of studies included in this meta-analysis, newstudies are necessary to clarify the efficacy and safety ofthis intervention.

Keywords: Hypertonic dextrose; Prolotherapy; Infil-trations; Shoulder; Cuff rotator.

INTRODUCTION

The pathology of the rotator cuff has been consideredas the main cause of pain and disability of the shoulder1.The prevalence of injuries of the rotator cuff tendonsranges from 6% to 30%, increasing progressively withage1. For the treatment of this pathology conservativemodalities are commonly used including anti-inflam-matory drugs2, physical therapeutic modalities (3), ex-ercise programs (4), intra-articular and subacromial in-filtrations5, 6 and surgical procedures7, 8.

Regarding the different infiltration treatments, themost widely used is the application of corticosteroids5.Other infiltrations include the use of plasma rich inplatelets (PRP)5,6,9, hyaluronic acid5, 10, hypertonic dex-trose5, 6, botulinum toxin5, mesenchymal cells of bonemarrow6, 11 and a mixture of oxygen - medicinal ozone12.

On the other hand, injection therapy with sclerosingagents or irritant substances has been used for decadesas a complementary treatment for chronic muscu-loskeletal conditions. Dr. George Hackett defined theterm prolotherapy in the 1950s13, 14; this term involvesinjections of a solution with sclerosing agents or irri-

Efficacy of hypertonic dextrose infiltrations for pain control in rotator cuff tendinopathy:

systematic review and meta-analysis

Arias-Vázquez PI1, Tovilla-Zárate CA1, González-Graniel K1, Burad-Fonz W2, González-Castro TB3, López-Narváez ML4, Castillo-Avila RG5, Arcila-Novelo R6

ACTA REUMATOL PORT. 2021;46:156-170

ABSTRACT

Introduction.Our study aimed to assess the efficacy ofhypertonic dextrose infiltrations (HDI) for pain controlin individuals with rotator cuff tendinopathy and to as-sess the characteristics of the treatment and the pre -sence of side effects or adverse reactions through a sys-tematic review and meta-analysis. Methods. The search for the articles was performed inthe electronic databases PUBMED, EMBASE, SCOPUS,SCIELO, DIALNET and Google Scholar, published up toAugust 2020. The keywords used were "prolotherapy" or“proliferation therapy” or "hypertonic dextrose infiltra-tions" or "hypertonic dextrose injection" and "RotatorCuff" or "Rotator Cuff Injury" or “Rotator Cuff Tear” or“Rotator Cuff Tendinosis” or "supraspinatus". The effec-tiveness of HDI was expressed as standardized mean dif-ference (d) and 95% CI. Results. In the pooled analysis, HDI were an effectiveintervention to reduce long-term pain in patients withrotator cuff tendinopathy when compared to controls;furthermore, in the individual analyses, HDI were moreeffective in the short, medium and long terms than non-invasive treatments, and more effective in the long-termthan infiltrations with local anesthetics. On the otherhand, HDI were not more effective than injections withcorticosteroids or PRP. Finally, no complications or se -


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AriAs-VAzquez Pi et Al

tating properties in the ligament-bone or tendon-boneareas or the intra-articular space, performed repeated-ly at established intervals13, 14. The most common pro-lotherapy agent used in the clinical practice is the hy-pertonic dextrose solution at concentrations rangingfrom 12.5% to 25%, applied as intra-articular and/orextra-articular infiltrations on ligament and tendon in-sertions, to favor the repair processes of the affectedtissues13, 14. Hypertonic dextrose prolotherapy has beenreported to be effective for treating knee osteoarthritiswhere it has been reported to be more effective than in-filtrations with local anesthetics, as effective as infil-trations with hyaluronic acid, ozone or radiofrequen-cy, and less effective than PRP without side effects15.When used for treating tendinopathies of the lowerlimb it has been reported to be a safe and effective treat-ment for Achilles tendinopathy, plantar fasciitis andOsgood-Schlatter disease16, 17. When hypertonic dex-trose has been used for treating upper limb pathologiessuch as hand osteoarthritis, lateral epicondylitis androtator cuff disease, clinical studies have reported pos-itive results without side effects17, 18. However, HDI re-mains a controversial therapy for treating rotator cufftendinopathy and it is classified as a complementarytherapy. Therefore, the objective of our study was toperform a systematic search of clinical studies that usedHDI in patients with rotator cuff pathology, to analyzeits efficacy in pain control, the characteristics of thetreatment and the presence of side effects or adverse re-actions through a meta-analysis.

MeTHODOLOGy

The methodology used was based on the Preferred Re-porting Items for Systematic Reviews and Meta-Ana -lyses (PRISMA) guidelines19 for the presentation of sys-tematic review and meta-analysis.

MeTHODS AND SeARCH STRATeGy

Articles of interest were identified in electronicdatabases using a search period up to August 2020.The databases used were PUBMED, EMBASE, SCO-PUS, SCIELO, DIALNET and gray literature as GoogleScholar. The search terminology included the MESHterms (and entry terms) "prolotherapy" or “prolifera-tion therapy” or "hypertonic dextrose infiltrations" or"hypertonic dextrose injection" and "rotator cuff" or"rotator cuff injury" or “rotator cuff tear” or “rotatorcuff tendinosis” or "supraspinatus", as well as multiple

combinations between these terms. The search of eligible studies was performed with-

out language restrictions. After searching in thedatabases above mentioned, a hand search of the ref-erence list in the articles and reviews was conducted tofind additional eligible studies.

TypeS Of STUDIeS

This review included randomized controlled trials(RCTs) and observational studies (cases-controls, se-ries of cases) that used HDI as a therapeutic interven-tion for the treatment of pain in individuals with rota-tor cuff tendinopathy. In the RCTs HDI were comparedagainst physiotherapy, exercise programs or againstother infiltrations (placebo or other therapeutic sub-stances). We excluded reviews, one-case reports, stud-ies of shoulder pathologies other than rotator cufftendinopathy or unspecified pathologies. The studiesselected had to describe in detail the interventions car-ried out, forms of evaluation and their results.

pARTICIpANTS

The selected studies included patients with rotator cufftendinopathy and met the following criteria:• Adults of at least 18 years of age.• Clinical and imaging (ultrasonography or magnetic re -

sonance imaging) diagnosis of rotator cuff tendinopa-thy (tendinosis, partial tear or full-thickness tear).

• Presence of pain and functional alterations of morethan 3 months of evolution.

• Participants treated with HDI and compared withother interventions.

Type Of INTeRveNTIONS

The selected studies included patients with rotator cufftendinopathy who were treated with HDI and com-pared with other interventions.

The criteria for the type of interventions used in thepatients of study groups were:• One or more treatment sessions with HDI (at a con-

centration greater than 10%).• The infiltrations applied in the rotator cuff tendons

insertion and/or intratendinous application in thefocal area in case of rupture and/or in subacromialor intra-articular space.

• The infiltrations performed following the anatomi-cal technique or under ultrasound guidance.

• Patients in the control groups were treated withphysiotherapy, exercise programs or infiltrations ofother substances.


158

HyPertonic dextrose infiltrAtion in rotAtor cuff tendinoPAtHy

• Co-interventions were allowed as long as they wereuniform in all groups.

evALUATION Of THe RISk Of BIAS AND THe

MeTHODOLOGICAL qUALITy Of THe INCLUDeD

STUDIeS

Two researchers independently assessed the metho -dological quality and risk of bias of each included study.The evaluation of the clinical trials was based on theCochrane Handbook for Systematic Reviews recom-mendations, version 5.120. The assessment of the riskof bias in non-randomized observational studies wasperformed using the ROBINS-I tool21. The rating of thele vel of evidence for therapeutic studies was deter-mined for each study using the scale of the AmericanSociety of Surgeons22.

evALUATION Of eLIGIBILITy AND DATA exTRACTION

Two researchers independently examined titles, abs -tracts and full texts, then determined the eligibility ofeach study. Disagreements were solved by consensusthrough the opinion of a third researcher. For eligiblestudies, data were extracted independently and in-cluded: study design, risk of bias, clinical configura-tion, characteristics of the participants, characteristicsof the interventions, results, duration of follow-up andadverse events.

The efficacy of HDI in pain control was establishedas the primary endpoint. Pain control was measuredby the visual analog scale (VAS) and was inclu ded in thequantitative analysis.

The evaluation of the improvement in function, thecharacteristics of the treatment and the adverse effects wereestablished as secondary endpoints and were des cribedin the qualitative analysis according to the data providedin the included studies. Improvement in function wasmeasured in terms of validated function scales such asShoulder Pain and Disability Index (SPADI), AmericanShoulder and Elbow Surgeons Standardized (ASES) andDisability of Arm and Shoulder Score (DASH).

The follow-up time was evaluated in the short (≤ 6weeks), medium (12 weeks) and long terms (≤ 24weeks).

STATISTICAL ANALySIS

For the evaluation of RCTs, studies were grouped ac-cording to the follow-up time. The effectiveness of HDIin control pain were expressed as standardized meandifference (d) and 95% CI. The standardized mean dif-ference was calculated comparing the study group ver-

sus (vs.) the comparison group. Heterogeneity acrossstudies was measured using Q statistic and inconsis-tence index I2. When p (Q) was <0.10, the presence ofheterogeneity was considered. When I2 > 50% largeheterogeneity was determined; when I2 = 25-50%moderate heteroge neity was considered, and when I2< 25% absence of heterogeneity was determined. Thepublication bias was evaluated by Begg’s funnel plotsgraphically and Egger’s test quantitatively. For Begg’sfunnel plots an asymmetry was considered as a signif-icant presence of bias. For the Egger's test, the signifi-cance was fixed as p <0.05. The meta-analysis was per-formed using EPIDAT 3.1 Software.

To evaluate the characteristics of the treatment andadverse effects, they were summarized in descriptivemeasures, according to the data provided in the in-cluded studies.

ReSULTS

A total of 116 citations were identified and 63 dupli-cates were excluded. Titles and abstracts of the re-maining 53 studies were read; then, 24 studies thatcontained animal models, other tendinopathies, edito-rials, comments and others were also excluded. Of the29 remaining studies, 21 were additionally excludedfor the following reasons: review studies (n = 16), stu -dies of shoulder pathologies other than rotator cufftendinopathy (n = 3), as well as one-case reports (n = 2). Finally, six clinical trials (23-28) and two obser-vational studies29,30 were eligible for inclusion in thissystematic review. The flowchart of the systematizedsearch is shown in Figure 1.

The final six RCTs selected included 157 indivi dualswith rotator cuff tendinopathy treated with HDI, per-formed in the tendon insertion area or in the focal areaof rupture of the rotator cuff tendons and/or in sub-acromial or intra-articular space, while 236 controlswere treated with exercise programs or infiltrationswith corticosteroids, lidocaine, platelet-rich plasma orsaline solution. Regarding the observational studies, 78individuals with rotator cuff tendinopathy were trea tedwith HDI performed with the same characteristics, using 53 controls.

Of the RCTs included in the qualitative analysis, twostudies showed a low risk of bias23, 26, three had amodera te risk of bias24,25,27 and one of them showed ahigh risk of bias28. The two observational studies in-cluded in the qualitative analysis showed a moderate


159


fIGURe 1. Flow diagram of the systematic review

risk of bias29,30. Only RCTs with low or moderate riskof bias were included in our quantitative analysis. Thedesign characteristics and the risk of bias assessment ofthe included studies are summarized in Table I, Figure2 and Figure 3.

In the five RCTs included in the quantitative analy-sis23-27, all the groups studied were treated uniformlywith an exercise program as a co-intervention. Simi-larly, in these studies the use of NSAIDs during treat-ment or follow-up was restricted; the use of analgesicssuch as acetaminophen or tramadol was allowed in caseof post-infiltration pain.

The characteristics of the intervention and results ofeach study included are reported in Table II and III.

MeTA-ANALySIS Of THe effICACy Of

INfILTRATIONS wITH HypeRTONIC DexTROSe

fOR pAIN CONTROL IN ROTATOR CUff pATHOLOGy

In the five clinical trials included in this meta-analy-sis23-27, the treatment with HDI was compared with other interventions such as infiltration with local anes-thetics23,27, exercise programs24, infiltration with corti-costeroids25, 27, infiltration with saline solution26 and infiltrations with platelet-rich plasma27. The meta-anal-ysis was performed by time of follow-up and expressedit in terms of standardized mean difference.

Short–term follow-up: In the pooled analysis, no sta-tistically significant difference in pain reduction wasfound when comparing HDI vs. controls (d = -0.045,


160


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fIGURe 2. Risk of bias graph of the clinical trials included in the systematic review

fIGURe 3. Risk of bias assessment of the observational studiesincluded in the systematic review

when compared with exercise programs. Similarly, inthe study by Cole et al.25 a mean difference was foundin favor of the HDI group when compared with corti-costeroid infiltrations. On the other hand, in the studyby Sari et al.27, the mean difference was in favor of cor-ticosteroid infiltrations (Figure 4A).

Medium–term follow-up: In the pooled analysis, nostatistically significant difference in pain reduction wasfound when comparing HDI vs. controls (d = -0.009,95% CI -0.448 to 0.430, p(z)>0.968, I2=80.32). In in-dividual analyses, responses similar to those found inshort–terms were observed. In the Seven et al.24 andCole et al.25 studies, the mean differences were foundin favor of the HDI groups, while in the study by Sariet al.27 the observations were in favor of the group whoreceived corticosteroid infiltrations (Figure 4B).

Long–term follow-up: In the pooled analysis, the re-sults showed that HDI had a significant effect on re-ducing pain in individuals with rotator cuff pathology(d = -2.810, 95% CI -4.468 to -1.153, p <0.001,I2=97.86). In individual analyses, the mean differencewas found in favor of the groups that used HDI in thestudies of Seven et al.24 and Bertrand et al.23. None of thestudies found a mean difference that favored the con-trol groups (Figure 4C).

95% CI -0.712 to 0.622, p (z)>0.896, I2=89.22). How-ever, in individual analyses, statistically significant dif-ferences were found: in the study by Seven et al.24, amean difference was found in favor of the HDI group


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low

-up.

inflam

mat

ion

rota

tor

cuff, u

nde

r ult

raso

und

guid

ance

+ p

roto

col of

an

d hyp

oten

sion

ex

erci

se a

t hom

e.oc

curr

ed.

EX

GR

OU

P: 6

0 pa

tien

ts, a

vera

ge a

ge 4

6.3

year

s,

No

seve

re a

dver

setr

eate

d w

ith e

xerc

ise

prog

ram

.re

acti

ons

wer

e re

port

ed

in a

ny

pati

ent.

Col

e et

al.

(25)

DX

GR

OU

P: 1

7 pa

tien

ts, a

vera

ge a

ge 5

1 ye

ars,

tre

ated

Pai

n w

as a

sses

sed

when

per

form

ing

acti

viti

es a

bove

It

is

not

men

tion

ed if

wit

h a

n inje

ctio

n in t

he

hyp

oech

oic

or a

nec

hoi

c ar

eas

the

hea

d w

ith a

num

eric

al s

cale

fro

m 0

to

4, a

t 6,

12th

ere

wer

e si

de e

ffec

ts o

r of

the

supr

aspi

nat

us

tendo

n (

one

inje

ctio

n),

unde

r an

d 24

wee

ks o

f fo

llow

-up.

adve

rse

reac

tion

s in

ult

raso

und

guid

ance

, at

a ra

te o

f 0.

5ml pe

r zo

ne,

of

pati

ents

.a

25%

dex

tros

e so

luti

on +

exe

rcis

e pr

ogra

m.

CT

GR

OU

P :

19 p

atie

nts

, ave

rage

age

46

year

s, t

reat

ed

wit

h a

n infilt

rati

on in t

he

suba

crom

ial bu

rsa

adja

cent

to t

he

supr

aspi

nat

us

tendo

n, u

nde

r ult

raso

und

guid

ance

, of 2m

l of

a c

ombi

nat

ion o

f 40

mg

of

met

hyl

pred

nis

olon

e ac

etat

e an

d 1%

lid

ocai

ne

+ ex

erci

se p

rogr

am.

cont

inue

s on

the

nex

t pa

ge

VA

S D

X A

LD

A

LS

Bas

al7.

3 (0

.4)

6.9

(0.5

)6.

9(0.

4)

12 w

eeks

-3

.0(0

.51)

-2.7

(0.7

)-

2.7(

0.6)

36

wee

ks-2

.9(0

.6)

-1.8

(0.7

)-1

.3(0

.6)

VA

S D

XE

XBas

al7.

85 (

1.29

)7.

36 (

1.38

)6

wee

ks3.

35 (

1.67

)4.

39(1

.92)

12 w

eeks

2.35

(1.

98)

4.00

(2.

11)

48 w

eeks

0.89

(1.

64)

3.77

(2.1

2)

SPA

DI

DX

EX

Bas

al74

.76(

18.5

4)68

.62

(20.

4)

6 w

eeks

31.3

0(14

.19)

41.9

7(16

.42)

12 w

eeks

16.1

2(12

.82)

37.2

5(20

.32)

48 w

eeks

7.66

(10.

68)

34.9

4(19

.14)

PAIN

DX

CT

Bas

al2.

3(0.

2)2.

6(0.

2)6

wee

ks

2.1

(0.2

)2.

4(0.

2)12

wee

ks.9

(0.2

)2.

1 (0

.3)

24 w

eeks

1.7(

0.2)

1.7(

0.3)


163

AriAs-VAzquez Pi et AlTA

BLe

II. C

ON

TIN

UA

TIO

N

Stu

dy

Inte

rven

tion

Eva

luat

ion

s an

d r

esu

lts

Sid

e ef

fect

sLin

et

al. (

26)

DX

GR

OU

P: 1

6 pa

tien

ts, a

vera

ge a

ge 4

6.2

year

s,

Pai

n w

as e

valu

ated

wit

h V

AS

and

SPA

DI, a

t th

e M

inor

adv

erse

rea

ctio

ns

trea

ted

wit

h a

n inje

ctio

n o

f 5m

l of

20%

dex

tros

e in

be

ginnin

g, 2

and

6 w

eeks

of fo

llow

-up.

occu

rred

.th

e ar

ea o

f su

pras

pinat

us

inse

rtio

n, u

nde

r ult

raso

und

No

seve

re a

dver

se

guid

ance

, + e

xerc

ise

prog

ram

.re

acti

ons

wer

e re

port

ed

SS G

RO

UP: 1

5 pa

tien

ts, a

vera

ge a

ge 4

8.6

year

s,

in a

ny

pati

ent.

trea

ted

wit

h a

n infilt

rati

on o

f sa

line

solu

tion

(SS

) in

th

e ar

eas

of s

upr

aspi

nat

us

inse

rtio

n, u

nde

r ult

raso

und

guid

ance

, + e

xerc

ise

prog

ram

.

Sari

et

al. (

27)

DX

GR

OU

P: 3

0 pa

tien

ts, a

vera

ge a

ge 5

2.1

year

s,

Pai

n a

nd

Funct

ional

ity

was

eva

luat

ed w

ith V

AS

and

It is

not

men

tion

ed if

trea

ted

wit

h o

ne

suba

crom

ial in

ject

ion w

ith 5

ml.

of

ASE

S sc

ale

at t

he

begi

nnin

g an

d at

3,1

2,24

wee

ksth

ere

wer

e si

de e

ffec

ts o

r 20

% d

extr

ose

unde

r ult

raso

und

guid

ance

+ p

roto

col

of fol

low

-up:

adve

rse

reac

tion

s in

the

of e

xerc

ise.

pati

ents

tre

ated

.PR

P G

RO

UP: 3

0 pa

tien

ts, a

vera

ge a

ge 5

2.1

year

s,

trea

ted

wit

h o

ne

suba

crom

ial in

ject

ion w

ith 5

ml.

of

plat

elet

-ric

h p

lasm

a unde

r ult

raso

und

guid

ance

+

prot

ocol

of ex

erci

se.

CT

GR

OU

P: 3

0 pa

tien

ts, a

vera

ge a

ge 5

2.1

year

s,

trea

ted

wit

h o

ne

suba

crom

ial in

ject

ion w

ith 5

ml.

of

tria

mci

nol

one

acet

ónid

e (4

0mg)

unde

r ult

raso

und

guid

ance

+ p

roto

col of

exe

rcis

e.A

L G

RO

UP: 3

0 pa

tien

ts, a

vera

ge a

ge 5

2.1

year

s,

trea

ted

wit

h o

ne

suba

crom

ial in

ject

ion w

ith 5

ml.

of

lido

cain

e an

d so

luti

on s

alin

e unde

r ult

raso

und

guid

ance

+ p

roto

col of

exe

rcis

e at

hom

e.

cont

inue

s on

the

nex

t pa

ge

PAIN

D

XSS

Bas

al5.

56 (

0.81

)5.

33 (

0.82

) 2

wee

ks4.

63 (

0.62

)5.

21 (

0.69

)6

wee

ks5.

13(0

.72)

4.87

(0.6

4)

VA

S D

XSS

Bas

al60

.50(

7.87

)65

.00

(2.6

8)

2 w

eeks

52.6

9 (1

0.05

)62

.27(

12.8

2)

6 w

eeks

61.5

6 (4

.58)

60.0

0(4.

9)

VA

SD

XPR

PC

TA

LBas

al5.

95.

635.

635.

47(.

88)

(1)

(.93

)(.

86)

3 w

eeks

4.37

4.83

2.43

4.23

(1.1

6)(.

95)

(1.8

1)(1

.48)

12 w

eeks

4.27

3.9

3.53

3.87

(1.3

6)(.

99)

(1.4

1)(0

.97)

24 w

eeks

3.1

2.57

3.77

3.2

(1.5

2)(1

.19)

(1.4

1)(1

.19)

ASE

SD

XPR

PC

TA

LBas

al45

46.2

40.1

47.2

(9.4

)(8

.6)

(8.8

)(7

.4)

3 w

eeks

52.4

46.1

60.7

55.6

(11.

2)(7

.9)

(11.

4)(1

0.5)

12 w

eeks

56

.155

.758

.158

.8(9

.6)

(7.9

)(9

.03)

(8.8

)24

wee

ks60

.363

.855

.660

.2(1

1.4)

(11.

9)(1

1)(1

1.9)


164


TA

BLe

II. C

ON

TIN

UA

TIO

N

Stu

dy

Inte

rven

tion

Eva

luat

ion

s an

d r

esu

lts

Sid

e ef

fect

sG

eorg

e et

al.

(28)

DX

gro

up:

7 p

atie

nts

(m

ean a

ge 6

0 ye

ars)

tre

ated

wit

h

Pai

n a

nd

Funct

ional

ity

was

eva

luat

ed w

ith s

ubs

core

It

is

not

men

tion

ed if

one

dext

rose

inje

ctio

n (

at 1

2.5%

), just

in t

he

foca

l ar

eapa

in D

ASH

and

tota

l sc

ore

resp

ecti

vely

, at

ther

e w

ere

side

effec

ts o

r of

ten

dinos

is o

r ru

pture

unde

r ult

raso

und

guid

ance

.th

e be

ginnin

g an

d at

12

wee

ks o

f fo

llow

-up:

adve

rse

reac

tion

s in

the

PH

GR

OU

P: 5

pat

ients

(m

ean a

ge 5

8 ye

ars)

tre

ated

tr

eate

d pa

tien

ts.

wit

h c

onve

nti

onal

phys

ioth

erap

y.

Lee

et

al. (

29)

DX

gro

up:

57

pati

ents

; ave

rage

age

of 54

.1 y

ears

, Pai

n w

as e

valu

ated

wit

h V

AS

and

funct

ional

ity

wit

h

It is

not

men

tion

ed if

trea

ted

wit

h 4

(3

- 8)

dex

tros

e in

filt

rati

ons

(10m

l. at

SP

AD

I, b

efor

e tr

eatm

ent

and

48 w

eeks

aft

er t

he

ther

e w

ere

side

effec

ts o

r 16

.5%

) in

supr

aspi

nat

us

and

subs

capu

lar

tendo

ns,

at

appl

icat

ion o

f th

e sa

me.

adve

rse

reac

tion

s in

the

inte

rval

s ev

ery

2 -

4 w

eeks

.tr

eate

d pa

tien

ts.

CL G

roup:

53

pati

ents

, ave

rage

age

of 55

.8 y

ears

who

conti

nued

wit

h t

he

sam

e co

nse

rvat

iv t

reat

men

t pr

evio

usl

y es

tabl

ished

.

Treb

inja

c et

al.

(30)

21 p

atie

nts

; ave

rage

age

of 47

.8 y

ears

, tre

ated

wit

h

Pai

n w

as e

valu

ated

wit

h V

AS

and

funct

ional

ity

wit

h

It is

not

men

tion

ed if

6 in

tra

– ar

ticu

lar

dext

rose

inje

ctio

ns,

(6

ml at

25%

) SP

AD

I be

fore

tre

atm

ent

and

48 w

eeks

aft

er t

he

ther

e w

ere

side

effec

ts o

r an

d ex

tra

- ar

ticu

lar

(1 m

l pe

r de

xtro

se p

oint

at 1

5%),

ap

plic

atio

n o

f th

e sa

me.

adve

rse

reac

tion

s in

the

at m

onth

ly inte

rval

s.tr

eate

d pa

tien

ts.

VA

S

DX

CL

Bas

al6.

3 (1

.0)

6.1

(1.2

)

48 w

eeks

2.7(

1.0)

4.6(

1.4)

SPA

DI

DX

CL

Bas

al69

.4(9

.2)

67.6

(9.4

)

48 w

eeks

43.8

(11

.6)

51.1

(14.

4)

DA

SH s

ubs

core

Pai

n

DX

PH

Bas

al3.

293.

20

12 w

eeks

1.86

2.40

DA

SH t

otal

sco

re

DX

PH

Bas

al60

.14

56.8

6

12 w

eeks

43.8

946

.68

VA

SSP

AD

I

Bas

al8.

14 (

1.2)

76.9

9 (1

3.6)

48 w

eeks

2.29

(2.8

)20

.84

(23.

06)

Abb

revi

atio

ns:

ALD

= d

eep

loca

l anes

thet

ics,

ALS=

subc

uta

neo

us

loca

l anes

thet

ics,

DX

: dex

tros

e, E

X=

Exe

rcis

e, S

S= s

oluti

on s

alin

e, C

T=

cort

icos

tero

id, A

L=

loca

l anes

thet

ics,

PR

P=

plat

elet

-ric

h p

lasm

a, P

H=

Phys

ioth

erap

y, C

L=

Con

trol

. SPA

DI =

Shou

lder

Pai

n a

nd

Dis

abilit

y In

dex,

VA

S=A

nal

og V

isual

Sca

le. A

SES=

Am

eric

an S

hou

lder

and

Elb

owSu

rgeo

ns

Stan

dard

ized

, DA

SH: D

isab

ilit

y of

Arm

and

Shou

lder

Sco

re.


165


RevIew Of OBSeRvATIONAL STUDIeS

In the observational studies, Lee et al.29 reported sta-tistically significant reduction of pain and improvementof function in the HDI group compared with conser-vative treatments in long-term follow-up. Similarly, Tre-binjac et al.30 reported a series of cases treated with HDIwith statically significant pain reduction and functionimprovement in the long-term.

CHARACTeRISTICS AND DOSAGe Of HypeRTONIC

DexTROSe TReATMeNT

Four studies23,24,29,30 performed treatment schemes withmultiple sessions and multi-injections in the insertionof the rotator cuff tendons; other studies25,26,28 only useda single intratendinous application in the focal area ofrupture under ultrasound guidance. Sari et al.27 per-formed a single subacromial infiltration.

In the included studies, the number of sessions va -ried from 1 to 8 per participant, while the application

frequency was every 2 to 4 weeks. On the other hand,the concentrations of dextrose used varied from 12.5to 25%, with a mode of 25%.

ADveRSe ReACTIONS AND SIDe effeCTS

Three trials23,24,26 where participants received HDI re-ported minor adverse reactions such as pain during orafter application, inflammation after application andone study reported hypotension during treatment. Therest of the studies did not mention if there were ad-verse reactions.

DISCUSSION

effICACy Of INfILTRATIONS wITH HypeRTONIC

DexTROSe IN THe TReATMeNT Of ROTATOR CUff

TeNDINOpATHy

A recent review already evaluated the role of HDI in

fIGURe 4. Forest plot: A) Short-term, B) Medium-term, C) Long-term.


166


TA

BLe

III

. S

UM

MA

Ry

Of

TH

e C

HA

RA

CT

eR

IST

ICS

AN

D p

RO

pe

RT

IeS

Of

TH

e I

Nf

ILT

RA

TIO

NS

US

eD

fO

R T

He

TR

eA

TM

eN

T O

f p

AT

IeN

TS

wIT

H

RO

TA

TO

R C

Uf

f T

eN

DIN

Op

AT

Hy

IN

TH

e S

TU

DIe

S I

NC

LU

De

D I

N T

He

Re

vIe

w.

Mec

han

ism

E

ffec

ts o

n

Tre

atm

ent

mod

alit

ies

of a

ctio

np

ain

con

trol

Ad

vers

e ef

fect

sP

ossi

ble

adva

nta

ges

Pos

sibl

e d

isad

van

tage

sC

orti

cost

eroi

d in

filt

rati

onA

nti

-inflam

mat

ory

effe

ct.

Shor

t te

rm.

Pai

n d

uri

ng

appl

icat

ion.

Usu

ally

the

appl

icat

ion

Its

appl

icat

ion is

lim

ited

Lin

MT

et

al. (

5)Pro

babl

e de

lete

riou

s sc

hem

e in

volv

es a

sin

gle

to v

ery

few

ses

sion

s to

Col

e et

al.

(25)

effe

cts

to t

he

tendo

n if

inje

ctio

n intr

a-ar

ticu

lar

avoi

d ad

vers

e ef

fect

s.Sa

ri e

t al

. (27

)re

peat

ed infilt

rati

ons

are

or in t

he

suba

crom

ial

Intr

aten

dinou

s C

ook

et a

l. (4

0)ca

rrie

d ou

t.sp

ace.

appl

icat

ion is

not

R

amír

ez e

t al

. (41

)Pos

sibi

lity

of sy

stem

ic

reco

mm

ende

d.Ji

et

al. (

42)

side

effec

ts.

Loc

al a

nes

thet

ic infilt

rati

onIn

hib

itor

of noc

icep

tive

Sh

ort

term

.Pai

n d

uri

ng

appl

icat

ion.

It c

an b

e ap

plie

dPos

sibl

e ef

fect

only

in

Ber

tran

d et

al.

(23)

acti

vity

and

slig

ht

intr

a-ar

ticu

larl

y, in t

he

the

very

shor

t te

rm.

Sari

et

al. (

27)

anti

-inflam

mat

ory

effe

ct.

suba

crom

ial sp

ace

or in t

he

Car

acas

et

al. (

37)

enth

esis

of th

e te

ndo

n.

Coo

k et

al.

(40)

Hyp

erto

nic

dex

tros

e Tr

ophic

effec

t on

the

Lon

g te

rm.

Pai

n d

uri

ng

and

afte

r It

can

be

appl

ied

The

schem

es a

pplied

infilt

rati

onte

ndo

n.

appl

icat

ion.

intr

a-ar

ticu

larl

y, in t

he

invo

lve

mult

iple

Lin

MT

et

al. (

5)su

bacr

omia

l sp

ace,

in t

he

inje

ctio

ns

in t

he

sam

eBer

tran

d et

al.

(23)

enth

esis

of th

e te

ndo

n o

rse

ssio

n.

Seve

n e

t al

. (24

)in

trat

endi

nou

s.C

ole

et a

l. (2

5)M

ult

iple

ses

sion

s ca

n b

e Lin

et

al. (

26)

appl

ied,

whic

h c

ould

be

Sari

et

al. (

27)

use

ful in

ref

ract

ory

case

s.G

eorg

e et

al.

(28)

Lee

et

al. (

29)

Treb

inja

c et

al.

(30)

Cat

apan

o et

al.

(31)

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the management of rotator cuff tendinopathy; howev-er, it only performed qualitative analyses31. In our re-view, more recent studies were added and we addi-tionally performed quantitative analyses to clarify theefficacy of HDI.

In the pooled analysis, we found that HDI were moreeffective for reducing pain than others treatments usedin controls in a long-term follow-up. This observationis similar to the results of the meta-analysis by Lin etal.5, who reported that HDI are an effective interventionfor long-term pain control in individuals with rotatorcuff tendinopathy (nevertheless, that meta-analysisonly included one study where HDI were used). Thesame long-term symptomatic effects were reported inthe observational studies29,30.

The study by Seven et al.24 compared HDI vs. exer-cise programs, and found that HDI was more effectivein reducing pain in short, medium and long-terms in theindividual analysis. Non-invasive therapeutic strategiesare widely used for the treatment of rotator cufftendinopathy32. It has been reported that oral anti-in-flammatory drugs are effective for reducing pain only inthe short term, but they do not improve function2. Like-wise, physiotherapy modalities are frequently used forthe treatment of rotator cuff tendinopathy; neverthe-less, it has been reported that some of them such as thetranscutaneous electrical stimulation33 and therapeuticultrasound34 are not more effective than placebo for thecontrol of pain and improvement of function, while oth-ers such as laser therapy have shown a small beneficialeffect3,35. Therapeutic exercise probably represents themost effective non-invasive therapeutic modality for thetreatment of rotator cuff tendinopathy4,36. No previousmeta-analysis has reported a direct comparison betweenHDI vs. exercise programs; the results of our meta-anal-ysis suggest that HDI are more effective in the short,medium and long terms than exercise programs andcould be an alternative when exercise strategies fail.However, this comparison was only carried out in onestudy, so it should be taken with reserve.

Some studies directly compared HDI vs. infiltrationswith local anesthetics23,27. In the individual analyses inthe short and medium terms, no significant differenceswere reported between the groups. However, in thelong term however, the individual analysis of the studyby Bertrand et-al. showed significant differences in fa-vor of the group treated with HDI23. A previous meta-analysis5 reported that HDI are an effective interven-tion for the long-term control of pain in individualswith rotator cuff tendinopathy, based on the compari-


168


son between HDI and local anesthetic infiltrations.These results suggest that in the short and mediumterms HDI and local anesthetics infiltrations have thesame effect in patients with rotator cuff tendinopathy.However, in the long term, the effect of local anesthet-ics is lost, while the benefit achieved with HDI persists.Local anesthetics have been proposed to have analgesicand anti-inflammatory effects in addition to their anes-thetic effect37, which could explain its short-term ther-apeutic effect. Hypertonic dextrose on the other hand,has been proposed to have a mechanism of action basedon the increase of fibroblast proliferation, collagen pro-duction and extracellular matrix in the treated ten-dons38,39, which could explain why its efficacy is main-tained in the long-term.

Two studies directly compared HDI vs. conventio nalinfiltrations with corticosteroids25, 27. In the individualanalyses, the study of Cole et al.25 reported statisticallysignificant pain reduction in the short and mediumterms in favor of HDI, but not in the long term. On theother hand, the study by Sari et al.27 reported a statis-tically significant reduction of pain in favor of corti-costeroid infiltrations in the short and medium terms,but in the long-term there was no difference betweengroups. No previous meta-analysis has reported a di-rect comparison between HDI vs. corticosteroid infil-trations. Other meta-analyses have reported that corti-costeroid infiltrations are an effective intervention forpain control and function improvement in the rotatorcuff tendinopathy when compared with placebo5 or lo-cal anesthetics40; however, it was observed that the im-provement only lasted <6 weeks. Corticosteroids areprobably the most used infiltration in individuals withshoulder rotator cuff tendinopathy but its use has beenrelated to deleterious effects on the tendon in additionto its contraindication in some patient with comor-bidities. Basic studies have reported that infiltrationswith corticosteroids could be associated with an in-crease of cellular apoptosis in the infiltrated tendon41

and could facilitate the NF-KB signaling, which is in-volved in the pathogenesis of rotator cuff tears42, whichcontrasts with the trophic effects that hyperto nic dex-trose can have on the tendon38,39. When compa r ing HDIvs. corticosteroids infiltrations in individuals with ro-tator cuff tendinopathy, further studies are required toclarify whether HDI represents an alternative to infil-trations with corticosteroids when there is a con-traindication for their application.

Sari et al.27 compared HDI vs. infiltrations with PRPand in the individual analyses found no significant

diffe rences between both groups in the short, mediumand long terms. No previous meta-analysis reported adirect comparison between HDI vs. PRP infiltration.Others meta-analysis reported that PRP infiltrationswere effective for reducing pain and improving func-tion in long-term follow-up when compared with cor-ticosteroids9. In basic studies it has been reported thatin vitro applications of PRP favor tissue repair and in-crease the proliferation of rotator cuff tenocytes43, sim-ilar to the effects previously described for hypertonicdextrose38, 39; nonetheless, the application of PRP im-plies greater complexity in its preparation and the re-sults vary considerably44. Although HDI appear to havethe same efficacy as PRP infiltrations to reduce pain inthe long-term, these observations come from a singlestudy and more studies are necessary to corroboratethese results.

Regarding the characteristics of the treatment, stud-ies with multiple sessions and multi-injections23,24,29,30

showed greater benefits with statistically significant im-provement in favor of the groups treated with HDI. Onthe other hand, studies25, 28 that only included one treat-ment session (intratendinous) did not find greater clin-ical improvement in comparison with control groups.Multiple sessions and multi-injection schemes appearto be necessary to obtain clinical benefit in patientswith rotator cuff tendinopathy. Previous recommenda-tions suggest between 3 to 6 treatment sessions as wellas multi-injection schemes involving at least the inser-tion area of the rotator cuff tendons and subacromial orintra-articular space45.

Regarding the side effects and/or adverse reactions,pain during or after the application was the most fre-quently observed. None of the treated individuals re-ported serious complications such as infections or al-lergic reactions; nevertheless, not all studies reportedadverse effects or complications.

A comparative table was made, which summarizesthe mechanisms of action, effects on pain control, pos-sible advantages, disadvantages and adverse effects, ofthe types of infiltration used for the treatment of rota-tor cuff tendinopathy in the included studies (Table III).

It is important to mention possible limitations of thepresent study. Although the studies included in thequantitative analysis showed a good methodologicalquality design and low or moderate risk of bias, thesmall number of studies included, the small number ofindividuals treated in each study and the lack of stan-dardization in the application techniques most have in-fluenced the results and its consistency.


169


CONCLUSIONS

The results of this systematic review and meta-analysisindicate that HDI are an effective treatment for controlpain in long-term follow-up of individuals with rotatorcuff tendinopathy. Therefore, it can be concluded thatHDI were more effective than non-invasive treatmentsin the short, medium and long terms, as well as moreeffective than the use of local anesthetics in long term.HDI were not more effective than PRP and its efficacycomparing with corticosteroid infiltrations is not yetclear. On the other hand, HDI did not show complica-tions or serious adverse effect. Despite the favorable re-sults, the small number of studies included in our meta-analysis as well as their heterogeneity are the mainlimitations to draw definitive conclusions and goodquality RCTs are required.

CORReSpONDeNCe TO

Carlos Alfonso Tovilla-ZárateUniversidad Juárez Autónoma de Tabasco División Académica Multidisciplinaria de Comalcalco, RancheríaSur, Cuarta Sección C.P. 86650, Comalcalco, Tabasco, México. E-mail: [email protected]

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