A systematic review of four injection
therapies for lateral epicondylosis:
prolotherapy, polidocanol, whole
blood and platelet rich plasma
injections
16th Nordic Congress
Copenhagen Denmark
David Rabago, University of Wisconsin, USA
Rabago D, Best TM , Zgierska A , Zeisig E , Ryan M and Crane D; A
systematic review of four injection therapies for lateral epicondylosis:
prolotherapy, polidocanol, whole blood and platelet rich plasma; BJSM
doi:10.1136/bjsm.2008.052761; 2008
Basics: Tennis Elbow is Bad…
► Tendon disease:
7% of injury-related diagnoses
► Tennis Elbow: 1-3% (16% auto-industry)
4-7 cases / 1000 / year
► Often refractory to conservative care
► High quality-of-life and work impact
► Expensive: $ billions direct and indirect costs
► Conventional therapies do not treat the
underlying pathology
Systematic Review
►4
injection therapies with recent clinical trial
data
► Reviewed every database, paper, trial
registry for all reports assessing these
injections for lat epi in humans
Histology of Common
Tendinopathies
►
Common extensor tendon: Tennis Elbow
 neovascularization, collagen disruption,
↑ fibroblasts, mucoid degeneration
►
Achilles Tendon
 increased vascularity, lipoid degeneration,
collagen fibers degeneration & derangement
►
Patellar Tendon
 increased vascularity, disorganized collagen fibers,
mucoid degeneration
Histology of Tendinopathies
Normal Tendon
Tendinopathy
Pathophysiology of overuse
tendon injuries Successful Healing
Response
Increased Vulnerability
To Injury
Increased Demand On
Tendon / Repetitive Microtrauma
Tendinopathy Cycle
Decreased Collagen
Synthesis, Tenocyte
Death, Neovascularization
Acute
Inflammation?
Inadequate / Failed Healing
Tennis Elbow U/S
Hypo-echoic
Distal
humerus
Extensor
tendon origin
Radial
head
Joint
space
Tennis Elbow U/S
with color doppler
4 Injection Therapies
►Polidocanol
►Platelet
rich plasma and whole blood
►Prolotherapy with dextrose and sodium
morrhuate
Polidocanol?
Sclerosant: most widely used worldwide
► Disrupts venous cellular membrane,
causing fibrosis - most commonly used in
vein Tx (varicosities, telangectasias)
► Safe:
 low incidence of allergic reactions
 low incidence of staining
 relatively forgiving if extravasated
►
Platelet-rich Plasma/Autologous
Whole Blood?
Platelet Rich Plasma Biology
► PDGF
 Chemoattractive for Mesenchymal Stem Cells
 Differentiation of Fibroblasts and Osteoblasts
► TGF-B
 Promotes cell mitosis, Type I Collagen
► VEGF
 Stimulates angiogenesis
► Basic
Fibroblast GF, Epidermal GF, Connective
Tissue GF
► Many
other Bioactive Factors
► PRP
Application Technique
 Withdraw peripheral blood
 Place blood in canister
 Centrifuge
►
PRP Application Technique
 Remove PPP
 Shake vigorously for 30 seconds
Platelet Poor Plasma
(PPP)
Platelet Rich Plasma
(PRP)
Packed Red Blood Cells
Platelet Rich Plasma Biology
Growth Factors increase linearly with
platelet concentration
TGF-Beta (ng/ml)
300
R2 = 0.9815
225
150
75
0
0
200
400
600
800
1000
Platelet Concentration (thousand/m icroliter)
1200
1400
Prolotherapy Hyperosmolar
Dextrose?
►Traditionally
defined as causing osmotic
shock to localized cells
►Trauma of water exiting – disrupts cell
membrane
►Pro-inflammatory, anabolic reaction
Prolotherapy Sodium Morrhuate?
►Traditionally
identified as chemotactant
causing anabolic inflammatory response
►Sclerosant; direct disruption of
neovascular cellular membrane
►Regulation of VEGF, TGFβ, Substance P,
apoptosis, others?
Resident Macrophage - 24 hours post-injection
2
Normalized Cell Number [# / mm ]
800
600
Dextrose
Sodium Morrhuate
P2G
Saline
Needle Stick
Collagenase (positive control)
No Injection
* p < 0.04 vs. no injection at same location
*
*
*
*
400
*
*
*
*
*
*
200
0
Tibia
Femur
Response of stretch-injured rat
MCLs to Dextrose PrT
A
B
C
D
Systematic Review
►Reviewed
all major databases, paper
reference sections and trial registries
for all reports assessing these
injections for tennis elbow
Systematic Review Methods:
Assessment
►Overall
Methodological Quality
►Relative Effect Size Compared to
Controls
►Cohen’s d Effect Size when appropriate
►Effect size of secondary outcomes
Systematic Review: Results
► 2003-2008,
9 papers, 201 subjects 3
autologous whole blood, 2 polidocanol,2
prolo, 1 PRP
► Methodological quality moderate to strong
► Pain from 3-25 months, often refractory
► Adverse events: routine associated with inj.
► Follow up from 9-108 weeks
► Relative effect size from 51%-94%
► All but 1 used pre-post VAS scale
4 injection Txs for Lat Epi
Study
Tx
1°- VAS Pain c/t TØ
PRP
Inj x 1
81% 27 wks (exertional)
Inj x 3
0, 4, 8
90% at 16 wks (resting)
Inj x 1
55% at 35 wks (exertional)
Mishra, N=15
Prolo
Scarpone, N=10
Polid
Zeisig, N=11
Autol Wh Bl
Edwards, N=28
Inj x 1-3 88% at 43 wks (rest)
0, 6, 12
4 injection Txs for Lat Epi
Study
PRP
Tx,
weeks
Inj 1
2°Result (U/S, function)
Inj x 3
0, 4, 8
Improved isometric grip
Inj x 1
Reduced US defect,
vascularity, pts satisfied
Inj x 1-3
0, 6, 12
Improved Nirschl scale
Mishra, N=15
Prolo
Scarpone, N=10
Polid
Zeisig, N=11
Autol Wh Bl.
Edwards, N=28
Improved Mayo
questionnaire
What’s really going on?
Prolotherapy
Polidocanol
Platelet Rich Plasma/AWB
Conclusions/Future Directions
►Consistent
moderate-large effect sizes
in these pragmatic, pilot level studies
►Each therapy is likely of clinical use for
refractory tennis elbow in primary care
settings; confirmatory RCT and larger
pragmatic studies are warranted
 Larger, randomized
 Direct comparison of injectants
Citations
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Zeisig E, Fahlström M, Ohberg L, H. A. A 2-year sonographic follow-up after intratendinous
injection therapy in patients with tennis elbow. Br J Sports Med 2008;ePub
Zeisig E, Fahlström M, Ohberg L, Alfredson H. Pain relief after intratendinous injections in
patients with Tennis elbow - results of a randomised study. Br J Sports Med 2008;42:267-271
Scarpone M, Rabago D, Zgierska A, Arbogest J, Snell ED. The efficacy of prolotherapy for lateral
epicondylosis: a pilot study. Clinical J Sports Med 2008;18:248-254
Connell DA, Ali KE, Ahmad M, Lambert S, Corbett S, Curtis M. Ultrasound-guided autologous
blood injection for tennis elbow. Skeletal Radiol 2006;35(6):371-377
Mishra A, Pavelko T. Treatment of Chronic Elbow Tendinosis With Buffered Platelet-Rich Plasma.
Am. J. Sports Med 2006;34:1774 – 1778
Zeisig E, Ohberg L, Alfredson H. Sclerosing polidocanol injections in chronic painful elbowpromising results in a pilot study. Knee Surg Sports Traumatol Arthrosc 2006;14:1218-1224
Glick R et al. Prolotherapy for the treatment of lateral epicondylitis: A double-blind pilot study.
North American Research Conference on Complementary and Integrative Medicine; 2006;
Edmonton, Canada. Focus Altern Complement Ther
Lyftogt J. Subcutaneous prolotherapy treatment of refractory knee, shoulder and lateral elbow
pain. Australasian Musculoskeletal Medicine Journal 2007;12
Gani NU, Butt MF, Dhar SA, Farooq M, Mir MR, Kangu KA, et al. Autologous Blood Injection In
The Treatment Of Refractory Tennis Elbow . The Internet Journal of Orthopedic Surgery 2007;5.
Edwards SG, Calandruccio JH. Autologous blood injections for refractory lateral epicondylitis. J
Hand Surgery Am 2003;28:272-278.
Zeisig E, Ohberg L, Alfredson H. Extensor origin vascularity related to pain in patients with tennis
elbow. Knee Surg Sports Traumatol Arthrosc 2006;14:659-663
Thanks!
Discussion…