A systematic review of four injection therapies for lateral epicondylosis: prolotherapy, polidocanol, whole blood and platelet rich plasma injections 16 th Nordic Congress Copenhagen Denmark David Rabago, University of Wisconsin, USA Rabago D, Best TM , Zgierska A , Zeisig E , Ryan M and Crane D; systematic review of four injection therapies for lateral epicondylosis: prolotherapy, polidocanol, whole blood and platelet rich plasma doi:10.1136/bjsm.2008.052761; 2008 A ; BJSM

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 To Injury Tendon / Repetitive Microtrauma Tendinopathy Cycle Acute Inflammation?

Decreased Collagen Synthesis, Tenocyte Inadequate / Failed Healing Death, Neovascularization

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 300 R 2 = 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?

800 600 400

Resident Macrophage - 24 hours post-injection

Dextrose Sodium Morrhuate P2G Saline Needle Stick Collagenase (positive control) No Injection

*

p < 0.04 vs. no injection at same location

* * * * * * * * * *

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

PRP Mishra, N=15

Tx

Inj x 1

1°- VAS Pain c/t TØ

81% 27 wks (exertional) Prolo Scarpone, N=10 Polid Zeisig, N=11 Inj x 3 0, 4, 8 Inj x 1 90% at 16 wks (resting) 55% at 35 wks (exertional) Autol Wh Bl Edwards, N=28 Inj x 1-3 0, 6, 12 88% at 43 wks (rest)

Study

4 injection Txs for Lat Epi

PRP Mishra, N=15 Prolo Scarpone, N=10 Polid Zeisig, N=11 Autol Wh Bl.

Edwards, N=28

Tx, weeks

Inj 1 Inj x 3 0, 4, 8 Inj x 1 Inj x 1-3 0, 6, 12

2°Result (U/S, function)

Improved Mayo questionnaire Improved isometric grip Reduced US defect, vascularity, pts satisfied Improved Nirschl scale

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

► ► ► ► ► ► ► ► ► ► ► Zeisig E, Fahlström M, Ohberg L, H. A. A 2-year sonographic follow-up after intratendinous injection therapy in patients with tennis elbow. epicondylosis: a pilot study. blood injection for tennis elbow. Am. J. Sports Med promising results in a pilot study. pain. The Treatment Of Refractory Tennis Elbow . Hand Surgery Am Skeletal Radiol 2006;34:1774 – 1778 Br J Sports Med patients with Tennis elbow - results of a randomised study. Clinical J Sports Med Australasian Musculoskeletal Medicine Journal 2007;12 2008;ePub Zeisig E, Fahlström M, Ohberg L, Alfredson H. Pain relief after intratendinous injections in Br J Sports Med 2008;18:248-254 2006;35(6):371-377 2008;42:267-271 Scarpone M, Rabago D, Zgierska A, Arbogest J, Snell ED. The efficacy of prolotherapy for lateral Connell DA, Ali KE, Ahmad M, Lambert S, Corbett S, Curtis M. Ultrasound-guided autologous Mishra A, Pavelko T. Treatment of Chronic Elbow Tendinosis With Buffered Platelet-Rich Plasma. Zeisig E, Ohberg L, Alfredson H. Sclerosing polidocanol injections in chronic painful elbow 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 Gani NU, Butt MF, Dhar SA, Farooq M, Mir MR, Kangu KA, et al. Autologous Blood Injection In The Internet Journal of Orthopedic Surgery Edwards SG, Calandruccio JH. Autologous blood injections for refractory lateral epicondylitis. 2003;28:272-278.

Zeisig E, Ohberg L, Alfredson H. Extensor origin vascularity related elbow. Knee Surg Sports Traumatol Arthrosc 2006;14:659-663 2007;5.

to pain in patients with tennis J

Thanks!

Discussion…