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; A systematic review of four injection therapies for lateral epicondylosis: prolotherapy, polidocanol, whole blood and platelet rich plasma; BJSM doi: /bjsm ; 2008

Basics: is Bad… Basics: Tennis Elbow is Bad… ► Tendon disease: 7% of injury-related diagnoses ► Tennis Elbow: 1-3% (16% auto-industry) 4-7 cases / 1000 / year 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 Tendinopathy Normal Tendon

Pathophysiology of overuse tendon injuries Increased Demand On Tendon / Repetitive Microtrauma Inadequate / Failed Healing Decreased Collagen Synthesis, Tenocyte Death, Neovascularization Increased Vulnerability To Injury Successful Healing Response Acute Inflammation? Tendinopathy Cycle

Tennis Elbow U/S Hypo-echoic Radial head Joint space Extensor tendon origin Distal humerus

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

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?

ABCD Response of stretch-injured rat MCLs to Dextrose PrT

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 ► , 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 weeks ► Relative effect size from 51%-94% ► All but 1 used pre-post VAS scale

4 injection Txs for Lat Epi StudyTx 1°- VAS Pain c/t TØ PRP Mishra, N=15 Inj x 1 81% 27 wks (exertional) Prolo Scarpone, N=10 Inj x 3 0, 4, 8 90% at 16 wks (resting) Polid Zeisig, N=11 Inj x 1 55% at 35 wks (exertional) Autol Wh Bl Edwards, N=28 Inj x 1-3 0, 6, 12 88% at 43 wks (rest)

4 injection Txs for Lat Epi Study Tx, weeks 2°Result (U/S, function) PRP Mishra, N=15 Inj 1 Improved Mayo questionnaire Prolo Scarpone, N=10 Inj x 3 0, 4, 8 Improved isometric grip Polid Zeisig, N=11 Inj x 1 Reduced US defect, vascularity, pts satisfied Autol Wh Bl. Edwards, N=28 Inj x 1-3 0, 6, 12 Improved Nirschl scale

What’s really going on? ProlotherapyPolidocanol 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. 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: ► 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: ► 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): ► 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 elbow- promising results in a pilot study. Knee Surg Sports Traumatol Arthrosc 2006;14: ► 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: ► Zeisig E, Ohberg L, Alfredson H. Extensor origin vascularity related to pain in patients with tennis elbow. Knee Surg Sports Traumatol Arthrosc 2006;14:

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