A systematic review of four A systematic review of four injection therapies for lateral injection therapies for lateral epicondylosis: prolotherapy, epicondylosis: prolotherapy, polidocanol, whole blood and polidocanol, whole blood and platelet rich plasma injectionsplatelet rich plasma injections

1616thth Nordic Congress Nordic CongressCopenhagen DenmarkCopenhagen Denmark

David Rabago, University of Wisconsin, USADavid Rabago, University of Wisconsin, USARabago D, Best TM , Zgierska A , Zeisig E , Ryan M  and Crane D; Rabago D, Best TM , Zgierska A , Zeisig E , Ryan M  and Crane D;

  A systematic review of four injection therapies for lateral A systematic review of four injection therapies for lateral epicondylosis: prolotherapy, polidocanol, whole blood and epicondylosis: prolotherapy, polidocanol, whole blood and

platelet rich plasmaplatelet rich plasma; BJSM doi:10.1136/bjsm.2008.052761; 2008; BJSM doi:10.1136/bjsm.2008.052761; 2008

Basics: Basics: Tennis Elbow is Bad… is Bad…► Tendon disease:Tendon disease:

7% of injury-related diagnoses7% of injury-related diagnoses► Tennis Elbow:Tennis Elbow: 1-3% (16% auto-industry)1-3% (16% auto-industry)

4-7 cases / 1000 / year4-7 cases / 1000 / year► Often refractory to conservative careOften refractory to conservative care► High quality-of-life and work impactHigh quality-of-life and work impact► Expensive: $ billions direct and indirect Expensive: $ billions direct and indirect

costscosts► Conventional therapies do not treat the Conventional therapies do not treat the

underlying pathologyunderlying pathology

Systematic ReviewSystematic Review►4 injection therapies with recent 4 injection therapies with recent

clinical trial dataclinical trial data►Reviewed every database, paper, trial Reviewed every database, paper, trial

registry for all reports assessing these registry for all reports assessing these injections for lat epi in humansinjections for lat epi in humans

Histology of Common Histology of Common TendinopathiesTendinopathies

► Common extensor tendon: Tennis ElbowCommon extensor tendon: Tennis Elbow neovascularizationneovascularization, collagen disruption,, collagen disruption,

↑↑ fibroblasts, mucoid degenerationfibroblasts, mucoid degeneration

► Achilles TendonAchilles Tendon increased vascularityincreased vascularity, lipoid degeneration, , lipoid degeneration,

collagen fibers degeneration & derangementcollagen fibers degeneration & derangement

► Patellar TendonPatellar Tendon increased vascularityincreased vascularity,, disorganized collagen disorganized collagen

fibers, mucoid degenerationfibers, mucoid degeneration

Histology of TendinopathiesHistology of Tendinopathies

TendinopathyTendinopathyNormal TendonNormal Tendon

Pathophysiology of overuse Pathophysiology of overuse tendon injuriestendon injuries

Increased Demand On Tendon / Repetitive Microtrauma

Increased Vulnerability To Injury

Inadequate / Failed Healing

Decreased Collagen Synthesis, Tenocyte

Death, Neovascularization

Successful Healing Response

Acute Inflammation?

Tendinopathy CycleTendinopathy Cycle

Tennis Elbow U/STennis Elbow U/SHypo-echoic

Radial head

Joint space

Extensor tendon origin

Distal humeru

s

Tennis Elbow U/STennis Elbow U/Swith color dopplerwith color doppler

4 Injection Therapies4 Injection Therapies

►Polidocanol Polidocanol ►Platelet rich plasma and whole Platelet rich plasma and whole

blood blood ►Prolotherapy with dextrose and Prolotherapy with dextrose and

sodium morrhuate sodium morrhuate

Polidocanol?Polidocanol?► Sclerosant: most widely used Sclerosant: most widely used

worldwideworldwide► Disrupts venous cellular membrane,Disrupts venous cellular membrane,

causing fibrosis - most commonly used causing fibrosis - most commonly used in vein Tx (varicosities, telangectasias)in vein Tx (varicosities, telangectasias)

► Safe:Safe: low incidence of allergic reactionslow incidence of allergic reactions low incidence of staining low incidence of staining relatively forgiving if extravasatedrelatively forgiving if extravasated

Platelet-rich Platelet-rich Plasma/Autologous Whole Plasma/Autologous Whole

Blood?Blood?

Platelet Rich Plasma BiologyPlatelet Rich Plasma Biology

► PDGFPDGF Chemoattractive for Mesenchymal Stem CellsChemoattractive for Mesenchymal Stem Cells Differentiation of Fibroblasts and OsteoblastsDifferentiation of Fibroblasts and Osteoblasts

► TGF-BTGF-B Promotes cell mitosis, Type I CollagenPromotes cell mitosis, Type I Collagen

► VEGFVEGF Stimulates angiogenesisStimulates angiogenesis

► Basic Fibroblast GF, Epidermal GF, Basic Fibroblast GF, Epidermal GF, Connective Tissue GFConnective Tissue GF

► Many other Bioactive FactorsMany other Bioactive Factors

►PRP Application TechniquePRP Application Technique Withdraw peripheral blood Withdraw peripheral blood Place blood in canisterPlace blood in canister CentrifugeCentrifuge

► PRP Application TechniquePRP Application Technique Remove PPPRemove PPP Shake vigorously for 30 secondsShake vigorously for 30 seconds

Platelet Poor PlasmaPlatelet Poor Plasma

(PPP)(PPP)

Platelet Rich PlasmaPlatelet Rich Plasma

(PRP)(PRP)

Packed Red Blood CellsPacked Red Blood Cells

Platelet Rich Plasma BiologyPlatelet Rich Plasma Biology

Growth Factors increase linearly Growth Factors increase linearly with platelet concentrationwith platelet concentration

R2 = 0.9815

0

75

150

225

300

0 200 400 600 800 1000 1200 1400

Platelet Concentration (thousand/microliter)

TG

F-B

eta

(ng

/ml)

Prolotherapy Hyperosmolar Prolotherapy Hyperosmolar Dextrose?Dextrose?

►Traditionally defined as causing Traditionally defined as causing osmotic shock to localized cellsosmotic shock to localized cells

►Trauma of water exiting – disrupts Trauma of water exiting – disrupts cell membranecell membrane

►Pro-inflammatory, anabolic Pro-inflammatory, anabolic reactionreaction

Prolotherapy Sodium Prolotherapy Sodium Morrhuate?Morrhuate?

►Traditionally identified as Traditionally identified as chemotactant causing anabolic chemotactant causing anabolic inflammatory responseinflammatory response

►Sclerosant; direct disruption of Sclerosant; direct disruption of neovascular cellular membraneneovascular cellular membrane

►Regulation of VEGF, TGFRegulation of VEGF, TGFββ, , Substance P, apoptosis, others?Substance P, apoptosis, others?

Resident Macrophage - 24 hours post-injection

0

200

400

600

800

Tibia Femur

Nor

mal

ized

Cel

l Num

ber

[# /

mm

2]

DextroseSodium MorrhuateP2GSalineNeedle StickCollagenase (positive control)No Injection

*

**

*

*

*

*

*

* p < 0.04 vs. no injection at same location

*

*

A B C D

Response of stretch-injured rat MCLs to Dextrose PrT

Systematic ReviewSystematic Review

►Reviewed all major databases, Reviewed all major databases, paper reference sections and trial paper reference sections and trial registries for all reports assessing registries for all reports assessing these injections for tennis elbowthese injections for tennis elbow

Systematic Review Methods: Systematic Review Methods: AssessmentAssessment

►Overall Methodological QualityOverall Methodological Quality►Relative Effect Size Compared to Relative Effect Size Compared to

ControlsControls►Cohen’s d Effect Size when Cohen’s d Effect Size when

appropriateappropriate►Effect size of secondary outcomesEffect size of secondary outcomes

Systematic Review: ResultsSystematic Review: Results

►2003-2008, 9 papers, 201 subjects 3 2003-2008, 9 papers, 201 subjects 3 autologous whole blood, 2 polidocanol,2 autologous whole blood, 2 polidocanol,2 prolo, 1 PRPprolo, 1 PRP

►Methodological quality moderate to Methodological quality moderate to strongstrong

►Pain from 3-25 months, often refractoryPain from 3-25 months, often refractory►Adverse events: routine associated with Adverse events: routine associated with

inj. inj. ►Follow up from 9-108 weeksFollow up from 9-108 weeks►Relative effect size from 51%-94%Relative effect size from 51%-94%►All but 1 used pre-post VAS scaleAll but 1 used pre-post VAS scale

4 injection Txs for Lat Epi4 injection Txs for Lat EpiStudyStudy TxTx 1°- VAS Pain c/t TØ1°- VAS Pain c/t TØ

PRPPRPMishra, N=15Mishra, N=15

Inj x 1Inj x 1 81% 27 wks (exertional)81% 27 wks (exertional)

ProloProloScarpone, Scarpone, N=10N=10

Inj x 3Inj x 3

0, 4, 8 0, 4, 8 90% at 16 wks (resting)90% at 16 wks (resting)

PolidPolidZeisig, N=11Zeisig, N=11

Inj x 1Inj x 1 55% at 35 wks 55% at 35 wks (exertional)(exertional)

Autol Wh Autol Wh BlBlEdwards, N=28Edwards, N=28

Inj x 1-3Inj x 1-3

0, 6, 120, 6, 1288% at 43 wks (rest)88% at 43 wks (rest)

4 injection Txs for Lat Epi4 injection Txs for Lat EpiStudyStudy Tx, Tx,

weeksweeks2°Result (U/S, 2°Result (U/S, function)function)

PRPPRPMishra, N=15Mishra, N=15

Inj 1Inj 1 Improved Mayo Improved Mayo questionnairequestionnaire

ProloProloScarpone, N=10Scarpone, N=10

Inj x 3Inj x 3

0, 4, 8 0, 4, 8 Improved isometric gripImproved isometric grip

PolidPolidZeisig, N=11Zeisig, N=11

Inj x 1Inj x 1 Reduced US defect, Reduced US defect, vascularity, pts satisfiedvascularity, pts satisfied

Autol Wh Bl.Autol Wh Bl.Edwards, N=28Edwards, N=28

Inj x 1-3Inj x 1-3

0, 6, 120, 6, 12Improved Nirschl scaleImproved Nirschl scale

What’s What’s reallyreally going on? going on?

Prolotherapy Polidocanol

Platelet Rich Plasma/AWB

Conclusions/FutureConclusions/Future DirectionsDirections

►Consistent moderate-large effect Consistent moderate-large effect sizes in these pragmatic, pilot level sizes in these pragmatic, pilot level studiesstudies

►Each therapy is likely of clinical use Each therapy is likely of clinical use for refractory tennis elbow in primary for refractory tennis elbow in primary care settings; confirmatory RCT and care settings; confirmatory RCT and larger pragmatic studies are larger pragmatic studies are warrantedwarranted Larger, randomizedLarger, randomized Direct comparison of injectantsDirect comparison of injectants

CitationsCitations► Zeisig E, Fahlström M, Ohberg L, H. A. A 2-year sonographic follow-up after Zeisig E, Fahlström M, Ohberg L, H. A. A 2-year sonographic follow-up after

intratendinous injection therapy in patients with tennis elbow. intratendinous injection therapy in patients with tennis elbow. Br J Sports Med Br J Sports Med 2008;ePub2008;ePub

► Zeisig E, Fahlström M, Ohberg L, Alfredson H. Pain relief after intratendinous injections Zeisig E, Fahlström M, Ohberg L, Alfredson H. Pain relief after intratendinous injections in patients with Tennis elbow - results of a randomised study. in patients with Tennis elbow - results of a randomised study. Br J Sports MedBr J Sports Med 2008;42:267-2712008;42:267-271

► Scarpone M, Rabago D, Zgierska A, Arbogest J, Snell ED. The efficacy of prolotherapy Scarpone M, Rabago D, Zgierska A, Arbogest J, Snell ED. The efficacy of prolotherapy for lateral epicondylosis: a pilot study. for lateral epicondylosis: a pilot study. Clinical J Sports MedClinical J Sports Med 2008;18:248-254 2008;18:248-254

► Connell DA, Ali KE, Ahmad M, Lambert S, Corbett S, Curtis M. Ultrasound-guided Connell DA, Ali KE, Ahmad M, Lambert S, Corbett S, Curtis M. Ultrasound-guided autologous blood injection for tennis elbow. autologous blood injection for tennis elbow. Skeletal RadiolSkeletal Radiol 2006;35(6):371-377 2006;35(6):371-377

► Mishra A, Pavelko T. Treatment of Chronic Elbow Tendinosis With Buffered Platelet-Rich Mishra A, Pavelko T. Treatment of Chronic Elbow Tendinosis With Buffered Platelet-Rich Plasma. Plasma. Am. J. Sports MedAm. J. Sports Med 2006;34:1774 – 1778 2006;34:1774 – 1778

► Zeisig E, Ohberg L, Alfredson H. Sclerosing polidocanol injections in chronic painful Zeisig E, Ohberg L, Alfredson H. Sclerosing polidocanol injections in chronic painful elbow-promising results in a pilot study. elbow-promising results in a pilot study. Knee Surg Sports Traumatol ArthroscKnee Surg Sports Traumatol Arthrosc 2006;14:1218-12242006;14:1218-1224

► Glick R et al. Prolotherapy for the treatment of lateral epicondylitis: A double-blind pilot Glick R et al. Prolotherapy for the treatment of lateral epicondylitis: A double-blind pilot study. North American Research Conference on Complementary and Integrative study. North American Research Conference on Complementary and Integrative Medicine; 2006; Edmonton, Canada. Focus Altern Complement TherMedicine; 2006; Edmonton, Canada. Focus Altern Complement Ther

► Lyftogt J. Subcutaneous prolotherapy treatment of refractory knee, shoulder and lateral Lyftogt J. Subcutaneous prolotherapy treatment of refractory knee, shoulder and lateral elbow pain. elbow pain. Australasian Musculoskeletal Medicine JournalAustralasian Musculoskeletal Medicine Journal 2007;12 2007;12

► Gani NU, Butt MF, Dhar SA, Farooq M, Mir MR, Kangu KA, et al. Gani NU, Butt MF, Dhar SA, Farooq M, Mir MR, Kangu KA, et al. Autologous Blood Autologous Blood Injection In The Treatment Of Refractory Tennis Elbow . Injection In The Treatment Of Refractory Tennis Elbow . The Internet Journal of The Internet Journal of Orthopedic SurgeryOrthopedic Surgery 2007;5. 2007;5.

► Edwards SG, Calandruccio JH. Autologous blood injections for refractory lateral Edwards SG, Calandruccio JH. Autologous blood injections for refractory lateral epicondylitis. epicondylitis. J Hand Surgery AmJ Hand Surgery Am 2003;28:272-278. 2003;28:272-278.

► Zeisig E, Ohberg L, Alfredson H. Extensor origin vascularity relatedZeisig E, Ohberg L, Alfredson H. Extensor origin vascularity related to pain in patients with to pain in patients with tennis elbow. tennis elbow. Knee Surg Sports Traumatol ArthroscKnee Surg Sports Traumatol Arthrosc 2006;14:659-663 2006;14:659-663

Thanks!Thanks!Discussion…Discussion…