A systematic review of four inje

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					A systematic review of four injection
 therapies for lateral epicondylosis:
  prolotherapy, polidocanol, whole
   blood and platelet rich plasma
                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
► Reviewed every database, paper, trial
  registry for all reports assessing these
  injections for lat epi in humans
         Histology of Common
►   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

    Increased Vulnerability        Increased Demand On
           To Injury           Tendon / Repetitive Microtrauma

                      Tendinopathy Cycle            Acute

      Decreased Collagen
    Synthesis, Tenocyte
                                Inadequate / Failed Healing
Death, Neovascularization
     Tennis Elbow U/S
               Distal     Extensor
Hypo-echoic             tendon origin


Tennis Elbow U/S
with color doppler
       4 Injection Therapies
►Plateletrich plasma and whole blood
►Prolotherapy with dextrose and sodium
► 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
   Chemoattractive for Mesenchymal Stem Cells
   Differentiation of Fibroblasts and Osteoblasts

   Promotes cell mitosis, Type I Collagen

   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

                    Platelet Rich Plasma

                         Packed Red Blood Cells
                   Platelet Rich Plasma Biology
                         Growth Factors increase linearly with
                         platelet concentration
                             R2 = 0.9815

TGF-Beta (ng/ml)



                         0         200       400       600       800       1000      1200   1400
                                     Platelet Concentration (thousand/m icroliter)
    Prolotherapy Hyperosmolar

►Traditionallydefined as causing osmotic
 shock to localized cells
►Trauma of water exiting – disrupts cell
►Pro-inflammatory, anabolic reaction
 Prolotherapy Sodium Morrhuate?

►Traditionallyidentified 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
                                         Dextrose                             * p < 0.04 vs. no injection at same location
                                         Sodium Morrhuate
Normalized Cell Number [# / mm2]

                                         Needle Stick                                 *
                                         Collagenase (positive control)
                                         No Injection

                                                                                *                       *
                                                                   *                                          *
                                                             *            *


                                                           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:

►Overall Methodological Quality
►Relative Effect Size Compared to
►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)
Mishra, N=15

Prolo            Inj x 3   90% at 16 wks (resting)
Scarpone, N=10   0, 4, 8
Polid            Inj x 1   55% at 35 wks (exertional)
Zeisig, N=11

Autol Wh Bl      Inj x 1-3 88% at 43 wks (rest)
Edwards, N=28    0, 6, 12
        4 injection Txs for Lat Epi
Study            Tx,         2°Result (U/S, function)
PRP              Inj 1       Improved Mayo
Mishra, N=15                 questionnaire

Prolo            Inj x 3     Improved isometric grip
Scarpone, N=10   0, 4, 8
Polid            Inj x 1     Reduced US defect,
Zeisig, N=11                 vascularity, pts satisfied

Autol Wh Bl.     Inj x 1-3   Improved Nirschl scale
Edwards, N=28    0, 6, 12
      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
►   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
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►   Scarpone M, Rabago D, Zgierska A, Arbogest J, Snell ED. The efficacy of prolotherapy for
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►   Connell DA, Ali KE, Ahmad M, Lambert S, Corbett S, Curtis M. Ultrasound-guided autologous
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►   Mishra A, Pavelko T. Treatment of Chronic Elbow Tendinosis With Buffered Platelet-Rich
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►   Zeisig E, Ohberg L, Alfredson H. Sclerosing polidocanol injections in chronic painful elbow-
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►   Glick R et al. Prolotherapy for the treatment of lateral epicondylitis: A double-blind pilot study.
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►   Lyftogt J. Subcutaneous prolotherapy treatment of refractory knee, shoulder and lateral elbow
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►   Edwards SG, Calandruccio JH. Autologous blood injections for refractory lateral epicondylitis. J
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►   Zeisig E, Ohberg L, Alfredson H. Extensor origin vascularity related to pain in patients with tennis
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