Prolotherapy Research:

Summary and Status

AAOM 29th Annual Conference April 18-21 2012K. Dean Reeves, M.D.

Clinical Associate ProfessorUniversity of Kansas

Sections of Talk• Definitions and Focus

• Is Prolotherapy Experimental?

• Studies by Topic.

Definition of Prolotherapy: Option One

• Injection to repair or restore function of soft tissue which includes cartilage, ligament, tendon, nerve, and supportive matrix.

• PRP, stem cell, and ozone injection are all methods of reparative injection and can reasonably be called prolotherapy.

• For billing purposes connective tissue or joint prolo should be distinct from Neural prolo.

Definition of Prolotherapy: Option Two

• Injection to repair soft tissue which includes cartilage, ligament, tendon, nerve, and supportive matrix.

• Injection to restore nerve function neural prolotherapy is best termed Lyftogt technique.

• For billing purposes connective tissue or joint prolo should be distinct from Neural prolo.

Focus of This Talk

• Dextrose prolotherapy as data on other types of injectants is much more limited.

• However, we will consider how other injectants can be evaluated in similar ways.

Dextrose Prolotherapy Is Not Experimental Because

• It is taught as an acceptable method procedure by one or more approved post graduate programs for the healing arts? (Univ Wisconsin, specialty college in AOA), and

• It is based upon sufficient learned publications supporting the safety and efficacy? (Level B or higher in multiple areas)

• “Prolotherapy is performed and taught to Family Medicine residents on a regular basis at the University of Wisconsin School of Medicine and Public Health.  Residents in this program also participate in a 2 week hands on CME training program in prolotherapy in Honduras.   This counts as part of their orthopedic elective time in the residency.”  

 Jeffrey J. Patterson, Professor of F.P. at U.W Wisconsin

Taught in Department of Family Medicine at University of Wisconsin

• “In addition the The University of Wisconsin School of Medicine and Public health sponsors post graduate CME programs in prolotherapy through the UW Department of Continuing Medical Education.   These are held annually on the UW campus. “

Jeffrey J. Patterson, Professor of Family Practice at U.W Wisconsin

Taught in Continuing Education Programming By University of

Wisconsin

Prolotherapy is An Official Specialty College Listing Within the American

Osteopathic Association.

• The official listing of Specialty Colleges within the American Osteopathic Association on the AAOM website includes 23 specialties: addiction medicine, allergy and immunology, anesthesiology, dermatology, emergency medicine, family medicine, internal medicine, medical informatics, neurology and psychiatry, obstetrics and gynecology, occupational and preventative medicine, ophthalmology and otolaryngology, orthopedics, osteopathy, pathology, pediatrics, physical medicine and

rehabilitation, proctology, prolotherapy and integrative pain management, radiology, rheumatology, sports medicine, and surgery.

• http://www.osteopathic.org/inside-aoa/about/affiliates/Pages/osteopathic-specialty-colleges.aspx

U.S. Preventative Service Task Force Classification of Evidence

• Level I: Well designed RCT (s) with clinical and statistically significant evidence.

• Level II: Well designed:

II-1 Controlled trials without randomization

II-2 Cohort or case control studies from more

than one center.

II-3 Dramatic result from uncontrolled trial,

Blinded Machine Measure case control

Level III. Substantially flawed RCTs or other controlled studies. Single well designed cohort or case control study

When SHOULD You Discuss Prolotherapy With Patients

• A: Good evidence Benefit > Risk

• B: Fair evidence Benefit > Risk

• C. Fair evidence Benefit = Risk

• D. Fair evidence Benefit < Risk

• I. Insufficient , poor quality or conflicting evidence.

References for Levels of Evidence

Rabago D, Slattengren A, Zgierska A. Prolotherapy in Primary Care Practice. Prim Care. 2010;37(1):65-80.

Reeves KD. Lyftogt J Prolotherapy: Regenerative injection therapy. In: Waldman SD (ed): Pain Management. Philadelphia; Saunders (Elsevier), 2nd ed; 2011:1027-1044.

Low Risk Level With Prolotherapy Therefore Quality Level ≈ Recommendation

Good RCT I=A Osgood Schlatter

Good NRCTFair RCT

II-1=B Achilles Tendinosis , Finger OA, Knee OA (2000), Lat Epicond (2008),

Low Back Pain, S-I Pain (2010)>1 Cohort II-2= B

Dramatic CC, BMM CC, >1 CC, Many CP

II-3= B Adductor tendinopathy

1 Cohort, Small BMM CC, Med # CP

III=C Coccygodynia , Plantar fasciosis, ACL laxity.

NRCT = Nonrandomized Controlled Study, CC = Case Controlled, CP = Consecutive Patient , BMM = Blinded Machine Measure

Referrals for Prolotherapy AreNot Just Based on Evidence

• Competition

• Literature ignorance

• Invasiveness

• Artfulness

Insurance Coverage Is Not Just Based on Evidence

• Standardized method. This will require introduction into medical schools or repeated RCTs.

• Simple method compatible with single level payment.

Benefit of Insurance Coverage Is Not Just Based on Evidence

• Option to bill above single level payment for more complex cases? (Time based or condition based approach is too advanced to expect in a socialist system)

• Insurance company abuse.

Achilles Tendinosis (Chronic) • RCT Nonblinded: #40 (15/14/15), Yelland 2009, 20%

Dextrose + .1 Lido/Ropiv, subcu, weekly, mean 9.5 Rx, 1 Yr fup, 5 dropouts (3 intolerant of ELE). Neural prolo = Best Usual Care (ELE),

• Case series: #35, Maxwell 2007. 25% Dextrose + 1% Lido, intratendon, 6 week interval, 4(2-11) Rx, 1 Yr fup, 90% data, VAS sport 78%, HRUS injection guidance but no fup image

• Case series #108, Ryan 2010, 25% Dextrose + .5% Lido, intratendon, 6 wk interval, 5(1-13) Rx, 28 wk(5-73) HRUS fup, 1-4 Yr symptom fup, 70% data, VAS sport 74% improvement, HRUS correlation.

• CONCLUSION = Fair evidence of benefit and objective ultrasound findings but methods needing improvement in efficacy to exceed therapy standard of care. = B

ACL Ligament Laxity • Case series #18: Reeves 2003, KT-1000 ADD >1, single intraartic

10% Dextrose + .1 Lido + .9 BA in water VS same without 10% Dextrose. 9 ml Q 2 mo X 3 and then PRN for 3 years. (25% dextrose given in some injections after year one) 2 dropout (1 disseminated cancer and 1 w/c bound with travel issues), 10/16 no laxity and sustained at 3 months, pain with walking improved 43%, subjective swelling improved 63%, ROM by 10.5 degrees total flexion.

ACL Ligament Laxity

• Summary: Single case series but with objective end point. (KT-1000 measure) Level B/C Safety plus fair evidence of effectiveness but small study needing confirmation.

• Option: Repeat with delayed treatment cohort and blinded machine measure.

• Reeves KD, Hassanein K. Long-term effects of dextrose prolotherapy for anterior cruciate ligament laxity. Altern Ther Health Med (United States), May-Jun 2003, 9(3) p58-62

Adductor Tendinosis

• Case Series #72 Topol 2008,12.5% dextrose + 0.5% lido, enthesis, 1 month interval, μ (1-6) Rx, μ 26(6-72) month fup, 100% data capture, 82% improvement in groin pain, 92% return to full sport.

Adductor Tendinosis

• Summary: Moderate size study with failure of usual treatment and clear endpoint of unrestricted sport. Level B Evidence. Safety and good evidence of efficacy.

• Options: Repeat study for stronger B level evidence as blinding not feasible/ethical. Consider neural therapy approaches as they are clarified.

Topol GA, Reeves KD: Regenerative injection of elite athletes with career-altering chronic groin pain who fail conservative treatment: a consecutive case series. Am J Phys Med Rehabil. 2008;87(11):890-902

Coccygodynia Pain

• Case Series #37: Khan 2008, 20% dextrose + .4% lido 10 ml over most tender area, 2 week interval, 2-3 Rx, fup time not mentioned, marked improvement in VAS for pain in 30/37.

Coccygodynia Pain

• Summary: Level B/C Evidence. Attractive surgery alternative but small size and fup time not specified. May have neural effect via large volume.

• Option: Repeat with neural prolo and potentially enthesis injection as well and more defined followup timing.

• Khan SA, Kumar A, Varshney MK, Trikha V, Yadav CS. Dextrose prolotherapy for recalcitrant coccygodynia. J Orthop Surg 2008;16:27–29.

Finger Osteoarthritis • RCT #27 (13 Dextrose/ 14 Lido): Reeves 2000, medial

and lateral injection of ½ ml of either 10% Dextrose + .1 Lido + .9 BA in water VS same without 10% Dextrose. Q 1 mo X 3. 6 mo fup blinded. Then all received dextrose through 1 year. 100% data capture to 1 year. 6 month data showed pain with movement significantly better with dextrose (42% vs 15% p = .027) and flexion range improved more (+8 vs -8.7 degrees, p =.003)

Finger Osteoarthritis• Summary: Small single RCT. Level A Safety plus fair

evidence of effectiveness. However other classification is 1B evidence with small high quality RCT with fewer than 2 consistent RCTs. Discomfort with injection is drawback to this method.

• Option: Vitamin D study due to pain with injection as an alternative.

Reeves KD, Hassanein K: Randomized prospective placebo-controlled double-blind study of dextrose prolotherapy for osteoarthritic thumbs and fingers (DIP, PIP and trapeziometacarpal Joints) : Evidence of clinical efficacy. Jnl Alt Compl Med 2000;6(4):311-320.

Knee Osteoarthritis • RCT #120: Reeves 2000, single intraartic 10% Dextrose

+ .1 Lido + .9 BA in water VS same without 10% Dextrose. 9 ml Q 2 mo X 3. 6 mo fup blinded. 6 Month additional fup for 1 yr. 9 dropouts (5 medial, 4 efficacy[3 lido]). 100% data capture for remaining 111. Pain improvements not different but ROM and subjective swelling and buckling episodes were better in the dextrose group. (Overall Dextrose better with P = .015)

• RCT # ___ UW Study with final results pending. • Pre and Post Arthroscopy study Argentina in bone on

bone (medial compartment) knees with results pending.

Knee Osteoarthritis • Summary: Level B Evidence. Risks minimal (dextrose

alone). Good clinical response but not level A because control improved pain enough that lidocaine or benzyl alcohol or hypotonic solution injection may not be a control intervention. Needs further confirmation for that reason.

• Option: Await UW Study and arthroscopy study results. May repeat without lidocaine vs Saline. (Dextrose has been found to be analgesic). OR may combine neural therapy, or alternatively treat with neural prolotherapy without intraarticular prolo.

Reeves KD, Hassanein K: Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Alt Ther Hlth Med 2000;6(2):68-80.

Lateral Epicondylosis (Chronic, non PRP)

• RCT #24 (12,12), Scarpone 2008, .7NaMorr + 10% Dex + .3 Lid + .03 Sensorcaine, bone contact 3 locations, 4 wk interval, 3 Rx, 1 Yr fup, 1 dropout (control), 90% vs 27% VAS impr resting elbow pain, impr grip and isometric strength.

Lateral Epidondylosis (Chronic, Non PRP)

• Summary: Small single RCT. Level A Safety plus fair evidence of effectiveness. However other classification is 1B evidence with small high quality RCT with fewer than 2 consistent RCTs.

• Option: Vit D cream or US guided dextrose blinded, subcu dextrose vs usual care RCT, consec subcu +/- bone contact in failure usual care.

• Note: Method refinements marked in subcu method. • Scarpone M, Rabago DP, Zgierska A, Arbogast G, Snell E: The efficacy of prolotherapy for lateral

epicondylosis: a pilot study. Clin J Sport Med 2008;18(3):248-54

Low Back Pain: Non specific

• RCT: Ongley 87, Klein 93. Multiple simultaneous treatments but strong sustained effects on pain and disability.

• RCT: Dechow 99. Incorrect injection areas with strong proliferant. Non interpretable.

• RCT #110: Yelland 2003, 20% Dextrose + .2% Lido, enthesis, 2 week Rx interval, μ7.1 Rx, 96% data capture 1 year and 80% at 2 years, no signif differences with saline but 36%/33% improvement in pain and 42%/31% improvement in disability scores at 1 year, sustainable to 2 years.

Low Back Pain: Non specific

• Summary: Level B/C Evidence. Fair sized study with safety and fair efficacy for dextrose but control appeared as efficacious. (Could be level B if control shown not to be control)

• Option: Cluneal nerve treatment, dextrose versus steroid epidural.

Ongley MJ, Klein RG, Dorman TA, Eck B: A new approach to the treatment of chronic low back pain. Lancet 1987;2:143-146.

 Klein RG, Bjorn CE, DeLong B, Mooney V: A randomized double-blind trial of dextrose-glycerine-phenol injections for chronic low back pain. J Spinal Disord 1993;6(1):23-33.

Dechow E, Davies RK, Carr AJ, Thompson P: A randomized, double-blind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology 1999;38(12):1255-1259.

Yelland MJ, Glasziou PP, Bogduk N, Schluter PJ, McKernon M: Prolotherapy injections, saline injections, and exercises for chronic low-back pain: A randomized trial. Spine 2003;29(1):9-16.

Osgood-Schlatter Disease

• RCT #65: Topol Pending, Dextrose > Lidocaine > Usual Care.

Plantar fasciosis (Chronic)

• Case series #20, Ryan 2009, 25% Dextrose + 1% Lido, Intratendon, 6 week internal, 3(1-12) Rx, 11 month (6-20 mo) fup, 100% data capture, 75% improvement in 80% of patients, no fup HRUS.

Plantar Fasciosis (Chronic)

• Summary: Level B/C Evidence. Safety and fair evidence of efficacy but consec patient and small without HRUS fup.

• Option: Vit D cream, subcu dextrose, US driven dextrose.

• Note: Nerve involvement has been clarified. • Ryan MB, Wong AD, Gillies JH, Wong J, Traunton JE Sonographically guided intratendinous injections of

hyperosmolar dextrose/lidocaine: a pilot study for the treatment of chronic plantar fasciitis. Br J Sports Med 2009;43:303-306.

Sacroiliac Pain

• RCT #48 (23 dextrose, 25 steroid): Kim 2010, Dextrose water conc? vs triamcinolone (INTRAARTICULAR) in confirmed SI via anethetic injection with 50% improvement for 3 months or longer, Q2 week Rx, 3 Rx. 59% vs 10% improvement at 15 month fup.

• Case series #25. Cusi 2010, 17% Dextrose + . 4% bupivicaine + contrast. .8 in SI ligament via guidance. (EXTRAARTICULAR) 3 Rx. 76% data capture at 1 year. Marked reduction in SI laxity measures by exam and improvement in Quebec Back Pain Diabilitity and Roland Morris Questionnaire measures.

Sacroiliac Pain • Summary: Level A/B evidence for SI injection in

anesthetic confirmed SI pain. Need detail confirmation and another study for confirmation of level A. Level B/C evidence for small volume SI ligament only injeciton with exam confirmed SI pain due to small size, measurable but not blinded end points, significant dropout.

• Option: Clarify details for confirmation via consecutive patient data of Kim et al. For Cusi et al repeat with delayed treatment and blinded testing between immediate and delayed treatment groups.

• Kim WM; Lee HG; Won Jeong C; Kim CM; Yoon MH. ARTICLE TITLE: A randomized controlled trial of intra-articular prolotherapy versus steroid injection for sacroiliac joint pain [In Process Citation] ARTICLE SOURCE: J Altern Complement Med (United States), Dec 2010, 16(12) p1285-90

• Cusi M, Saunders J, Hungerford B, Wisbey-Roth T, Lucas P, Wilson S: The use of prolotherapy in the sacro-iliac joint. Br J Sports Med 2010;44:100-110.