K. Dean Reeves, M.D.

Clinical Associate Professor            Physical Medicine and Rehabilitation

Emphasis on Research in Use of Prolotherapy (Also called  Regenerative Injection Therapy)

Spectrum of Research- Research Results in Regenerative Injection Therapy (Prolotherapy) 

American Academy of Orthopaedic Medicine 

24th Annual Conference and Scientific Seminar

April 11-14, 2007

The Rivera Hotel, Las Vegas, Nevada 

Greetings From A  University of Kansas Jayhawk

K. Dean Reeves, M.D. 

Clinical Associate Professor 

Physical Medicine and Rehabilitation 

DrReeves.com    dreeves1@kc.rr.com

The concept of prolotherapy is completely misunderstood by most.

Reeves KD. Prolotherapy:Regenerative Injection Therapy. In: Waldman SD (ed): Pain Management. Philadelphia; Elsevier; 2007; pg 1106-1127. 

Growth of new tissue does not require inflammation.  Acute inflammation does elevate levels of growth factors, (complex proteins that repair and grow new cells) but growth factor levels can be elevated in other ways that are not by inflammation. Also, scarring does not occur with prolotherapy. Instead prolotherapy causes growth of normal, organized tissue. This is demonstrated by use of serial X-Rays that look at ligament and tendon (ultrasound) and by biopsy studies. 

Types of Prolotherapy

Reeves KD Fullerton BD Topol GA Evidence-based regenerative injection therapy in sports medicine. In Seidenberg PH. Sports Medicine. Elsevier; 2007: Pending.

Regenerative injection can use: 
Single growth factor injection:  Injection of special proteins that turn on cell growth.  This is not very helpful since normal healing requires cooperation of several or many growth factors.  

Multiple Growth Factor Injection:  Injection of many growth factors at one time.  In normal healing, many growth factors work together.   The least expensive way to provide these growth factors is to inject a patients own blood or to concentrate the clear part of the blood called the plasma.  Blood has many important growth factors.  

Multiple growth factor stimulation:   The body produces its own growth factors and cells in an area of weakness or damage can be stimulated to do so rather easily by by injecting a simple dextrose solution.   Dextrose concentrations of 0.6% to 10% stimulate  key growth factor production without inflammation.

Inflammatory Injection:  Chronic inflammation is harmful, but prolotherapy with inflammatory solutions creates a temporary inflammation, which is how we always heal from injury.  Without temporary inflammation, none of our injuries in everyday life would heal.   This temporary inflammation is typically started with Dextrose concentrations more than 10%, Phenol, or Sodium Morrhuate. 

Needle Stimulation Alone Is Helpful, Making It Difficult to Find a  Control for Research

19% improvement (sustained 6 mo) in chronic low back pain  (LBP)with saline injections with bone contact.  Ongley MJ, Klein RG, Dorman TA, et al. A New Approach to the Treatment of Chronic Low Back Pain. Lancet 1987; 2: 143-146.

27% improvement (sustained 6 mo) in chronic LBP with anesthetic injection with bone contact. Klein RG, Bjorn CE, DeLong B, et al. A randomized double-blind trial of dextrose-glycerine-phenol injections for chronic low back pain. J Spinal Disord 1993; 6: 23-33.

36% improvement (sustained 1 yr) in chronic LBP with saline injection with bone contact   Yelland MJ, Glasziou PP, Bogduk N, et al. Prolotherapy Injections, Saline Injections, and Exercises for Chronic Low-Back Pain: A Randomized Trial. Spine 2004; 29(1): 9-16.

Also evidence of benefit from needling alone with bone contact in arch pain (plantar (fasciosis) and in tennis elbow (lateral epicondylosis) 

Kiter E, Celikbas E, Akkaya S, Demirkan F, Kilic BA. Comparison of injection modalities in the treatment of plantar heel pain: a randomized controlled trial. J Am Podiatr Med Assoc (United States), Jul-Aug 2006, 96(4) p293-6.

Altay T, Gunal I, Ozturk H. Local injection treatment for lateral epicondylitis. Clin Orthop, May 2002, (398) p127-30.

Keys to Controlling  Clinical Research in Prolotherapy 

Avoid bone contact: Example knee study with simple single needle entry without bone contact. 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

Add non injection arm:  Example study underway at Univ. Of Wisconsin on Knee Arthritis and study underway on Osgood Schlatter Disease

Reeves KD, Fullerton BD, Topol GA, Bancroft G. Study seeks treatment to keep athletes in the game. The effects of Osgood-Schlatter disease can extend beyond resolution of pain to a patient’s sports career. Biomechanics 2006; 13(4):31-39.

Growth Factor Teamwork Is Critical

Molloy T, Wang Y, Murrell G. The roles of growth factors in tendon and ligament healing. Sports Med, 2003, 33(5) p381-94.

M= Stimulate migration of new cells to the area. G= Grow new cells locally

V = Grow additional blood vessels

R = Remodeling of tissue

C = Collagen production. 

Producing Growth Takes More Than Growth Factors.  IE: Several Critical Stages

(Note this system is a strong example of irreducible complexity and could not have occurred in stages, and thus a stepwise process such as evolution could not produce this system) 

1.  Produce a team of GFs

2.  Escape being tied up by binding proteins. 

Although sometimes binding proteins can support or help growth factors rather than bind them and prevent them from working.  

3.  Overcome disrepair factors 

IE: Interleukins, metalloproteinases.

4.  Hook up with a receptor on the cells surface specific for the growth factor and able to carry the effect into the cell.

5.  Turn on growth and repair

Dextrose Research: The Spectrum

1. Animal Study: Cartilage protection in Knees. 2007 Study

2. Human cells: GF and proliferant effects of dextrose > 0.6%

3.  Human joint: DB study knee, DB study fingers.

4.  Human ligament/tendon:

        4A.  Machine documented change: KT-1000 ACL.

        4B.  Consecutive patient elite athlete studies: Groin pain.

        4C.  Large consecutive patient studies. Back pain pending.

        4D.  Radiographic documented change: Ultrasound 

5.  Dextrose plus disrepair factor blocker:  In design.

6.  Dextrose Neurolytic Effect:   Disc Injection study 

1. Animal Study:  Cartilage Repair

Park Y, Lim S, Lee I, Lee T, Kim T, Han JS. Intra-articular injection of a nutritive mixture solution protects articular cartilage from osteoarthritic progression induced by anterior cruciate ligament transection in mature rabbits: a randomized controlled trial. Arthritis Research & Therapy 2007. 9(1):R8

Cut ACL in rabbits –> Substantial OA in 3 months --> Inject 10% dextrose versus saline in left knee only with right uninjected knee as control  --> 19 week animal sacrifice and cartilage examination.

Results: Control knee approx = dextrose

Saline significantly worse than dextrose.

Stains  showing cartilage preserving effects of simple dextrose injection.

Left: Control Knee. Note no significant surface irregularity

Middle:  Dextrose-injected knee: Moderate surface irregularity, swelling of cartilage cells, extra cells.

Right:  Saline-injected knee: Severe surface irregularity. Cartilage cell loss. Loss of cartilage down to bone. 

2.   Human Cell Dextrose Effects 

P = Platelet derived growth factor  T = Transforming growth Factor beta

E = Epidermal growth Factor   B = basic Fibroblast Growth factor  

I = Insulin-like growth factor   C = Connective tissue growth factor 

3A.  Large Human Joint Studies: Ex Double Blind Knee Arthritis Study 

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):37-46.

111 knees. 35 with no cartilage left in at least one compartment. 

9 ml of 10% dextrose versus anesthetic @ 0, 2, and 4 months. 

---> Dextrose solution  group was better at 6 months. (P = .015) 

Flexion range of motion improved 13.2 degrees.

3B.  Small Human Joint Studies: Ex Double Blind Finger Arthritis Study 

Randomized prospective placebo controlled double blind study of dextrose prolotherapy for osteoarthritic thumbs and finger (DIP, PIP and Trapeziometacarpal) joints: Evidence of Clinical Efficacy. Jnl Alt Compl Med 2000;6(4):311-320.

150 joints in 27 patients. 1/4 to 1/2 ml each side of joint @ 0, 2, 4 months 

Dextrose solution improved movement  pain (p = .027) and range (p = .003) more than lidocaine injection.

4A.  Human Ligament/Tendon 

Machine Documented Change: Ex ACL

Reeves KD Hassanein KM Long term effects of dextrose prolotherapy for anterior cruciate ligament laxity: A prospective and consecutive patient study. Alt Ther Hlth Med (United States), May-Jun 2003, 9(3) p58-62.

Range of motion of the knee in these patients who also had substantial arhritis improved by 10.5 degrees over 3 years.  Improvements in walking pain and swelling of the knee and tightness of the knee improved over 3 years as well as seen below 

4B.  Human Ligament/Tendon Consecutive Elite Athlete Studies:  Ex  Groin Pain

Topol GA, Reeves KD, Hassanein K. Efficacy of Dextrose Prolotherapy in Elite Male Kicking-Sport Athletes With Chronic Groin Pain. Archives Phys Med Rehabil, 2005;86:697-702.

24 players (22 Rugby)  with groin pain preventing full performance chronically

Failure of physical therapy approaches

Injection of 12.5% Dextrose + 0.5 lidocaine 

2.8 Rx average  led to 84% average decrease in pain and 22/24 athletes then played their sport fully.

Note a follow up study with 75 athletes is underway. 

4C. Human Ligament/Tendon Large Consecutive Patient Study.  Ex:  Chronic Low Back Pain. 

In pre publication phase at this time. 

485 consecutive patient study of regenerative injection (primarily with dextrose) in virtually all comers with low back pain. 

95% data capture

Only 2.3 treatments sessions needed

Results excellent --> To be reported at conference by Dr. John Merriman 

4D: Human Ligament/Tendon Objective X-Rays Studies:  Ex Patellar Tendon Serial Ultrasound 

Reeves KD Fullerton BD Topol GA Evidence-based regenerative injection therapy in sports medicine. In Seidenberg PH. Sports Medicine. Elsevier; 2007: Pending

An example of repair of a patellar tendon by simple dextrose injection is shown below. 

In this picture the big black area is the front of the bone below the knee that the patellar tendon attaches to and the

5.  Dextrose plus disrepair factor blocker:  At this point the only disrepair factor blocker in clinical use is steroid.   Studies to look at whether steroid injection is more or less effective with lidocaine alone or lidocaine plus dextrose have not been performed. Therefore, regardless of what fluid the physician chooses to dilute the steroid in to deliever it, the process is considered steroid injection and not prolotherapy. 

6.  Dextrose Neurolytic Effect:    

This Disc Injection study is an example where results occurred in hours to days rather than weeks, indicating the effect here was not proliferation, but rather a neurolytic (nerve blocking) effect.  Again this is an effect of dextrose but it is not prolotherapy.   It is of interest, however, that these were consecutive patients with multiple grade IV or V tears. (Severe disc disease too badly affected for any other treatment except fusion).   33 out of 76 were sustained reponders to hypertonic (25%) dextrose injection with 77% improvement at 18 months follow up.   

Whole  Blood and Platelet Rich Plasma

Whole blood (WB) and platelet rich plasma (PRP) have many potent growth factors useful in stimulating regeneration/repair in connective tissue (ligament/tendon). At this point there are less studies on WB and PRP but a number of studies are underway or in the design phase.   So far there are no studies on growth factor effects on human cells.   Animal work is promising.  There is no clear advantage demonstrated yet for platelet rich plastma over whole blood use.  This treatment will be more expensive than dextrose injection but potency may be enough to overcome the expense difference.  For more information please see.

Reeves KD Fullerton BD Topol GA Evidence-based regenerative injection therapy in sports medicine. In Seidenberg PH. Sports Medicine. Elsevier; 2007: Pending

Summary of Regenerative Injection Therapy (Prolotherapy) Research Thus Far: 

Dextrose is the most studied regenerative injection solution to this point.   Elevated dextrose levels as little as 0.6% have proven effects on elevating multiple key growth factor levels in human cells. Protective effects on cartilage are indicated by a recent animal study and by fovorable outcomes clinically in double blind studies on large and small human joints.  A reparative effect on the ACL ligament has been demonstrated by a machine measurement study, and a consecutive elite athlete study has demonstrated a very favorable results.  Very large consecutive patient studies, such as on low back pain, are nearing publication.  Objective radiographic evidence of healing of connective tissue by dextrose injection is in process of publication.  Overall the literature on the regeneration effects and clinical benefit of dextrose injection is convincing for those who read the literature, and evidence is growing rapidly. However, there is no drug company or patient advocacy group pressing hard for insurance coverage and with substantial treatment method variation  between physicians, coverage by insurance is expected to be delayed.   

Funding Help needed:   Overseas research emphasis is better for both cost and compliance reasons.  A team has been developed to emphasize this in particular.  See below.  

If the reader is aware of any physician or patient who has benefited from proliferant injection and able to support research financially, the KAT (Kansas[Dr Reeves] Argentina [Dr Topol] Texas [Dr Fullerton]) research team is in need of $4,000 per month to complete current projects.  These researchers have completely self funded their research to this point but are unable to do do indefinitely.  Please contact  Dr. Reeves if so at dreeves1 @ kc.rr.com and he will direct you to the Hackett Foundation which can accept and direct donations for regenerative injection therapy research. 

For those wanting resources, almost all icons above represent studies that have a pdf availble on this website.  Please click on research to find most of these.

Good Day To You. Hope this has been helpful. 

Dr Reeves 

To contact us:   General questions  --> reevesoffice@kc.rr.com    Billing related questions -->   reevesbilling@kc.rr.com   Research related questions -->  dreeves1@kc.rr.com  
Last modified: September 28, 2008