K. Dean Reeves, M.D.
Clinical Associate Professor Physical Medicine and Rehabilitation
Emphasis on Research in Use of Prolotherapy (Also called Regenerative Injection Therapy)
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K. Dean Reeves, M.D. Clinical Associate Professor Physical Medicine and Rehabilitation
Emphasis on Research in Use of Prolotherapy (Also called Regenerative Injection Therapy)
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| Brief research summaries follow these abbreviations. (Page down). However more detailed information can be found by clicking on areas to the left according to the abbreviation guide. ANIMAL = Animal Research. IN VITRO = In vitro ("Test Tube") studies with human cells. RCT LBP = Randomized Clinical Trials in Low Back Pain
RCT ARTH = Randomized Clinical Trials in Arthritis RCT OM = Randomized Clinical Trials (Other) With Objective Measures
RCT OTH = Randomized Clinical Trials Without Objective Measures. CP OM = Consecutive Patients with Objective Measures
CP OTH = CP Other CASE OM = Case Studies With Objective Measures KEY REL = Key related research
ABBREVIATIONS FOR PROLIFERANT TYPE Dextrose(DEX), inflammatory non dextrose or combination proliferants (INFLAM), autologous blood (AB), platelet rich plasma (PRP) , neovessel treatment (NT), stem cell inclusive (SC).
A. Animal Research: For details click Animal
DEX: Jenson et al 2008 The
University of Wisconsin published their work in the rat
B. Human Cell Research: For details click IN VITRO
In Vitro Research: Primarily on Human Cells In summary, many studies have shown dextrose effects on growth factors. These are found in diabetic research due to the large interest in why dextrose elevations in diabetics causes unwanted growth of cells in many areas such as blood vessels in the eye, lining cells in arteries, glomerular cells in the kidney, etc. Those who consider dextrose a placebo are correct when it is taken by mouth but wrong when it is administered by injection, bypassing the effects of digestion. In prolotherapy the intent is not to elevate dextrose throughout the body. Rather the intent is to localize dextrose by injection to create a response at the site of injection only. Human cell studies are not including cartilage and ligament and tendon cells harvested from humans, such as patients during knee and hip replacements, enabling a number of studies to be done.
Both glucose (dextrose) and glucosamine increase hyaluronic acid production by synovial (joint lining) tissue from human knees. Uitterlinden EJ; Koevoet JL; Verkoelen CF; Bierma-Zeinstra SM; Jahr H; Weinans H; Verhaar JA; van Osch GJ. Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants [epub ahead of print] BMC Musculoskelet Disord (), Sep 11 2008, 9(1) p120.
Cells often produce growth factors which cause their own repair and multiplication. Ligament and tendon and cartilage cells are stimulated to produce the key growth factors for repair and replication by exposure to as little at 0.6% dextrose. Note also that growth factors for bone ARE NOT stimulated by dextrose exposure. Therefore there is no concern about causing spur formation of bony responses to dextrose. Reeves KD Topol GA Fullerton BD Evidence-based regenerative injection therapy (prolotherapy) in sports medicine. In Seidenberg PH, Beutler PI. (Eds). The Sports Medicine Resource Manual. Saunders (Elsevier); 2008: 611-619.
Anitua et al 2007: Growth Factors From Platelets Stimulate Hyaluronic Acid and Other Growth Factors As Well. E.Anitua, M. Sánchez, A. T. Nurden, M. M. Zalduendo, M. de la Fuente, J. Azofra and I. Andía Platelet-released growth factors enhance the secretion of hyaluronic acid and induce hepatocyte growth factor production by synovial fibroblasts from arthritic patients Rheumatology 2007 46(12): Karpie et al 2007 Injection of anesthetics likely damage cartilage. Recent work with cartilage cells taken from cows, and more lately humans indicate that lidicaine is bad for cartilage cells even with exposure as little as 15 minutes of 1% lidocaine..There is definitely cartilage cells death and especially the more concentrated and longer lasting the anesthetic. It is also important to point out that the fluid injected in knees is diluted rigtht away in the joint fluid. Nevertheless is makes us pause and consider whether we should be injecting lidocaine other than low concentration in joints. Karpie JC; Chu CR Lidocaine exhibits dose- and time-dependent cytotoxic effects on bovine articular chondrocytes in vitro. Am J Sports Med (United States), Oct 2007, 35(10) p1621-7 Chu CR; Izzo NJ; Coyle CH; Papas NE; Logar A The in vitro effects of bupivacaine on articular chondrocytes J Bone Joint Surg Br (England), Jun 2008, 90(6) p814-20
Morrison et al 2006: Injection of preservative (benzyl alcohol) may damage human cells. Work with live cartilage cells has not thus far included work with beyzyl alochol directly but two abstracts related to eyes are very important to consider. The eye fluid (vitreous) is a fluid area with a lot of hyaluronic acid, a bit like a synoviial joint. Tthe following stuidies show substantial harm to the retina in animals injected in the eye with steroids including the preservative benzyl alochol . This needs to be shown in other studies of course and specifically on cartilage cells but it raises a word of caution about the merit of "making our solutions safer" by putting preservative in them. Cliick KEY REL to view abstracts. Special thanks to Paul Tortland of Avon, Connecticut for drawing this to my attention first. Morrison VL; Koh HJ; Cheng L; Bessho K; Davidson MC; Freeman WR A Intravitreal toxicity of the kenalog vehicle (benzyl alcohol) in rabbits. Retina (United States), Mar 2006, 26(3) p339-44.
DEX: Yelland et al 2004 Injection alone, even without proliferant, is effective long term for chronic intractable back pain. Yelland MJ, Glasziou PP, Bogduk N, et al: Prolotherapy injections, saline injections, and exercises for chronic low-back pain: A randomized trial. Spine 29(1):9, 2004. PDG: (Phenol Dextrose Glycerine) Dechow et al 1999 Incorrect injection sites along with failure to examine lead to worse rather than better outcomes. Dechow E, Davies RK, Carr AJ, et al: A randomized, double-blind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology 39:1255, 1999. PDG: Klein et al 1993 Near significant (P = .056) evidence for superior effect of the inflammatory proliferant solution anesthetic needling (Klein et al) in chronic low back pain. 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 6:23, 1993. PDG: . Ongley et al 1987 Significant (P < .001) evidence for superior effect of the inflammatory proliferant solution over saline needling in chronic low back pain. Ongley MJ, Klein RG, Dorman TA, et al: A new approach to the treatment of chronic low back pain. Lancet 2:143, 1987.
D. Randomized Clinical Trials in Arthritis: For details click RCT ARTH
E. Randomized Clinical Trials with Objective Measures (IE Machine or Radiographic). For details click O.M. RCT
F. Randomized Clinical Trials: Other: For details click RCT OTH
Dextrose and Sodium morrhuate: Scarpone et
al 2008
H. Consecutive Patient Trials Other: For details click CP OTH
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; – .
25 consecutive patients with chronic low back pain localized to the SI joint region (posterior superior iliac spine) and positive on examination test for sacroiliac laxity/pain source were treated with 3 injections at 6 week intervals using 17% dextrose with CT guidance in the ligament and specifically not inside the joint itself. 12 month followup data revealed that the SI laxity maneuver score improved from a mean of 7.2 to 2.2 at 1 years (p < .001), the Quebec Pain Disability Scale improved from 57.7 to 39.5 (p = .002), the Roland Morris Back Pain Questionnaire improved from 13.3 to 7.2 (p = .001) and the Roland Morris Multi Form Questionnaire improved from 146.5 to 108.6 to 12 months. (P = .016) Cusi M; Saunders J; Hungerford B; Wisbey-Roth T; Lucas P; Wilson S. The use of prolotherapy in the sacro-iliac joint. [E pub ahead of print] Br J Sports Med (England), Published On line Apr 9 2008, doi:10.1136/bjsm.2007.042044.
I. Case Studies With Objective Measures: For details click CASE OM Dextrose + Sodium Morrhuate: Centeno
2008: Injection to Fullerton BD 2007 Healing of a
medial meniscus
J. Key Related Research: For details click KEY REL
Aprotinin injection helps repair Achilles and patellar tendon damage. Injection of Solutions that block breakdown of tissue may also help healing. Metalloproteinase (Collagenase is an example) breaks down issue and an inhibitor of metalloprotinease has been found to help some cases of tendon damage. Patellar tendon and Achilles tendon are two examples. Orchard J; Massey A; Brown R; Cardon-Dunbar A; Hofmann J. Successful management of tendinopathy with injections of the MMP-inhibitor aprotinin. |
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To contact us: General questions --> reevesoffice@kc.rr.com
Billing related questions --> reevesbilling@kc.rr.com
Research related questions --> dreeves1@kc.rr.com
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model this year showing that needle injection, with or without saline,
produces an inflammatory reaction. This means that saline injection
and injection with a needle are not a placebo. This is very
important in design of clinical studies.
Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R Early inflammatory
response of knee ligaments to prolotherapy in a rat model. J Orthop Res, Jun
2008, 26(6) p816-23
DEX: Park et al 2007 10%
Dextrose injection protects cartilage in
rabbits after cutting
the ACL.
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
Uitterlinden
et al 2008: Hyaluronic Acid (Joint Lubricant) Production Increases With Exposure
to Dextrose (Glusose ) or Glucosamine. 
Reeves
et al 2008: Growth Factor Production Occurs Promptly After Exposure By A Variety
of Body Cells to Dextrose and Thus Would Be Expected to Increase Hyaluronic Acid
Production as Well. 
C. Randomized Clinical Trials in Low Back Pain:
For Details Click 
DEX:
Reeves et al 2000-2: 10% dextrose
superior to hypotonic lidocaine in finger and thumb OA.
Injection was primarily periarticular here (medial and lateral) and in this
study 10% dextrose was superior with no obvious effect of control
solution. Reeves KD, Hassanein K. 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. 
Injection
of combination of sodium morrhuate (.72%) and dextrose (10.7%) on 3
occasions in patients with tennis elbow (lateral epicondylosis) resulted in
marked improvement in pain, wrist extension and grip strenth in comparision to
injection of saline.
Scarpone M, Rabago DP, Zgierska A, Arbogast G, Snell E. The efficacy of
prolotherapy for lateral epicondylosis: a pilot study [In Process Citation] Clin
J Sport Med (United States), May 2008, 18(3) p248-54 
Polidocanol: Alfredson et al 2005
Injection
of small amount of polidocanol were targeted using, ultrasound and color doppler
guidance, to areas of abnormal small blood vessels found just outside the tendon
on the anterior (deeper) side. The control group received anesthetic injection
to the same areas. 5/10 patients in the polidocanol group responded to treatment
within 2 treatments and the additional 5 responded to additional treatment. 0/10
of the anesthetic patients responded to 2 treatments, but this group then
received polidocanol injection and 9/10 responded. Alfredson
H; Ohberg L Sclerosing injections to areas of neo-vascularisation reduce pain in
chronic Achilles tendinopathy: a double-blind randomised controlled trial.
Knee Surg Sports Traumatol Arthrosc May 2005, 13(4) p338-44.
POLIDOCANOL: Alfredson et al
2005 15 elite or
recreational athletes with patellar tendinosis/jumpers knee were injected with
Polidocanol, targeting areas of neovascularization. At 6 month followup there
was a good clinical result in 12/15 tendons. With previous sport level reached
in 12/15 and pain decrease (VAS) from 81 to 10 on a 100 point scale. Alfredson
H; Ohberg L Neovascularisation in chronic painful patellar tendinosis--promising
results after sclerosing neovessels outside the tendon challenge the need for
surgery. Knee Surg Sports Traumatol Arthrosc (Germany), Mar 2005, 13(2) p74-80
DEX: Reeves et al 2003
Dextrose 10-25% tightens loose ACLReeves KD
Hassanein K Long term effects of dextrose prolotherapy for anterior cruciate
ligament laxity: A prospective and consecutive patient study. Alt Ther Hlth Med
May-Jun 2003, 9(3): p58-62.
Dextrose:
Topol et al 2008. Dextrose Injection for Groin Pain and Sports Hernia in Elite
Athletes Dextrose 12.5%
injection returns 66/72 elite rugby and soccer players to full sport who
were prevented from high level
Dextrose:
Khan et al 2008. Dextrose injection for chronic pain after coccyx
fracture. Treatment of coccygodynia after fracture
was the subject of a consecutive patient study recently published in the Journal
of Orthopedic Surgery. 30 out of 37 patients with chronic non-responding
coccygodynia responded to 2 injections of 20% dextrose. The recommendation was a
trial of dextrose prolotherapy prior to proceeding to coccygectomy. Khan
SA; Kumar A; Varshney MK; Trikha V; Yadav CS: Dextrose prolotherapy for
recalcitrant coccygodynia [In Process Citation] J Orthop Surg (Hong Kong)
(China), Apr 2008, 16(1) p27-9. 
Dextrose:
Cusi et al 2008: Dextrose injection markedly improves laxity testing of the SI
joint. 
DEX:
Miller et al 2006. 25% dextrose
injected in severely degenerative lumbar discs (too severe for IDET) with
multiple tears reduced pain in a durable manner. Effects were quick enough
to suggest a neurolytic mechanism via hypertonicity or other (IE neovessel)
mechanisms. Miller MR, Mathews RS, Reeves KD.
Treatment of painful advanced internal disc derangement with intradiscal
injection of hypertonic dextrose. Pain Physician 2006 9:115-121.
Shrink a Baker's Cyst WIth X-Ray Confirmation
Centeno et al demonstrated a case of MRI use to
demonstrate shrinking of a Baker's cyst by simply injecting the knee, since the
knee lining is connected with the Baker's cyst. This suggests a favorable
change in the joint to stop overproduction of joint fluid which allows the cyst
to shrink since it is connected with the knee joint. Simple intra articular
injection of 12.5% dextrose and sodium morrhuate on 3 occasions in a patient who
failed conservative care and drainage was described. In the present
and near future both MRI and ultrasound scans can be used to objectively
document in this way. Anticipate more such studies.
Centeno CJ; Schultz J; Freeman M. Sclerotherapy of Baker's cyst with imaging
confirmation of resolution. Pain Physician (United States), Mar-Apr 2008, 11(2)
p257-61 
tear. The
medial meniscus of the knee is non linear structure. Dr. Fullerton
published examples of regeneration from dextrose injection, including an example
of repair of a tear in the medial meniscus.. Image B was actually
taken after one injection and Image D after 3 injections, with the obvious tear
closing in favor of meniscus tissue with normal appearance. The patient stopped
having symptoms, the McMurray test became negative and the meniscus also healed
according to pre and post MRI scans. Fullerton
BD. High-Resolution Ultrasound and Magnetic Resonance Imaging to Document Tissue
Repair After Prolotherapy Arch PM&R 2008. 89(2):377-385
