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'''Editors-In-Chief:''' [[User:Bobby Schwartz|Robert G. Schwartz, M.D.]] [mailto:RGSHEAL@aol.com], [http://www.piedmontpmr.com Piedmont Physical Medicine and Rehabilitation, P.A.]; Dean Reeves, M.D., Clinical assistant/associate professor University of Kansas Medical School, Dept of Physical Medicine and Rehabilitation 1986-2015; Felix Linetsky, M.D., Clinical Associate Professor, Department of Osteopathic Principles and Practice, Nova Southeastern College of Osteopathic Medicine [mailto:flinetsky@me.com]   
'''Editors-In-Chief:''' [[User:Bobby Schwartz|Robert G. Schwartz, M.D.]] [mailto:RGSHEAL@aol.com], [http://www.piedmontpmr.com Piedmont Physical Medicine and Rehabilitation, P.A.]; Dean Reeves, M.D., Clinical assistant/associate professor University of Kansas Medical School, Dept of Physical Medicine and Rehabilitation 1986-2015; Felix Linetsky, M.D., Clinical Associate Professor, Department of Osteopathic Principles and Practice, Nova Southeastern College of Osteopathic Medicine [mailto:flinetsky@me.com]   


Note for recent edits Captcha has been blocking external links so additional references have been placed after each paragraph until administration can correct that. See support desk comment "When editing, asking to type two words in a box that does not exist"  (Dr Reeves)  
Note for recent edits Captcha has been blocking external links so additional references have been placed in an "Additional References" section  until administration can correct that. See support desk comment "When editing, asking to type two words in a box that does not exist"  (Dr Reeves)  
   
   
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Stimulation of tissue growth was then confirmed by Mayo Clinic researchers (Biomechanics Laboratory, Division of Orthopedic Research, and Department of Neurology),(Oh 2008, Yoshii 2009, Yoshii 2011, Yoshii 2014), who performed four controlled studies (three blinded) to determine if dextrose could thicken and strengthen a rabbit ligament without inflammation and with production of normal tissue without any scarring. Their purpose was to thicken the ligament that is responsible for producing carpal tunnel syndrome so that they would have an animal model for research.  In the process, results in every study showed that 10% dextrose injection, compared to saline injection, consistently resulted in a increase in total energy absorption and tensile load tolerated by the ligament (transverse carpal ligament equivalent) before rupture. The ligament approximately doubled in thickness and, histologically was normal tissue, without scarring.  This proliferation effect with normally organized fibrosis (growth of connective tissue) in the absence of scarring distinguishes prolotherapy from [[sclerotherapy]]. ''Oh S, Ettema AM, Zhao C, Zobitz ME, Wold LE, An KN, et al. Dextrose-induced subsynovial connective tissue fibrosis in the rabbit carpal tunnel: A potential model to study carpal tunnel syndrome? Hand 2008;3:34-40. DOI: 10.1007/s11552-007-9058-y'' ''Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. The effects of hypertonic dextrose injection on connective tissue and nerve conduction through the rabbit carpal tunnel. Arch Phys Med Rehabil 2009;90:333-9. DOI: 10.1016/j.apmr.2008.07.028'' ''Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. Effects of hypertonic dextrose injections in the rabbit carpal tunnel. J Orthop Res 2011;29:1022-7. DOI: 10.1002/jor.21297'' ''Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. Effects of multiple injections of hypertonic dextrose in the rabbit carpal tunnel: a potential model of carpal tunnel syndrome development. Hand (N Y) 2014;9:52-7. DOI: 10.1007/s11552-013-9599-1''
Stimulation of tissue growth by dextrose prolotherapy was confirmed by Mayo Clinic researchers (Biomechanics Laboratory, Division of Orthopedic Research, and Department of Neurology),(Oh 2008, Yoshii 2009, Yoshii 2011, Yoshii 2014), who performed four controlled studies (three blinded) to determine if dextrose could thicken and strengthen a rabbit ligament without inflammation and with production of normal tissue without any scarring. Their purpose was to thicken the ligament that is responsible for producing carpal tunnel syndrome so that they would have an animal model for research.  In the process, results in every study showed that 10% dextrose injection, compared to saline injection, consistently resulted in a increase in total energy absorption and tensile load tolerated by the ligament (transverse carpal ligament equivalent) before rupture. The ligament approximately doubled in thickness and, histologically, normal tissue was seen without scarring.  This proliferation effect with normally organized fibrosis (growth of connective tissue) in the absence of scarring distinguishes prolotherapy from [[sclerotherapy]].  




Prolotherapy is often used as an treatment option rather than antiinflammtory approaches (such as steroids or non steroid antiinflammatory drugs [NSAIDS]) in the presence of chronic pain involving ligaments and tendons, as chronic changes in ligaments and tendons are primarily degenerative in nature rather than primarily inflammatory. (Scott 2015). Prolotherapy is also used as an alternative in the presence of chronic pain involving joints, in which histologic findings are also primarily degenerative.  Lack of benefit in general with anti-inflammatory approaches on the clinical course of osteoarthritis is emphasized by a recent clinical  trial of saline versus steroid (triamcinolone) injection in knee osteoarthritis showing unequivocal acceleration of cartilage loss with quarterly injection of steroid for 2 years in comparison with a saline control injection, reported in JAMA. (McAlindon 2017) ''Scott A, Backman LJ, Speed C. Tendinopathy: Update on Pathophysiology. J Orthop Sports Phys Ther 2015;45:833-41. DOI: 10.2519/jospt.2015.5884''  ''McAlindon TE, LaValley MP, Harvey WF, Price LL, Driban JB, Zhang L, et al. Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis: A Randomized Clinical Trial. JAMA 2017;317:5283. DOI: 10.1001/jama.2017.5283''
Prolotherapy is often used as an treatment option rather than antiinflammatory approaches (such as steroids or non steroid antiinflammatory drugs [NSAIDS]) in the presence of chronic pain involving ligaments and tendons, as chronic changes in ligaments and tendons are primarily degenerative in nature rather than primarily inflammatory. (Scott 2015). Prolotherapy is also used as an alternative in the presence of chronic pain involving joints, in which histologic findings are also primarily degenerative.  Lack of benefit in general with anti-inflammatory approaches on the clinical course of osteoarthritis is emphasized by a recent clinical  trial of saline versus steroid (triamcinolone) injection in knee osteoarthritis showing unequivocal acceleration of cartilage loss with quarterly injection of steroid for 2 years in comparison with a saline control injection, reported in JAMA. (McAlindon 2017)  




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==Prolotherapy in clinical practice==
==Prolotherapy in clinical practice==


Prolotherapy involves the injection of either an irritant or proliferant solution into the area where connective tissue has been weakened or damaged through injury or strain. Many solutions are used, including [[Dextrose]], [[Lidocaine]] (a commonly used local anesthetic), [[Phenol]] (an alcohol), [[Glycerine]], [[Cod Liver Oil]] extract or Sodium Morrhuate .  The injection is placed onto ligament, into joint capsules or where [[tendon]] connects to bone. Many points may require injection. The Injected solution causes the body to heal itself through the process of [[inflammation]] and repair.  In the case of weakened or torn connective tissue, induced inflammation and release of growth factor at the site of injury may result in a 40% strengthening of the attachment points.
===Solutions===
Prolotherapy solutions are commonly injected into the area where connective tissue has been weakened or damaged through injury or strain. The injection is placed into ligaments, into joint capsules or where [[tendon]] connects to bone. Many points may require injection. The most commonly used solutions in order from most common to less commonly used and in order from least to most inflammatory include [[Dextrose]], P2G (a combination of dextrose and low d ose [[Phenol]] and [[Glycerine]], and sodium morrhuate.  


Most clinicians say that at least three injections, done at 2-3 week intervals, are required to accomplish this result. In addition, patients may receive treatment beyond the initial three injections until treatments are required only every several years, if at all.<ref name="RationalForProlotherapy">{{cite web|url= http://www.prolotherapy.com/articles/banks.htm |title=A Rationale for Prolotherapy}}</ref>  Allen R Banks, Ph.D., has described in detail the theory behind prolotherapy in "A Rationale for Prolotherapy".<ref name="RationalForProlotherapy" /> Robert G. Schwartz, MD has also published a biochemical literature review on the topic "Prolotherapy: A Literature Review and Retrospective Study"[http://www.piedmontpmr.com/prolotherapy-treatment-for-ligament-pain].
===Mechanism===
The mechanism is often described as initiation of a brief inflammatory reaction to stimulate the repair cascade, but is likely complex. (Rabago 2017-1) Time-limited reactive inflammation has been confirmed in animal models in which dextrose concentrations exceed 12.5% (Jensen 2008), some evidence of cartilage cell growth has been suggested upon repeat arthroscopy in humans,(Topol 2016), ligament growth without inflammatory required was described above in a series of controlled studies,(see overview section)  and a direct therapeutic sensorineural effect has been proposed with early clinical support. (Yelland 2009 )
 
The theory of inflammatory prolotherapy was nicely summarized by Allen R Banks, Ph.D., in "A Rationale for Prolotherapy".<ref name="RationalForProlotherapy">{{cite web|url= http://www.prolotherapy.com/articles/banks.htm |title=A Rationale for Prolotherapy}}</ref> Robert G. Schwartz, MD has also published a biochemical literature review on the topic "Prolotherapy: A Literature Review and Retrospective Study"[http://www.piedmontpmr.com/prolotherapy-treatment-for-ligament-pain]. Recent reviews of basic science are available in several recent publications which cover the spectrum of mechanisms. (Rabago 2017-2, Reeves 2016) 
 
===Typical Treatment Course===
Most clinicians say that at least three injections, done at 2-8 week intervals, are typically required to accomplish the desired result, but accuracy and completeness of treatment  are likely key to treatment efficiency, and determination of optimal treatment approaches will require diagnosis-specific research. Given the non-proprietary nature of proliferant agents in current use, this will also take considerable time due to lack of financial incentives to support non-pharmacutical research. 


===History===
===History===
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'''General Narrative Review Articles 2005 to 2011'''  
'''General Narrative Review Articles 2005 to 2011'''  


The first comprehensive review article on safety and potential efficacy of prolotherapy was published in 2005. (Rabago 2005) On the basis of 34 case reports or case series, 2 nonrandomized controlled trials, and 6 RCTs, prolotherapy was considered “safe when performed by an experienced clinician” but  “conclusive data for prolotherapy as a treatment for musculoskeletal  pain was lacking”. Since 2010 there has been an acceleration in publication of randomized controlled trials (RCTs) for dextrose prolotherapy and both general and specific systematic reviews. A 2011 review noted growing evidence to recommend use in tendinopathies  and early evidence  of benefit in osteoarthritis. (Distel 2011)  
The first comprehensive review article on safety and potential efficacy of prolotherapy was published in 2005. (Rabago 2005) On the basis of 34 case reports or case series, 2 nonrandomized controlled trials, and 6 RCTs, prolotherapy was considered “safe when performed by an experienced clinician” but  “conclusive data for prolotherapy as a treatment for musculoskeletal  pain was lacking”. Since 2010 there has been an acceleration in publication of randomized controlled trials (RCTs) for dextrose prolotherapy and both general and specific systematic reviews. A 2011 review noted growing evidence to recommend use in tendinopathies  and early evidence  of benefit in osteoarthritis. (Distel 2011)




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In the field of general practice, a practical way to consider the merit of employing a specific treatment for a specific condition was developed by Ebell et al,(Ebell 2004) and has been increasingly utilized. It is called the Strength of Recommendation Taxonomy and is composed of 3 assessments, study quality (bias), study quantity (and number of subjects), and study consistency (do studies agree?). Strength of recommendations were included as part of narrative reviews beginning with Covey at al (Covey 2015) who assigned a level A strength of recommendation (SOR) (recommendation based on consistent and good-quality patient-oriented evidence) for dextrose prolotherapy for knee osteoarthritis and level B SOR (recommendation based on inconsistent or limited-quality patient-oriented evidence) for Achilles tendinopathy, lateral epicondylosis, Osgood Schlatter disease, and plantar fasciosis.  Two 2016 general review articles expanded level B strength of recommendations to  include low back/sacroiliac pain and rotator cuff tendinopathy. (Reeves 2016, Hauser 2016) A SOR for the use of prolotherapy in acute pain, myofascial pain or as first-line therapy, cannot be determined based on current literature. (Hauser 2016) It is important to keep in mind, when considering the assignment of strength of recommendation, that a single RCT cannot lead to a level A SOR recommendation. Thus despite a single high quality study the SOR will only be B (recommendation based on inconsistent or limited-quality patient-oriented evidence). In a field in which research is virtually all self-funded, with no proprietary interest, studies will accumulate slowly and a level B recommendation may mean a "poor quantity" of studies or low patient numbers, rather than "poor quality".  
In the field of general practice, a practical way to consider the merit of employing a specific treatment for a specific condition was developed by Ebell et al,(Ebell 2004) and has been increasingly utilized. It is called the Strength of Recommendation Taxonomy and is composed of 3 assessments, study quality (bias), study quantity (and number of subjects), and study consistency (do studies agree?). Strength of recommendations were included as part of narrative reviews beginning with Covey at al (Covey 2015) who assigned a level A strength of recommendation (SOR) (recommendation based on consistent and good-quality patient-oriented evidence) for dextrose prolotherapy for knee osteoarthritis and level B SOR (recommendation based on inconsistent or limited-quality patient-oriented evidence) for Achilles tendinopathy, lateral epicondylosis, Osgood Schlatter disease, and plantar fasciosis.  Two 2016 general review articles expanded level B strength of recommendations to  include low back/sacroiliac pain and rotator cuff tendinopathy. (Reeves 2016, Hauser 2016) A SOR for the use of prolotherapy in acute pain, myofascial pain or as first-line therapy, cannot be determined based on current literature. (Hauser 2016) It is important to keep in mind, when considering the assignment of strength of recommendation, that a single RCT cannot lead to a level A SOR recommendation. Thus despite a single high quality study the SOR will only be B (recommendation based on inconsistent or limited-quality patient-oriented evidence). In a field in which research is virtually all self-funded, with no proprietary interest, studies will accumulate slowly and a level B recommendation may mean a "poor quantity" of studies or low patient numbers, rather than "poor quality".  


'''Back pain/Sacroiliac Pain Articles: Treatment Comparison Trials Rather Than Placebo Trials Due to Extensive Needling Effects'''
'''Back pain/Sacroiliac Pain Articles: Treatment Comparison Trials Rather Than Placebo Trials Due to Extensive Needling Effects'''


A 2007 review of prolotherapy in adults with chronic low-back pain found unclear evidence of effect. (Dagenais 2007) A 2009 review mentioned prolotherapy but did not review the studies and deferred to the 2007 review.(Staal 2009) There was tentative evidence of benefit when used with other low back pain treatments. (Distel 2001) These prior reviews focused primarily on phenol-containing solutions, which have declined in use in favor of hypertonic dextrose which is less inflammatory and better studied. (Rabago 2017) More recent reviews of dextrose-only studies interpreted the dextrose-only controlled trials as treatment comparison studies in that the first study (Yelland 2003) utilized a control with substantial needling effect on multiple occasions and both saline and dextrose groups had a persistent benefit with "greater than 50% pain reduction in 46% and 36% of dextrose and saline groups respectively at 12 months," (Reeves 2016) and the second study favored dextrose over steroid injection (triamcinolone) for injection of the SI joint.(Kim 2010) Recent reviews conclude that evidence of benefit remains tentative (level B) for dextrose prolotherapy in low back/sacroiliac pain based on two favorable but inconsistent treatment comparison studies. (Reeves 2016. Hauser 2016)
A 2007 review of prolotherapy in adults with chronic low-back pain found unclear evidence of effect. (Dagenais 2007). There was tentative evidence of benefit when used with other low back pain treatments. (Distel 2011) These prior reviews focused primarily on phenol-containing solutions, which have declined in use in favor of hypertonic dextrose which is less inflammatory and better studied. (Rabago 2017) More recent reviews of dextrose-only studies interpreted the dextrose-only controlled trials as treatment comparison studies in that the first study (Yelland 2003) utilized a control with substantial needling effect on multiple occasions and both saline and dextrose groups had a persistent benefit with "greater than 50% pain reduction in 46% and 36% of dextrose and saline groups respectively at 12 months," (Reeves 2016) and the second study favored dextrose over steroid injection (triamcinolone) for injection of the SI joint.(Kim 2010) Recent reviews conclude that evidence of benefit remains tentative (level B) for dextrose prolotherapy in low back/sacroiliac pain based on two favorable but inconsistent treatment comparison studies. (Reeves 2016. Hauser 2016)
 


==Criticism==
==Criticism==
While many major [[medical insurance]] policies cover the treatment, not all do. Twenty years ago (After a 1999 review of the medical evidence) Medicare declined prolotherapy coverage for chronic low back pain (citing that prolotherapy "was last examined for coverage by the Health Care Financing Administration (HCFA) in September 1992").<ref>[http://www.quackwatch.org/01QuackeryRelatedTopics/prolo.html] HCFA Decision Memorandum</ref>
In 1999, Medicare considered the low back clinical trials on prolotherapy at that time (which were with P2G only) and determined that prolotherapy would remain a non-covered service for low back pain.  ''cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=68&fromdb=true'' Their concerns were insufficient patient numbers in the trials (only 160 patients to that point) and flaws in the clinical studies. Other insurers have mirrored Medicare's position, and, over the years, although randomized trials have continued to increase in numbers and quality, the number of studies in any one area have not accumulated sufficiently to challenge Medicare's determination. Level A SOR requires multiple randomized controlled trials that agree and the study numbers are diluted across a great variety of clinical conditions. Treatment of knee osteoarthritis with prolotherapy has reached a level A SOR, and some insurers cover prolotherapy for knee osteoarthritis.  


===Ongoing Study===
====Knee injuries====
A randomized, [[double-blind]], [[placebo]] control study is currently recruiting patients to determine whether prolotherapy can decrease pain and disability from knee [[osteoarthritis]].  This study is Sponsored by the National Center for Complementary and Alternative Medicine ([[NCCAM]]).<ref>[http://clinicaltrials.gov/show/NCT00085722] Clinicaltrials.Gov, Joint Injections for Osteoarthritic Knee Pain, web page last updated October 16, 2006</ref>
====Tennis elbow====
A randomized, [[double-blind]], [[placebo]] control study is currently recruiting patients to determine whether prolotherapy can be an effective treatment for lateral epicondylitis (tennis elbow).<ref>http://clinicaltrials.gov/ct2/show?cond=%22Tennis+Elbow%22&rank=3 Clinicaltrials.Gov, Efficacy Study of Prolotherapy vs Corticosteroid for Tennis Elbow</ref>


==See also==
==See also==
*[[Pin firing]]
*[[Pin firing]]
*Gustav Hemwall
*Gustav Hemwall
==Additional References==
Covey 2015  ''Covey CJ, Sineath MHJ, Penta JF, Leggit JC. Prolotherapy: Can it help your patient? J Fam Pract 2015;64:763-8. PMCID: PMID: 26844994''
Dagenais 2007  ''Dagenais S, Caro J, Haldeman S. A systematic review of low back pain cost of illness studies in the United States and internationally. Spine J 2007;8:8-20. DOI: 10.1016/j.spinee.2007.10.005''
Distal 2011  ''Distel LM, Best TM. Prolotherapy: a clinical review of its role in treating chronic musculoskeletal pain. PMR 2011;3:S78-81. DOI: 10.1016/j.pmrj.2011.04.003 ''
Ebell 2004  ''Ebell MH, Siwek J, Weiss BDW, S.H., Susman J, Ewigman BB, M. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:549-56. PMCID: 14971837 ''
Hauser 2016  ''Hauser RA, Lackner JB, Steilen-Matias D, Harris DK. A Systematic Review of Dextrose Prolotherapy for Chronic Musculoskeletal Pain. Clin Med Insights Arthritis Musculoskelet Disord 2016;9:139-59.  DOI: 10.4137/CMAMD.S39160''
Jensen 2008  ''Jensen KT, Rabago D, Best TM, Patterson JJ, Vanderby R. Early inflammatory response of knee ligaments to prolotherapy in a rat model. J Orthop Res. 2008;26(6):816–23. DOI: 10.1002/jor.20600''
McAlindon 2017  ''McAlindon TE, LaValley MP, Harvey WF, Price LL, Driban JB, Zhang L, et al. Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis: A Randomized Clinical Trial. JAMA 2017;317:5283. DOI: 10.1001/jama.2017.5283''
Oh 2008  ''Oh S, Ettema AM, Zhao C, Zobitz ME, Wold LE, An KN, et al. Dextrose-induced subsynovial connective tissue fibrosis in the rabbit carpal tunnel: A potential model to study carpal tunnel syndrome? Hand 2008;3:34-40. DOI: 10.1007/s11552-007-9058-y''
Rabago 2005  ''Rabago D, Best TM, Beamsley M, Patterson J. A systematic review of prolotherapy for chronic musculoskeletal pain. Clin J Sport Med 2005;15:366-80. PMCID: 16162983''
Rabago 2017-1  ''Rabago D, Nourani B. Prolotherapy for Osteoarthritis and Tendinopathy: a Descriptive Review. Curr Rheumatol Rep 2017;19:34.  DOI: 10.1016/j.ctim.2015.04.003''
Rabago 2017-2 ''Rabago D, Nourani B, Reeves KD, Weber M. Prolotherapy: Histology, biology, mechanism of  action, preparation and clinical applications In: Manchikanti L, Navani A, eds. Essentials of regenerative medicine in interventional pain management 2017: In Press.''
Reeves 2016 ''Reeves KD, Sit RWS, Rabago D. A narrative review of basic science and clinical research, and best treatment recommendations. Phys Med Rehabil Clin Nth Am 2016;27:783-823. DOI: 10.1016/j.pmr.2016.06.001''
Scott 2015  ''Scott A, Backman LJ, Speed C. Tendinopathy: Update on Pathophysiology. J Orthop Sports Phys Ther 2015;45:833-41. DOI: 10.2519/jospt.2015.5884''
Topol 2016  ''Topol GA, Podesta LA, Reeves KD, Giraldo MM, Johnson LJ, Grasso R, et al. The chondrogenic effect of intra-articular hypertonic-dextrose (prolotherapy) in severe knee osteoarthritis. PM&R 2016;8:1072-82. DOI:10.1016/j.pmrj.2016.03.008.''
Yelland 2004  ''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 2004;29:9-16. PMID:14699269''
Yelland 2009  ''Yelland MJ, Sweeting KR, Lyftogt JA, Ng SK, Scuffham PA, Evans KA. Prolotherapy injections and eccentric loading exercises for painful Achilles tendinosis: a randomised trial. Br J Sports Med 2009;45:421-8. DOI: 10.1136/bjsm.2009.057968''
Yoshii 2009  ''Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. The effects of hypertonic dextrose injection on connective tissue and nerve conduction through the rabbit carpal tunnel. Arch Phys Med Rehabil 2009;90:333-9. DOI: 10.1016/j.apmr.2008.07.028''
Yoshii 2011  ''Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. Effects of hypertonic dextrose injections in the rabbit carpal tunnel. J Orthop Res 2011;29:1022-7. DOI: 10.1002/jor.21297''
Yoshii 2014  ''Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. Effects of multiple injections of hypertonic dextrose in the rabbit carpal tunnel: a potential model of carpal tunnel syndrome development. Hand (N Y) 2014;9:52-7. DOI: 10.1007/s11552-013-9599-1''


==References==
==References==

Latest revision as of 03:08, 30 July 2017

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Editors-In-Chief: Robert G. Schwartz, M.D. [1], Piedmont Physical Medicine and Rehabilitation, P.A.; Dean Reeves, M.D., Clinical assistant/associate professor University of Kansas Medical School, Dept of Physical Medicine and Rehabilitation 1986-2015; Felix Linetsky, M.D., Clinical Associate Professor, Department of Osteopathic Principles and Practice, Nova Southeastern College of Osteopathic Medicine [2]

Note for recent edits Captcha has been blocking external links so additional references have been placed in an "Additional References" section until administration can correct that. See support desk comment "When editing, asking to type two words in a box that does not exist" (Dr Reeves)

Please Join in Editing This Page and Apply to be an Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [3] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.

Overview

Prolotherapy ("Proliferative Injection Therapy") involves injecting an otherwise non-pharmacological and non-active proliferant or irritant solution into the body, generally in the region of tendons or ligaments for the purpose of strengthening weakened connective tissue and alleviating musculoskeletal pain. In 2005, Robert D. Sheeler, MD (Medical Editor, Mayo Clinic Health letter), who first learned of prolotherapy through C. Everett Koop’s interest in the treatment, listed ankles, knees, elbows, and sacroiliac joint in the low back as areas most likely to benefit from prolotherapy treatment and stated that "unlike corticosteroid injections — which may provide temporary relief — prolotherapy involves improving the injected tissue by stimulating tissue growth."[1]


Stimulation of tissue growth by dextrose prolotherapy was confirmed by Mayo Clinic researchers (Biomechanics Laboratory, Division of Orthopedic Research, and Department of Neurology),(Oh 2008, Yoshii 2009, Yoshii 2011, Yoshii 2014), who performed four controlled studies (three blinded) to determine if dextrose could thicken and strengthen a rabbit ligament without inflammation and with production of normal tissue without any scarring. Their purpose was to thicken the ligament that is responsible for producing carpal tunnel syndrome so that they would have an animal model for research. In the process, results in every study showed that 10% dextrose injection, compared to saline injection, consistently resulted in a increase in total energy absorption and tensile load tolerated by the ligament (transverse carpal ligament equivalent) before rupture. The ligament approximately doubled in thickness and, histologically, normal tissue was seen without scarring. This proliferation effect with normally organized fibrosis (growth of connective tissue) in the absence of scarring distinguishes prolotherapy from sclerotherapy.


Prolotherapy is often used as an treatment option rather than antiinflammatory approaches (such as steroids or non steroid antiinflammatory drugs [NSAIDS]) in the presence of chronic pain involving ligaments and tendons, as chronic changes in ligaments and tendons are primarily degenerative in nature rather than primarily inflammatory. (Scott 2015). Prolotherapy is also used as an alternative in the presence of chronic pain involving joints, in which histologic findings are also primarily degenerative. Lack of benefit in general with anti-inflammatory approaches on the clinical course of osteoarthritis is emphasized by a recent clinical trial of saline versus steroid (triamcinolone) injection in knee osteoarthritis showing unequivocal acceleration of cartilage loss with quarterly injection of steroid for 2 years in comparison with a saline control injection, reported in JAMA. (McAlindon 2017)


Prolotherapy has enjoyed increased acceptance within the medical community, especially in light of the focus being given to regenerative medicine as a discipline. Eighteen randomized controlled trials were found on PubMed as of June, 2017. (see Evidence Based Medicine section below)

Prolotherapy in clinical practice

Solutions

Prolotherapy solutions are commonly injected into the area where connective tissue has been weakened or damaged through injury or strain. The injection is placed into ligaments, into joint capsules or where tendon connects to bone. Many points may require injection. The most commonly used solutions in order from most common to less commonly used and in order from least to most inflammatory include Dextrose, P2G (a combination of dextrose and low d ose Phenol and Glycerine, and sodium morrhuate.

Mechanism

The mechanism is often described as initiation of a brief inflammatory reaction to stimulate the repair cascade, but is likely complex. (Rabago 2017-1) Time-limited reactive inflammation has been confirmed in animal models in which dextrose concentrations exceed 12.5% (Jensen 2008), some evidence of cartilage cell growth has been suggested upon repeat arthroscopy in humans,(Topol 2016), ligament growth without inflammatory required was described above in a series of controlled studies,(see overview section) and a direct therapeutic sensorineural effect has been proposed with early clinical support. (Yelland 2009 )

The theory of inflammatory prolotherapy was nicely summarized by Allen R Banks, Ph.D., in "A Rationale for Prolotherapy".[2] Robert G. Schwartz, MD has also published a biochemical literature review on the topic "Prolotherapy: A Literature Review and Retrospective Study"[4]. Recent reviews of basic science are available in several recent publications which cover the spectrum of mechanisms. (Rabago 2017-2, Reeves 2016)

Typical Treatment Course

Most clinicians say that at least three injections, done at 2-8 week intervals, are typically required to accomplish the desired result, but accuracy and completeness of treatment are likely key to treatment efficiency, and determination of optimal treatment approaches will require diagnosis-specific research. Given the non-proprietary nature of proliferant agents in current use, this will also take considerable time due to lack of financial incentives to support non-pharmacutical research.

History

Injections of irritant solutions were performed in the late 1800’s to repair hernias and in the early 1900’s for jaw pain due to temporomandibular (jaw) joint laxity. Dr. George Hackett, MD developed the technique of prolotherapy in the 1940’s. Dr. Gustav Hemwall was a pioneer, beginning his studies and treatments in the 1950s and continuing until the mid 1990s. In his study of almost 10,000 prolotherapy cases, Dr. Hackett found that over 99 percent of the patients found relief from their chronic pain. [3]

Guidelines used by practitioners as indicators for prolotherapy

  • Recurrent swelling or fullness involving a joint or muscular region
  • Popping, clicking, grinding, or catching sensations with movement
  • A sensation of the “leg giving way” with associated back pain
  • Temporary benefit from chiropractic manipulation or manual mobilization that fails to ultimately resolve the pain
  • Distinct tender points and “jump signs” along the bone at tendon or ligament attachments
  • Numbness, tingling, aching, or burning, referred into an upper or lower extremity
  • Recurrent headache, face pain, jaw pain, ear pain
  • Chest pain with tenderness along the rib attachments on the spine or along the front of the chest
  • Spine pain that does not respond to surgery, or whose origin is not clear or consistent based on extensive studies

Evidence based medicine

General Narrative Review Articles 2005 to 2011

The first comprehensive review article on safety and potential efficacy of prolotherapy was published in 2005. (Rabago 2005) On the basis of 34 case reports or case series, 2 nonrandomized controlled trials, and 6 RCTs, prolotherapy was considered “safe when performed by an experienced clinician” but “conclusive data for prolotherapy as a treatment for musculoskeletal pain was lacking”. Since 2010 there has been an acceleration in publication of randomized controlled trials (RCTs) for dextrose prolotherapy and both general and specific systematic reviews. A 2011 review noted growing evidence to recommend use in tendinopathies and early evidence of benefit in osteoarthritis. (Distel 2011)


General Narrative Reviews 2012 to Present and Strength of Recommendations

In the field of general practice, a practical way to consider the merit of employing a specific treatment for a specific condition was developed by Ebell et al,(Ebell 2004) and has been increasingly utilized. It is called the Strength of Recommendation Taxonomy and is composed of 3 assessments, study quality (bias), study quantity (and number of subjects), and study consistency (do studies agree?). Strength of recommendations were included as part of narrative reviews beginning with Covey at al (Covey 2015) who assigned a level A strength of recommendation (SOR) (recommendation based on consistent and good-quality patient-oriented evidence) for dextrose prolotherapy for knee osteoarthritis and level B SOR (recommendation based on inconsistent or limited-quality patient-oriented evidence) for Achilles tendinopathy, lateral epicondylosis, Osgood Schlatter disease, and plantar fasciosis. Two 2016 general review articles expanded level B strength of recommendations to include low back/sacroiliac pain and rotator cuff tendinopathy. (Reeves 2016, Hauser 2016) A SOR for the use of prolotherapy in acute pain, myofascial pain or as first-line therapy, cannot be determined based on current literature. (Hauser 2016) It is important to keep in mind, when considering the assignment of strength of recommendation, that a single RCT cannot lead to a level A SOR recommendation. Thus despite a single high quality study the SOR will only be B (recommendation based on inconsistent or limited-quality patient-oriented evidence). In a field in which research is virtually all self-funded, with no proprietary interest, studies will accumulate slowly and a level B recommendation may mean a "poor quantity" of studies or low patient numbers, rather than "poor quality".


Back pain/Sacroiliac Pain Articles: Treatment Comparison Trials Rather Than Placebo Trials Due to Extensive Needling Effects

A 2007 review of prolotherapy in adults with chronic low-back pain found unclear evidence of effect. (Dagenais 2007). There was tentative evidence of benefit when used with other low back pain treatments. (Distel 2011) These prior reviews focused primarily on phenol-containing solutions, which have declined in use in favor of hypertonic dextrose which is less inflammatory and better studied. (Rabago 2017) More recent reviews of dextrose-only studies interpreted the dextrose-only controlled trials as treatment comparison studies in that the first study (Yelland 2003) utilized a control with substantial needling effect on multiple occasions and both saline and dextrose groups had a persistent benefit with "greater than 50% pain reduction in 46% and 36% of dextrose and saline groups respectively at 12 months," (Reeves 2016) and the second study favored dextrose over steroid injection (triamcinolone) for injection of the SI joint.(Kim 2010) Recent reviews conclude that evidence of benefit remains tentative (level B) for dextrose prolotherapy in low back/sacroiliac pain based on two favorable but inconsistent treatment comparison studies. (Reeves 2016. Hauser 2016)


Criticism

In 1999, Medicare considered the low back clinical trials on prolotherapy at that time (which were with P2G only) and determined that prolotherapy would remain a non-covered service for low back pain. cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=68&fromdb=true Their concerns were insufficient patient numbers in the trials (only 160 patients to that point) and flaws in the clinical studies. Other insurers have mirrored Medicare's position, and, over the years, although randomized trials have continued to increase in numbers and quality, the number of studies in any one area have not accumulated sufficiently to challenge Medicare's determination. Level A SOR requires multiple randomized controlled trials that agree and the study numbers are diluted across a great variety of clinical conditions. Treatment of knee osteoarthritis with prolotherapy has reached a level A SOR, and some insurers cover prolotherapy for knee osteoarthritis.


See also

Additional References

Covey 2015 Covey CJ, Sineath MHJ, Penta JF, Leggit JC. Prolotherapy: Can it help your patient? J Fam Pract 2015;64:763-8. PMCID: PMID: 26844994

Dagenais 2007 Dagenais S, Caro J, Haldeman S. A systematic review of low back pain cost of illness studies in the United States and internationally. Spine J 2007;8:8-20. DOI: 10.1016/j.spinee.2007.10.005

Distal 2011 Distel LM, Best TM. Prolotherapy: a clinical review of its role in treating chronic musculoskeletal pain. PMR 2011;3:S78-81. DOI: 10.1016/j.pmrj.2011.04.003

Ebell 2004 Ebell MH, Siwek J, Weiss BDW, S.H., Susman J, Ewigman BB, M. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:549-56. PMCID: 14971837

Hauser 2016 Hauser RA, Lackner JB, Steilen-Matias D, Harris DK. A Systematic Review of Dextrose Prolotherapy for Chronic Musculoskeletal Pain. Clin Med Insights Arthritis Musculoskelet Disord 2016;9:139-59. DOI: 10.4137/CMAMD.S39160

Jensen 2008 Jensen KT, Rabago D, Best TM, Patterson JJ, Vanderby R. Early inflammatory response of knee ligaments to prolotherapy in a rat model. J Orthop Res. 2008;26(6):816–23. DOI: 10.1002/jor.20600

McAlindon 2017 McAlindon TE, LaValley MP, Harvey WF, Price LL, Driban JB, Zhang L, et al. Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis: A Randomized Clinical Trial. JAMA 2017;317:5283. DOI: 10.1001/jama.2017.5283

Oh 2008 Oh S, Ettema AM, Zhao C, Zobitz ME, Wold LE, An KN, et al. Dextrose-induced subsynovial connective tissue fibrosis in the rabbit carpal tunnel: A potential model to study carpal tunnel syndrome? Hand 2008;3:34-40. DOI: 10.1007/s11552-007-9058-y

Rabago 2005 Rabago D, Best TM, Beamsley M, Patterson J. A systematic review of prolotherapy for chronic musculoskeletal pain. Clin J Sport Med 2005;15:366-80. PMCID: 16162983

Rabago 2017-1 Rabago D, Nourani B. Prolotherapy for Osteoarthritis and Tendinopathy: a Descriptive Review. Curr Rheumatol Rep 2017;19:34. DOI: 10.1016/j.ctim.2015.04.003

Rabago 2017-2 Rabago D, Nourani B, Reeves KD, Weber M. Prolotherapy: Histology, biology, mechanism of action, preparation and clinical applications In: Manchikanti L, Navani A, eds. Essentials of regenerative medicine in interventional pain management 2017: In Press.

Reeves 2016 Reeves KD, Sit RWS, Rabago D. A narrative review of basic science and clinical research, and best treatment recommendations. Phys Med Rehabil Clin Nth Am 2016;27:783-823. DOI: 10.1016/j.pmr.2016.06.001

Scott 2015 Scott A, Backman LJ, Speed C. Tendinopathy: Update on Pathophysiology. J Orthop Sports Phys Ther 2015;45:833-41. DOI: 10.2519/jospt.2015.5884

Topol 2016 Topol GA, Podesta LA, Reeves KD, Giraldo MM, Johnson LJ, Grasso R, et al. The chondrogenic effect of intra-articular hypertonic-dextrose (prolotherapy) in severe knee osteoarthritis. PM&R 2016;8:1072-82. DOI:10.1016/j.pmrj.2016.03.008.

Yelland 2004 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 2004;29:9-16. PMID:14699269

Yelland 2009 Yelland MJ, Sweeting KR, Lyftogt JA, Ng SK, Scuffham PA, Evans KA. Prolotherapy injections and eccentric loading exercises for painful Achilles tendinosis: a randomised trial. Br J Sports Med 2009;45:421-8. DOI: 10.1136/bjsm.2009.057968

Yoshii 2009 Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. The effects of hypertonic dextrose injection on connective tissue and nerve conduction through the rabbit carpal tunnel. Arch Phys Med Rehabil 2009;90:333-9. DOI: 10.1016/j.apmr.2008.07.028

Yoshii 2011 Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. Effects of hypertonic dextrose injections in the rabbit carpal tunnel. J Orthop Res 2011;29:1022-7. DOI: 10.1002/jor.21297

Yoshii 2014 Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. Effects of multiple injections of hypertonic dextrose in the rabbit carpal tunnel: a potential model of carpal tunnel syndrome development. Hand (N Y) 2014;9:52-7. DOI: 10.1007/s11552-013-9599-1


References

  1. ↑ Mayo Clinic (2005). "Alternative treatments: Dealing with chronic pain". Mayo Clinic Health Letter. 23 (4).
  2. ↑ "A Rationale for Prolotherapy".
  3. ↑ "The History of Prolotherapy". Retrieved 2007-08-26. In 1955, at an American Medical Association meeting, Dr. Gustav Hemwall was astonished to see so many doctors at one particular exhibit. The presenter was talking about a very successful treatment for chronic low back pain. Nothing was worse at the time for Dr. Hemwall than having a chronic low back pain patient come to him, because the treatments he was able to offer were not very successful. The doctor doing the presentation was George S. Hackett, M.D., and he was discussing the technique of Prolotherapy. Once the crowd diminished, Dr. Hemwall asked Dr. Hackett how he could learn the treatment described in his book, Ligament and Tendon Relaxation Treated by Prolotherapy. Dr. Hemwall went to Dr. Hackett's office in Canton, Ohio, to learn the technique. Dr. Hemwall became so proficient at administering the technique that Dr. Hackett would later refer patients to him. Prolotherapy owes a great debt to Dr. Hemwall. Between 1955 until his retirement in 1996, he was the main instructor and proponent of Prolotherapy in the United States. He was not a researcher but a clinician, and perhaps the world's greatest Prolotherapist. He treated more than 10,000 patients world wide and collected data on 8,000 of these patients. In 1974, Dr. Hemwall presented his largest survey of 2,007 Prolotherapy patients to the Prolotherapy Association.

External links

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