Prolotherapy
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# 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 Koops 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."
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 ) 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". Robert G. Schwartz, MD has also published a biochemical literature review on the topic "Prolotherapy: A Literature Review and Retrospective Study". 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 1800s to repair hernias and in the early 1900s for jaw pain due to temporomandibular (jaw) joint laxity.  Dr. George Hackett, MD developed the technique of prolotherapy in the 1940s.  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. 

## 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.