Quick Hit Summary
Many individuals suffer from chronic connective tissue injuries such as strained ligaments, damaged tendons and/or degenerating cartilage. Although it has been around for 100’s of years, a “new” treatment technique, referred to as prolotherapy, has been promoted by some physicians (aka – prolotherapist) as an effective non-surgical technique to heal these injuries. It purportedly accomplishes this by acutely increasing inflammation in select regions of damaged tissue, kick-starting the healing process. Thus, from a theoretical standpoint, it may lead to strengthening of connective tissue, removal of potential laxity and spurring new growth in the targeted ligament/tendon/cartilage. In Part I of this series, animal based research is explored as we examine the potential mechanisms by which prolotherapy may benefit the end user. Upon review, research has shown that sodium morrhuate may increase tendon-bone strength 27-35% vs. that of control ligaments. However, dextrose based prolotherapy failed to strengthen MCL ligaments. Both dextrose and sodium morrhuate based solutions have been shown to increase ligament size. Although interesting, caveats are present, preventing hard conclusions from being made from the animal based research.
Prolotherapy Series
This is the 1st part of our Prolotherapy Series. This collection of articles will focus in on an emerging therapeutic technique in sports medicine as well as general orthopedic/physiatry health known as prolotherapy. In all, there will be 3 parts to this series:
- Prolotherapy Part III: Proliferents 2.0 – HGH, Platelet Rich Plasma, and Orthokine/Regenokine
Body Heal Thyself?
Figure 1. The Vitruvian Man (c. 1485) Accademia, Venice. Image source12
Any hard training individual has likely suffered a connective tissue injury (ie – tendons, ligaments, cartilage) at one point or another. Furthermore, even if one doesn’t exercise at all, it’s still likely that he/she has suffered a musculoskeletal injury of sorts related to a freak accident or general wear and tear on joints from poor biomechanics, etc. As many already know, the standard practice for handling such musculoskeletal issues usually involve following a R.I.C.E protocol which involves R -est, I -ce, C -ompression & E -levation. In addition, a dose or two of anti-inflammatory medicine such as cortisone or its less potent sibling, NSAIDS (Ibuprofen, Aleve, etc) may be recommended depending on the severity of the connective tissue injury. As one can likely guess, the goals of these therapies are to minimize inflammation as much as possible. Yet, for anyone who has suffered a connective tissue injury such as a sprained ankle, despite following the RICE protocol “to the T”, quite often there is still a sense of laxity (ie – looseness) in the area and it’s much easier to re-injure in the future.
Interestingly, within the last 5-10 years, there has been a new therapeutic technique (I say “new”, but in all actually, it’s been awhile for quite some time), referred to as prolotherapy, that has started to gain steam with respect to healing injuries. In stark contrast to traditional healing techniques, which focus on minimizing inflammation as much as possible, prolotherapy takes the opposite approach; proactively INCREASING inflammation at the point of injury, by injecting it (via needle based shots) with various inflammatory compounds referred to as proliferants.
I know what you’re thinking, “Why would anyone want to increase inflammation in a given tissue… Especially in one that is already painful?” Well, for those of you who subscribe to the CasePerformance Newsetter and have read the free ebook that comes with it, Post Workout Recovery Techniques you’ll recall my mentioning that acute inflammation is a requirement for normal, healthy, muscle growth.1 (For those looking for a more in-depth discussion on the relationship between muscle growth and inflammation, I refer you to my friend Adel Moussa’s SuppVersity article on the subject.) Likewise, inflammation is a needed for the strengthening of connective tissue (tendons, ligaments, etc)2. Thus, from a theoretical standpoint, if one acutely increases inflammation in specific areas of a tendon, ligament or piece of cartilage, the potential exists to re-heal the tissue.
In the first part of this article series, we’re going to cover the following topics:
- A) The history of prolotherapy
- B) Modern day research using animal studies to assist our understanding of the potential mechanisms at work
The History of Prolotherapy
As I alluded to above, although it is a “newer” technique with respect to becoming more mainstream, prolotherapy has actually been around for quite some time. In fact, the act of injecting a proliferative agent to harden and strengthen weak tissue, dates back to first century BC in ancient Rome.3 Fast forward to 1773, and it’s noted that England’s Dr. Samuel Sharp began to use a proliferative agent to treat hydrocele caused by hernias. Its first appearance in the USA is believed to have occurred around 1830 where various physicians began to use it to strengthen the connective tissue, most notably in the area surrounding the inguinal ring. By the early 1900s, physicians were using this technique to treat varicose veins, hemorrhoids, hydroceles and hernias. This proliferating injection therapy technique was coined “sclerotherapy” in 1936 by Dr. H.I. Biegeleisen due to its ability to strengthen and toughen up an area (sclera comes from the greek word “skleros” which means “hard”).
The first use of sclerotherapy on musculoskeletal related issues took place in the late 1930’s by Dr. Louis Schultz, who was both a dentist and medical doctor. He began using sclerotherapy to treat those in his clinic who suffered jaw pain related to temporomadibular joint disorders.3 He reported that 3-4 treatments, given at biweekly intervals usually strengthened the joint capsule to the point where excess mobility was reduced and TMJ discomfort was eliminated; Dr. Schultz results were published in a 1937 issue of the Journal of the American Medical Association4.
The next major contributor in the development of this technique was Dr. George S. Hacket, who is attributed with giving the therapy it’s modern name, “prolotherapy”, due to its proliferative effect on connective tissue growth.3 (It is from the word “prolotherapy”, that practicing physicians of this technique are called prolotherapist). Dr. Hackett used it extensively in treating those with “low back pain, neck pain, arthritis and sciatica.” He firmly believed ligament and tendon pathologies were “significant contributors to the chronic pain syndromes.” Dr. Hacket also made detailed maps of referral pain patterns generated by ligament and tendon laxity; he accomplished this by injecting an anesthetic into a given tendon or ligament and noting if both the local and referred pain disappeared in the given areas. If so, the connective tissue in the given area eliciting the pain was treated via prolotherapy.
From this point forward, other prolotherapists such as Dr. Earl Gedney, Dr. David Shuman, Dr. Gustav Hemwall, and Dr. Ross Hauser are credited with advancing the technique as well as increasing the awareness of prolotherapy.3
Is Prolotherapy Legit?
Is Prolotherapy Taught in Medical Schools? I posed this question to two of my cousins who graduated from medical school ~2010, one from University of Iowa (USA) and the other from the University of Wisconsin (USA). My cousin from Iowa stated that prolotherapy was never mentioned in any of her studies. Likewise, my cousin who attended Wisconsin stated that it was mentioned minimally, maybe 1 or 2 times during her entire medical school education.
Most of the prolotherapists mentioned in the preceding section noted an 80-100% success rate at curing or significantly relieving the pain associated with connective tissue laxity and weakness.3 However, as has been well documented here at CasePerformance, the placebo effect is alive and well. Furthermore, as your parents likely told you while growing up (or at least should have!), “If it sounds too good to be true, it likely is too good to be true”. Additionally, if it was as effective as proclaimed, why are so few individuals aware of it, including doctors (see sidebox discussion)? Surely this much cheaper non-surgical technique to heal connective tissue injuries would be widely practiced throughout the medical field… right? (As I write this, I can hear the wheels turning in the minds of all you conspiracy theorist out there about … Surely those in the traditional medical community, who financially benefit when someone has surgery, must be suppressing this knowledge in order to further their profit!). Answers to these questions get to be rather interesting when one looks at contemporary prolotherapy research …
Contemporary Research using Traditional Proliferants – Animal Based Research
To answer the questions posed above, it’s important to first establish the effects of prolotherapy at the mechanistic level. Namely does it increase strength, while simultaneously decreasing laxity in connective tissue? To quantitatively answer these questions, one has to inject a given connective tissue with prolotherapy, measure changes in laxity before yanking on the tendons/ligaments till they give out. Although this may come as a surprise to you, not many individuals tend to sign up for these studies ;-); Thus, one must turn to animal studies.
Figure 2 Bone-ligament-bone junction strength in prolotherapy vs. saline injected rabbit ligaments. Image created by Sean Casey and adapted from the work of Liu et al5
The most widely quoted study in this regards is a 1983 double blind study completed by Liu et al in which prolotherapy (5% solution of sodium morrhuate) was injected into the medial collateral ligaments (MCL) ligaments of rabbits, at both the femoral and tibial attachments [ FYI – MCL is a ligament of the knee. Femur is upper leg/thigh bone and tibia = lower leg bone); prolotherapy shots were given at days 1,5,19,26 over the course of a 42 day experimental period.5 Likewise, the same procedure was carried out on the MCL of the rabbit’s opposite knee using a “control” saline solution. Compared to the control ligaments, those which received prolotherapy demonstrated a 27% greater “bone-ligament-bone” junction strength, as well as a 56% larger collagen fiber diameter.
How many sessions are needed? Unless pain completely resolves prior, a minimum of 3 injections spaced 4-6 weeks apart is recommended by some clinicians7. If no improvement is found after 3 injections, it’s suggested that alternative means of treating the issue are pursued by the patient and physician.
More recently, Aneja et al also found that a similar prolotherapy solution increased the biomechanical strength of the patellar tendons of female rats.6 Using a solution similar to Liu et al5, Aneja found that 28 days following an acute treatment, prolotherapy increased the tendon-bone attachment strength 136% vs. that of the rat’s non injected patellar tendon. In terms of removing the laxity of the tendon, one of the purported effects of prolotherapy, the ligament shrunk to 95% +/- 2% of the untreated ligament. Although this wasn’t statistically significant, the researchers do emphasize that this was tested after an acute injection vs. the standard procedure which involves multiple injections; thus they hypothesized that more injections may be required to produce significant effects in ligament laxity (see sidebox discussion).
I should note that not all animal studies found benefit with increasing connective tissue strength. Using a rat model, Jensen et al administered dextrose based prolotherapy injections on two separate occasions, 2 and 3 weeks following a stretch induced MCL injury.8 When assessed 5 weeks after the induced injury, no differences in ligament strength or laxity were found between the control ligaments which were treated with saline and those which received prolotherapy. However, they did find that dextrose injections did significantly increase MCL cross sectional area 90% greater than uninjured control, which was also 30% greater increase in surface area vs. those in a 2nd control group receiving saline injections. Jensen et al state that the clinical significance, if any, of this increased size (but similar strength and laxity measures vs controls) is to be determined.
Jensen et al hypothesized that there may be 2 different reasons as to why results from their study differed from the other two studies.8 1) Jensen et al used dextrose based prolotherapy vs sodium morrhuate and/or 2) The ligaments used in the other studies were “healthy” vs. theirs which used ligaments following a stretch induced injury. Due to the lack of significant biomechanical alterations in strength/laxity vs. the controls, the group also postulated that the improvement in pain and movement reported by various prolotherapy clinicians may be related to dextrose’s interaction with the nerves associated with the pathological neovascularization (formation of blood vessels) observed in some connective tissue overuse injuries. For instance, removal of neovascularisation, brought about by eccentric training9, as well as treatment with the sclerosing agent known as polidocanol10 has been shown to reduce Achilles tendon pain in humans. To my knowledge, this “anti-neovascularisation” effect of dextrose has yet to be shown.
The final animal study worth discussing was also completed by Jensen et al11. In it, the research team compared the early inflammatory response between 84 rats who were randomly divided amongst the following groups11:
3 Prolotherapy Based Groups
- 15% dextrose
- 5% sodium morrhuate
- Phenol-glucose-glycerine (P2G)
3 Control Groups
- Saline Solution based injections
- Needle stick
- No Treatment
The given treatment was administered to the rat’s MCLs, one injection at the tibia insertion and a second one at the femur attachment.11 The inflammatory response of all groups was assessed at 24 hours post injection and a subset of the dextrose, saline and no treatment groups were analyzed at 6 and 72 hours. Final results of the study indicated that although some differences were present (sodium morrhuate appeared to have a little bit more consistent effects on increasing CD43+ leukocytes), inflammatory responses were relatively similar between all groups which was significantly higher vs. that of the control group which received no treatment.
A note of caution … Based off this study alone, I wouldn’t prematurely label Jensen’s et al.‘s 2nd study as definitive proof that prolotherapy wasn’t effective despite, contrary to the research groups hypothesis, the traditional prolotherapy treatments failed to enhance the acute inflammatory responses vs. that of saline and needlestick (which were all higher than the “no treatment” control group). Rather, I interpreted it that saline and needlesticks alone (without any added proliferants) may provide benefit with respect to healing damaged ligaments. Thus, the question which is needed to be asked is, “Do traditional proliferants provide potential healing benefits that go above and beyond that of needlesticks/saline injections alone?”
Bottom Line
Despite being around since the time of ancient Rome, it’s only been within the last 5-10 that prolotherapy has started to creep into mainstream medicine as a means to treat connective tissue injuries. Anecdotally, amazing results have been reported by various practitioners. Yet, as we all know, “If it sounds too good to be true, it likely IS to good to be true”.
As we saw in Part I of this series, various animal studies have examined the mechanistic route in which prolotherapy may benefit those suffering from connective tissue injuries. Although some interesting results were shown, caveats were present making it impossible to form firm conclusions; Namely, different solutions were used, only 1 study actually involved injured tissue (and that was an acute injury vs. chronic injury), etc, etc.
That said, enough discussion on the animal studies; Who cares what happens in them if the results fail to translate over to you & I, right?! Thus, let’s flip the switch and turn it over to the human studies…
… And for that, you’ll have to come back for Part II of our Prolotherapy Series!
References
1 Tidball JG, Villalta SA. Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol. 2010 Mar 10.
2 Almekinders LC, Baynes AJ, Bracey LW. An in vitro investigation into the effects of repetitive motion and nonsteroidal antiinflammatory medication on human tendon fibroblasts. Am J Sports Med. 1995 Jan-Feb;23(1):119-23.
3 Linetsky F.“The History of Prolotherapy” Chapter 4 in Prolo Your Sports Injuries Away. RA Hauser. 2001 Beulah Land Press
4 Schultz, L. A treatment of subluxation of the temporomandibular joint. JAMA., September 25, 1937
5 Liu YK, Tipton CM, Matthes RD, Bedford TG, Maynard JA, Walmer HC. An in-situ study of the influence of a sclerosing solution in rabbit medial collateral ligaments and its junction strength.Connective Tissue Research. 1983;11:95–102.
6 Aneja A, Karas SG, Weinhold PS, Afshari HM, Dahners LE. Suture plication, thermal shrinkage, and sclerosing agents: effects on rat patellar tendon length and biomechanical strength. Am J Sports Med. 2005 Nov;33(11):1729-34. Epub 2005 Aug 10.
7 Rabago D, Slattengren A, Zgierska A. Prolotherapy in primary care practice. Prim Care. 2010 Mar;37(1):65-80.
8 Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R Jr. Response of knee ligaments to prolotherapy in a rat injury model. Am J Sports Med. 2008 Jul;36(7):1347-57. doi: 10.1177/0363546508314431. Epub 2008 Feb 29.
9 Ohberg L, Alfredson H. Effects on neovascularisation behind the good results with eccentric training in chronic mid-portion Achilles tendinosis? Knee Surg Sports Traumatol Arthrosc. 2004 Sep;12(5):465-70. Epub 2004 Apr 2.
10 Lind B, Ohberg L, Alfredson H. Sclerosing polidocanol injections in mid-portion Achilles tendinosis: remaining good clinical results and decreased tendon thickness at 2-year follow-up. Knee Surg Sports Traumatol Arthrosc. 2006 Dec;14(12):1327-32. Epub 2006 Sep 12.
11 Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R Jr. Early inflammatory response of knee ligaments to prolotherapy in a rat model. J Orthop Res. 2008 Jun;26(6):816-23. doi: 10.1002/jor.20600.
12 The Vitruvian Man (c. 1485) Accademia, Venice by Leonardo da Vinci. This work is in the public domain in the United States because it was published (or registered with the U.S. Copyright Office) before January 1, 1923.Image accessed April 21, 2013 from: http://commons.wikimedia.org/wiki/File:Uomo_Vitruviano.jpg