Evidence Update: Prolotherapy

Back in 2011 I wrote about a therapy popular with alternative practitioners called prolotherapy. I try to check in from time to time to see if there is any new evidence for the treatments I consider, and in doing so I did find some new evidence. First, here’s my conclusion from the previous review:

Prolotherapy is a purported treatment for connective tissue and joint pain and disability. It involves injecting substances which induce inflammation and other chemical and cellular reactions into affected tissues. These reactions are theorized to relieve pain and improve function. The logic of this theory is questionable, and no clear mechanism for beneficial effects from prolotherapy has been described, but it is possible that the theory could be valid.

The clinical research on prolotherapy in humans is generally of low quality and results have been mixed. There is great variation in the techniques used by different investigators, so it is difficult to compare or generalize between studies.

There is virtually no controlled research investigating prolotherapy in companion animals, and all claims made for safety and efficacy in these species are based solely on anecdotal evidence.

The use of proltherapy in pets should be viewed as experimental with unknown risks and benefits. Such treatments should be reserved for patients that have significant symptoms that have failed to respond or cannot be treated by conventional means.

What Is It?
Prolotherapy involves injecting substances into joints or musculoskeletal tissue to treat pain and dysfunction. The particular substances used vary. Some are clearly useless (e.g. homeopathic remedies), but the evidence is growing that others may have some beneficial clinical effects. The most common substance currently used is dextrose, a form of sugar, but there are many others, and of course each substance has to be evaluated individually for specific uses.

Does It Work?
The in vitro and lab evidence suggests some potentially useful effects on joint tissues and in lab animals, but of course this level of evidence frequently turns out to be unreliable in predicting the actual effects in patients. At the time of my previous article, most systematic reviews were inconclusive, and the quality of the clinical trial evidence in humans was weak. There is still significant differences of opinions in different reviews, and all call for better quality evidence, but there is an emerging consensus that dextrose prolotherapy may be useful for arthritis in people. Other uses are still not supported by very convincing evidence. Here are some samples of the systematic review literature:

Limited evidence from low-quality studies indicates a beneficial effect of prolotherapy for OA management. The number of participants in these studies was too small to provide reliable evidence…Current data from trials about prolotherapy for OA should be considered preliminary, and future high-quality trials on this topic are warranted.1

Although anecdotal clinical success guides the use of prolotherapy for many conditions, clinical trial literature supporting evidence-based decision-making for the use of prolotherapy exists for low back pain, several tendinopathies, and osteoarthritis.2

This systematic review suggests that ST and PT may be effective treatment options for AT and that they can be considered safe. Long-term studies and RCTs are still needed to support their recommendation.3

Within the limitations of the study, dextrose prolotherapy may cause significant reduction in mouth opening and pain associated with TMJ hypermobility. Conclusions with regard to reduction of episodes of subluxation/dislocation cannot be drawn. There is a need of more high-quality RCTs with larger sample size and homogenous prolotherapy protocol to draw stronger conclusions on the effect of dextrose prolotherapy in patients with TMJ hypermobility.4

Dextrose injections decreased pain in osteoarthritis patients but did not exhibit a positive dose-response relationship following serial injections. Dextrose prolotherapy was found to provide a better therapeutic effect than exercise, local anesthetics, and probably corticosteroids when patients were retested 6 months following the initial injection.5

Use of dextrose prolotherapy is supported for treatment of tendinopathies, knee and finger joint OA, and spinal/pelvic pain due to ligament dysfunction. Efficacy in acute pain, as first-line therapy, and in myofascial pain cannot be determined from the literature.6

Moderate evidence suggests that prolotherapy is safe and can help achieve significant symptomatic control in individuals with OA. Areas for developing research Future research should focus on larger sample size, standardization of treatment protocol and basic science evidence.7

Overall, prolotherapy conferred a positive and significant beneficial effect in the treatment of knee OA. Adequately powered, longer-term trials with uniform end points are needed to better elucidate the efficacy of prolotherapy.8

Systematic review, including meta-analysis, and randomized controlled trials suggest that prolotherapy may be associated with symptom improvement in mild to moderate symptomatic knee osteoarthritis and overuse tendinopathy. Although the mechanism of action is not well understood and is likely multifactorial, a growing body of literature suggests that prolotherapy for knee osteoarthritis may be appropriate for the treatment of symptoms associated with knee osteoarthritis in carefully selected patients who are refractory to conservative therapy and deserves further basic and clinical science investigation for the treatment of osteoarthritis and tendinopathy.9

Unfortunately, the same proliferation of research evidence has not happened in veterinary medicine. To date, there is only one study of this treatment in dogs10 and none in cats.

Sherwood JM, Roush JK, Armbrust LJ, Renberg WC. Prospective Evaluation of Intra-Articular Dextrose Prolotherapy for Treatment of Osteoarthritis in Dogs. J Am Anim Hosp Assoc. 2017;53(3):135-1

This was a small but very high-quality study with appropriate blinding, randomization, control groups, and a mix of subjective and objective outcome measures. That’s the good news. The bad news is there was no significant difference between prolotherapy and placebo in any measure, so the therapy clearly didn’t work. This is only one study, and given the encouraging evidence in humans, it is possible that further studies will find some forms of prolotherapy helpful in veterinary patients.

Bottom Line
There are a variety of theories behind prolotherapy, some more plausible than others, but there is not yet a clearly established general mechanism. The clinical trial research in humans is mixed and not robust, but there is moderate evidence supporting the effectiveness of prolotherapy for arthritis. There has only been one small animal study, a clinical trial in dogs for elbow and knee arthritis, and it found no benefit.


  1. Krsti?evi? M, Jeri? M, Došenovi? S, Jeli?i? Kadi? A, Puljak L. Proliferative injection therapy for osteoarthritis: a systematic review. Int Orthop. 2017;41(4):671-679. doi:10.1007/s00264-017-3422-5
  2. Rabago D, Slattengren A, Zgierska A. Prolotherapy in primary care practice. Prim Care. 2010;37(1):65-80. doi:10.1016/j.pop.2009.09.013
  3. Morath O, Kubosch EJ, Taeymans J, et al. The effect of sclerotherapy and prolotherapy on chronic painful Achilles tendinopathy-a systematic review including meta-analysis. Scand J Med Sci Sports. 2018;28(1):4-15. doi:10.1111/sms.12898
  4. Nagori SA, Jose A, Gopalakrishnan V, Roy ID, Chattopadhyay PK, Roychoudhury A. The efficacy of dextrose prolotherapy over placebo for temporomandibular joint hypermobility: A systematic review and meta-analysis. J Oral Rehabil. 2018;45(12):998-1006. doi:10.1111/joor.12698
  5. Hung C-Y, Hsiao M-Y, Chang K-V, Han D-S, Wang T-G. Comparative effectiveness of dextrose prolotherapy versus control injections and exercise in the management of osteoarthritis pain: a systematic review and meta-analysis. J Pain Res. 2016;Volume 9:847-857. doi:10.2147/JPR.S118669
  6. 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:CMAMD.S39160. doi:10.4137/CMAMD.S39160
  7. Hassan F, Trebinjac S, Murrell WD, Maffulli N. The effectiveness of prolotherapy in treating knee osteoarthritis in adults: a systematic review. Br Med Bull. 2017;122(1):91-108. doi:10.1093/bmb/ldx006
  8. Sit RW, Chung VC, Reeves KD, et al. Hypertonic dextrose injections (prolotherapy) in the treatment of symptomatic knee osteoarthritis: A systematic review and meta-analysis. Sci Rep. 2016;6(1):25247. doi:10.1038/srep25247
  9. Rabago D, Nourani B. Prolotherapy for Osteoarthritis and Tendinopathy: a Descriptive Review. Curr Rheumatol Rep. 2017;19(6):34. doi:10.1007/s11926-017-0659-3
  10. Sherwood JM, Roush JK, Armbrust LJ, Renberg WC. Prospective Evaluation of Intra-Articular Dextrose Prolotherapy for Treatment of Osteoarthritis in Dogs. J Am Anim Hosp Assoc. 2017;53(3):135-142. doi:10.5326/JAAHA-MS-6508
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