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Am Fam Physician. 2021;103(7):395

Original Article: Chronic Musculoskeletal Pain: Nonpharmacologic, Noninvasive Treatments

Issue Date: October 15, 2020

To the Editor: We appreciate the article on therapeutic options for chronic musculoskeletal pain by Dr. Flynn. We want to highlight prolotherapy, an injection-based modality for chronic pain with protocols targeting intra- and extra-articular pain-generating tissue. Prolotherapy is supported by a growing body of literature reporting effectiveness for several chronic pain conditions, particularly knee osteoarthritis.

Prolotherapy dates from at least 1937 (then called sclerotherapy because of the observation that early, more caustic solutions caused scarring).1 Small volumes of a therapeutic solution, typically dextrose, are injected within the affected joint and at the bony attachments of tender tendons and ligaments around the joint. Injections are typically given monthly over three to six sessions. The mechanism of action is unclear; inflammatory and nerve-specific effects are hypothesized.2

A rigorous randomized clinical trial assessed the effectiveness of prolotherapy for knee osteoarthritis.3 One year after treatment, participants receiving prolotherapy reported statistically significant and clinically important improvements on a validated questionnaire compared with participants in two different control groups (blinded injection and at-home exercise). These findings have been corroborated in other clinical trials.4 Data from some have been subjected to systematic review and meta-analysis, with positive results.5 Satisfaction with prolotherapy in these studies was high, and there were no adverse events.

The prolotherapy protocol is appropriate for outpatient family medicine but requires training not typically available in residency and fellowship programs. Two nonprofit professional organizations offer such training: the Hackett Hemwall Patterson Foundation ( and the International Association for Regenerative Therapy ( These sibling organizations offer CME-eligible training through academic conference and service-learning activities in collaboration with the University of Wisconsin.6

Although more studies are needed to better understand prolotherapy's mechanism of action and clinical utility at the system level, existing literature supports considering prolotherapy in carefully selected patients with symptomatic knee osteoarthritis refractory to other care modalities.

In Reply: Thank you for your letter in response to my review of nonpharmacologic, noninvasive therapies for chronic musculoskeletal pain. Prolotherapy was outside the scope of the article, which did not include the evaluation of injection therapies. I agree that in a small number of clinical trials of knee osteoarthritis involving small sample sizes, study participants who received prolotherapy experienced small treatment effects compared with control participants. However, it is noteworthy that due to the limited quality of these studies, the 2019 American College of Rheumatology osteoarthritis treatment guidelines conditionally recommended against the use of prolotherapy for knee or hip osteoarthritis.1

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This series is coordinated by Kenny Lin, MD, MPH, deputy editor.

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