The prevalence of chronic pain among adults in the US is 20.4%,1 a concomitant opioid epidemic and subsequent opioid-related deaths have created a national emergency.2 In addition the World Health Organization reports 1.71 billion people with musculoskeletal conditions worldwide. Musculoskeletal conditions can significantly limit function and are the leading cause of disability. National organizations have therefore called for new treatments of chronic pain and musculoskeletal conditions, including therapy that addresses the underlying pain pathology. Therapeutic injections with dextrose are increasingly used for this purpose.
Basic science and clinical research suggest several ways in which dextrose can reduce pain, improve overall function, and restore connective tissue function. Hypothesized mechanisms and clinical trials suggest injection with dextrose has the potential to 1) slow, halt or even reverse degenerative changes in ligaments, tendons, and joints, 2) simultaneously localize and treat primary nociceptive sources by precise diagnostic injection, 3) reduce peripheral sensitization in neuropathic pain, and 4) directly release nerve entrapment and reduce neurogenic inflammation without risk of anesthetic toxicity.3,4
Clinical trials have assessed three distinct therapeutic dextrose-related modalities and reported positive clinical effects compared with blinded injection controls.
- Prolotherapy: Injection of hypertonic dextrose to treat chronic musculoskeletal pain.3 The purported mechanism focuses on proliferative repair.
- Perineural injection treatment (PIT): The injection of dextrose adjacent to peripheral nerves to reduce neuropathic pain.5 The purported mechanism is associated with a sensorineural effect.
- Hydrodissection: Dextrose is injected adjacent to peripheral nerves with continuous ultrasound guidance to release peripheral nerves from their encasing fascia in order to provide a decompressive effect.4
Each modality is in use as outpatient therapy in the U.S. Acquisition of these procedural skills is sometimes through formal medical training, but more often in continuing medical education contexts. Prolotherapy, PIT, and hydrodissection are supported for specific indications by a growing body of literature. The focus in this article is discussion of the evolving evidence base underpinning the therapeutic injection of dextrose.
Prolotherapy has been used in clinical practice since the 1950s and is supported by the strongest body of clinical evidence. It is also called regenerative injection therapy or proliferative therapy and involves the injection of dextrose into a joint, muscle, tendon, or other soft tissue area where it classically has been described as acting as an irritant to induce a local inflammatory response that triggers the natural healing cascade (proliferative phase of tissue repair).6 However, recent research in animal models has suggested that dextrose also stimulates proliferation via non-inflammatory mechanisms, as described later in this section.7,8
The ideal dextrose concentration in prolotherapy injections is still under investigation. Notable progress made was via an in vitro study done by Woo et el. comparing different concentrations and combinations of dextrose solutions in prolotherapy. Higher concentration of dextrose more than 5% induced cell apoptosis. 9 Wu et al (2022) also discussed that in vitro high glucose concentrations can mitigate TNF-α-induced NF-κB activation, upregulation of pro-inflammatory cytokines, and metabolic dysfunction. This study demonstrated that high glucose concentrations reduce inflammation-induced neurogenic deterioration, furthering the currently incomplete understanding of the effect of dextrose in wound healing cascade, proliferation, collagen deposition and tissue repair.10
The mechanisms of how dextrose injections work on physiologic and cellular levels in patients are not yet fully delineated. Proliferative effects of dextrose in fibroblasts have been studied in vivo using concentrations of dextrose that are hypertonic but not necessarily inflammatory. For example, Oh et al. reported that 10% dextrose injection, in contrast with a saline control injection, induced subsynovial tissue proliferation (ligament-equivalent proliferation) in a rabbit ligament model.7 A proliferative effect of dextrose on chondrocytes in stage IV human knee osteoarthritis was suggested by a clinical trial using pre-post arthroscopy. After intra-articular injection of 12.5% dextrose, biopsies within new areas of uptake of methylene blue confirmed a combination of fibro and hyaline-like cartilage on immunohistochemical staining.8
In the clinical realm, there is no standard of care for prolotherapy injection technique, concentration, or post-injection care at the time of this writing. Injection techniques can involve a peppering technique for tendon and ligament insertions, and for knee joint injections an infero-medial or infero-lateral approach seems to be preferred.6 Lidocaine is usually included with the dextrose to minimize discomfort from mechanical and chemical irritation to tissues, but even in low percentage, such as <0.5%, recent research indicates muscular and neural toxicity effects of local anesthetic that may be counterproductive.11 Precise concentrations of dextrose in studies vary from 5-25%. It is common to advise patients to rest for 2-3 days to allow time for healing. With knee OA typical injection intervals are 4-6 weeks apart with a total of about 4 injections.6 However, intervals are varied for each indication and practitioner. Often, NSAIDs are avoided following an injection for several days as it can theoretically interfere with the proliferative repair mechanisms.3
There has been a marked increase of new randomized control trials, reviews and meta-analyses since 2019 as seen in table 1. Prolotherapy with dextrose continues to be shown in these usually small trials to be an effective therapy with clinical improvement of function and pain demonstrated in a wide array of clinical areas. Despite the growing number of supportive RCTs on this topic, there are no major society guidelines clearly recommending dextrose prolotherapy at the time of this writing. Of note, the American College of Rheumatology conditionally recommended against prolotherapy in 2019 for knee and hip osteoarthritis due to small, limited trials and study variability.12 However, as evidence is mounting in favor of Prolotherapy, many Sports Medicine training programs now include training in regenerative injection with dextrose or platelet rich plasma.13
Table 1 lists systemic reviews and meta analyses for Prolotherapy by author and year. The overall trend in these studies seems to indicate that Prolotherapy shows positive clinical outcomes for chronic musculoskeletal conditions including knee osteoarthritis,3,14-21 hand osteoarthritis,3,20 plantar fasciopathy,3,22-25 lateral epicondylitis,3,24,26-28 rotator cuff tendinopathy,3,24,29-31 Osgood-Schlatter disease,3,25 Achilles tendinopathy,3,24,25,32 and temporomandibular joint dysfunction.24,33 None of these systemic reviews or meta-analyses demonstrated any significant adverse events due to injection of dextrose.
Based on a variety of measurement outcomes, dextrose prolotherapy still appears to be a promising alternative injection-based intervention. Nonetheless, there are significant limitations of the current body of research including heterogeneity of study designs, non-standardized injection techniques, and small sample size, which could contribute to varied interpretations of the results. More high quality research will be important to advance the use of prolotherapy for the many patients presenting with pain and musculoskeletal conditions.
Prolotherapy Table 1
Table one lists the systemic reviews and meta analyses by author and year with summarized evidences. The number of random trials is listed along with area of body: e.g., knee OA (8) Indicates that eight trials were included in the review.
S- systemic review; M- meta-analysis; DP – dextrose prolotherapy; HDP – hypertonic dextrose prolotherapy, HA – hyaluronic acid
WMD- weighted mean difference; SMD – standardized mean difference visual analog scale (VAS) pain score, foot function index (FFI), American Orthopaedic Foot and Ankle Society (AOFAS) score.
Perineural Injection Treatment
Perineural injections are an ultrasound guided technique used to inject medication adjacent to nerves, with the goal to reduce neuropathic pain. They have been performed classically with injectates including lidocaine, which has a short duration of action, and steroids, which have multiple associated risks. Dr. John Lyftogt anecdotally observed that injection of subcutaneous dextrose without local anesthetic over painful sensory nerves resulted in prompt elimination of hyperalgesia and allodynia in the area of injection.5 Perineural injection with dextrose has been used since then to target the peripheral nerve as a pain generator in chronic pain syndromes. The mechanism of action is thought to be related to an effect on neuropathic pain generators rather than proliferation.34 Note that this injection technique and hydrodissection, discussed in the next section, both involve injection of medication perineurally, thus PIT injections innately incorporate a more superficial level of hydrodissection. It is better to think of them as two mechanisms by which the same injection can provide pain relief.
To understand the mechanism of PIT injections, an understanding of the relationship between neuroinflammation and chronic pain is important and is briefly reviewed here. Upregulation of inflammatory mediators produced by acute changes after injury, including prostaglandins, nerve growth factor, bradykinin, interleukins, and tumor necrosis factor alpha modulate transient receptor potentials, sodium and piezo ion channels on central and peripheral nerves (predominantly peptidergic C fibers), and may result in a transition from acute to chronic pain.35 This transition to chronic pain is characterized by the self-perpetuating production and release of pain-producing and degenerative neuropeptides. These neuropeptides commonly include substance P and calcitonin gene related peptide (CGRP). The production and release of these neuropeptides by activated C fibers is termed neurogenic inflammation and is characterized by an absence of leukocytes.35 It is hypothesized that PIT injection therapy with dextrose has a rapid neurogenic effect on these pain-producing C fibers following injection.
Recent double blind RCT studies have been performed to show that perineural injection with dextrose is effective in various neuropathies. Studies have shown that PIT with dextrose is similar or better than steroid or saline injection in ulnar neuropathy at the elbow36,37 and better than saline for caudal epidural injection when assessing long-term follow up34. The number of studies on PIT with dextrose are still growing, and there are no meta-analyses at the time of this writing.
Hydrodissection Effects Using Dextrose
Hydrodissection refers to ultrasound guided injection using an injectate to mechanically release and decompress an entrapped nerve. Entrapment of nerves occurs at various sites in the body between two muscles, between muscle and bone, across joints, around blood vessels and through fascial tunnels. Compression of the nerve at these entrapment sites causes compressive neuropathies. As ultrasound imaging improves, pain due to nerve entrapment at classic and non-classic locations is being increasingly suspected as a contributor to chronic pain maintenance. In 2003 Bennett described three rat models used to study neuropathic pain: partial sciatic ligation model, chronic constriction injury model, and spinal nerve ligation model.38 The partial sciatic ligation model describes non-compressive contact of a ligature with the sciatic nerve resulting in functional nerve disruption and associated nerve swelling.38 This model supports the concept that even minimal compression of a nerve within the surrounding soft tissues can result in clinically important neurogenic inflammation and neuropathic pain.5 Hydrodissection can be performed with many injectates all aiming to target mechanical compression as well as neurogenic inflammation. Hydrodissection with dextrose has been increasingly studied as a safer and longer lasting option compared to lidocaine or steroid injections. In addition, there is increasing interest in studying hydrodissection without an anesthetic in order to preserve motor function.39
Carpal tunnel syndrome is the most common compressive neuropathy and has been the most studied area for hydrodissection. In 2018 Wu et al. demonstrated the benefits of mechanical tissue separation around nerves by comparing hydrodissection of the median nerve to subcutaneous injection with normal saline.40 Hydrodissection alone was found to be superior.41
There have been many further studies on hydrodissection that compare various injectates including dextrose. Most commonly an isotonic solution of 5% dextrose (D5W) is used. A proposed yet still uncertain mechanism of action of dextrose suggests that dextrose downregulates the TRPV-1 receptor which is upregulated in chronic pain. Another mechanism is theorized to be decrease of C-fiber activation which is increased in a hypoglycemic state.42 Two favorable systematic reviews included D5W as an injectate for hydrodissection in compressive neuropathy found that D5W showed consistently favorable outcomes in pain reduction, functional scales, cross sectional area reduction on ultrasound, and EMG findings compared to control and steroid groups. However, all of the 10 RCTs included compared different interventions with different factors and none could be matched for meta-analysis. In addition, the follow-up interval and volume of injectate varies greatly among studies limiting interpretation. All of the studies with dextrose involved the median nerve with entrapment at the carpal tunnel.42
While carpal tunnel syndrome is the most consistently studied entrapment, there have been RTCs looking at other areas of the body. To emphasize the potential generalizability of hydrodissection for neurogenic pain, Lam et al. hydrodissected a variety of nerves or ganglia in the upper body (stellate ganglion, brachial plexus, cervical nerve roots, and paravertebral spaces) in participants with severe neuropathic pain, and pain reduction exceeded 50% in all 26 participants and 75% in half of the participants.43 This high volume hydrodissection used only dextrose, and so had no lidocaine toxicity risk.
Comparisons of differing volumes of dextrose injections for carpal tunnel syndromes have also been made. The Lin group concludes that injection with dextrose of 4 mL provides better functional outcome and pain relief vs 1ml or 2ml.44,45 Further expansion of the perineural space and longitudinal drug spreading was observed with higher volume. Thus, dextrose hydrodissection appears to offer both mechanical hydrodissection and sensorineural effects in carpal tunnel syndrome.
Summary/ Cutting Edge Issues
Basic science and clinical studies suggest beneficial therapeutic effects of dextrose in conditions associated with tendinopathies, fasciopathies, osteoarthritis, neuropathic pain, and in the presence of nerve entrapment. A substantial percentage of those with idiopathic neuropathy may have symptom magnification due to the “double crush” effect caused by compression of vulnerable nerves. Treatment of those vulnerable nerves to reduce symptoms of neuropathy is a fertile ground for clinically important research. In addition, since research suggests that dextrose can act as an analgesic, it can be used for hydrodissection without anesthetic.43 Its use in therapeutic nerve blocks may facilitate diagnostic and therapeutic injection while preventing lidocaine-induced weakness or toxicity.11,43,44 Additionally, Prolotherapy injections are increasingly being used worldwide in low to middle-income countries due to their low-cost and ease of injection.46
Given the potential benefits for chronic pain and the favorable safety profile the clinical use for these injections is rapidly expanding. Dextrose injections are just starting to be studied in the treatment of GU dysfunction and PTSD. An ongoing RCT by Beco et al. uses perineural injections of dextrose 5% in sterile water (D5W) targeting obturator nerve for longstanding lower urinary tract symptoms and/or dyspareunia 47 Beco et al.’s. recent publication suggests good relief urinary symptoms of patient with obturator neuralgia.47 A case report by Reeves et al. showed bilateral cervical plexus hydrodissection with 10 mL DW5 had profound clinical and emotional improvement of a disabled veteran due to severe post-traumatic stress disorder (PTSD), who failed years of standard treatments.48
Other emerging clinical indications for prolotherapy include low back pain, sacroiliac joint (SIJ) pain and joint laxity.49 For low back pain various studies do not show superiority of prolotherapy alone compared to control, however, there does seem to be a benefit to prolotherapy when performed in conjunction with other standard interventions. Studies on prolotherapy for SIJ pain are more promising, showing significant improvements in function and pain with longer lasting effect than steroid.49 Many studies exist involving temporomandibular joint dysfunction some of which evaluate laxity of the joint in addition to pain and demonstrate decreased locking and hypermobility. There are a limited number of studies examining prolotherapy on laxity of other joints such as ACL laxity and lumbar spine instability. Results are promising but there is not yet enough data to determine the benefits of prolotherapy for joint laxity.49
Gaps in Knowledge/ Evidence Base
The usage of dextrose in prolotherapy, PIT, and hydrodissection continues to expand. Dextrose injections are a promising alternative treatment for long-standing clinical problems unsolvable by current standards of treatment. However, the current body of research is limited by small effect sizes and inability to generalize results due to highly varied injection schedules, injection sites, dextrose concentrations, controls and comparators studied. Additionally, proliferation has not been confirmed as a key component of clinical improvement in Prolotherapy, although it has seldom been directly measured.10,50
The safety of dextrose injection is supported by a growing number of small but methodologically rigorous clinical studies across many pain conditions.3,12 Since 2005 all meta-analyses have reported safety across various indications. Discussion of treatment options with patients should include mention of dextrose-based therapies, given the amount of level B evidence in evidence-based literature.51 Each type of therapeutic dextrose injection can be appropriate for carefully selected chronic pain patients, many of whom have “tried everything” and risk sliding into chronic opioid-based care. Providers should remain alert to new guidelines and be sensitive to patient preferences. It will be important to emphasize ultrasound education in training so that clinicians will have the skill set required to safely incorporate such injection techniques in the future. Further research in these techniques, especially PIT and hydrodissection, is requisite and will help guide their clinical application.
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- Zhao AT, Caballero CJ, Nguyen LT, Vienne HC, Lee C, Kaye AD. A Comprehensive Update of Prolotherapy in the Management of Osteoarthritis of the Knee. Orthop Rev (Pavia). 2022;14(4):33921. Published 2022 May 31. Doi:10.52965/001c.33921
- Oh S, Ettema AM, Zhao C, Zobitz ME, Wold LE, An KN, Amadio PC. Dextrose-induced subsynovial connective tissue fibrosis in the rabbit carpal tunnel: A potential model to study carpal tunnel syndrome? Hand (N Y). 2008;3(1):34-40.
- Topol GA, Podesta LA, Reeves KD, Giraldo MM, Johnson LJ, Grasso R, Jamín A, Clark T, Rabago D. The chondrogenic effect of intra-articular hypertonic-dextrose (prolotherapy) in severe knee osteoarthritis. PMR. 2016;8(11):1072-1082.
- Woo MS, Park J, Ok SH, et al. The proper concentrations of dextrose and lidocaine in regenerative injection therapy: in vitro study. Korean J Pain. 2021;34(1):19-26. Doi:10.3344/kjp.2021.34.1.19
- Wu Z, Tu X, Tu Z. Hyperosmolar dextrose injection for Osgood-Schlatter disease: a double-blind, randomized controlled trial. Arch Orthop Trauma Surg. 2022;142(9):2279-2285. Doi:10.1007/s00402-021-04223-1
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Original Version of the Topic
K. Dean Reeves, MD, David Rabago, MD. Therapeutic Injection of Dextrose: Prolotherapy, Perineural Injection Therapy and Hydrodissection 10/24/2019
Mooyeon Oh-Park, MD
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Emma Desjardins, DO
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Areeb Chator, MD
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Lili Wang, DO
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Dean Reeves, MD
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