Therapeutic Injection of Dextrose: Prolotherapy, Perineural Injection Therapy and Hydrodissection

Author(s): Dean Reeves, MD, David Rabago, MD

Originally published:10/24/2019

Last updated:10/24/2019

1. INTRODUCTION

The prevalence of chronic pain among adults in the US is 20.4%;1 a concomitant opioid epidemic and subsequent opioid-related death have created a national emergency.2 National organizations have called for new therapies to treat chronic pain, including therapy that addresses the underlying pain pathology. An overarching goal is to produce improved non-opioid treatment regimens.

The focus is this article is discussion of the evidence base underpinning the therapeutic injection of dextrose, an agent used in several emerging, distinct but related injection-based modalities. Recent basic science and clinical research suggest several ways in which dextrose can reduce pain, improve overall function and restore connective tissue function. While the mechanism of action of dextrose is not well understood at a cellular level, clinical trials have assessed three distinct therapeutic dextrose-related modalities and reported positive clinical effects compared with blinded injection controls.

  1. Prolotherapy: Injection of hypertonic dextrose to treat chronic musculoskeletal pain.3 Hypertonic dextrose is the most commonly used injectant; the purported mechanism focuses on proliferative repair.
  2. Perineural injection treatment (PIT) with dextrose: The injection of dextrose adjacent to peripheral nerves to reduce neuropathic pain.4 A nearly isotonic dextrose solution (5% dextrose in water; D5W) is most commonly used. The purported mechanism is associated with a sensorineural effect.
  3. Hydrodissection with dextrose: 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.5

Each is in use as outpatient therapy in the U.S. Acquisition of procedural skills for each is sometimes through formal medical training, but more often in continuing medical education contexts. Prolotherapy is supported for specific indications by a moderate and growing body of literature with fifteen positive narrative reviews or metaanalyses, PIT by two RCTs and hydrodissection by three RCTs. Hypothesized mechanisms and attributes suggest these techniques have 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.

2. PROLOTHERAPY

Prolotherapy is supported by the strongest body of clinical evidence of the 3 modalities using dextrose as an agent to treat chronic pain. The term is a portmanteau of “proliferative” and “therapy”. Basic science does not yet elucidate a clear mechanism, and precise concentration of dextrose in studies varies from non-inflammatory solutions of 10% to inflammatory solutions of 12.5-25%. No studies have compared the relative proliferative effect of differing concentrations.

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.6 Two subsequent RCTs using the same model resulted in significant proliferation of organized, linear, ligament-equivalent tissue with dextrose injection,7,8 and a third9 demonstrated subsynovial tissue proliferation to nearly double the thickness of the saline-injected control tissue, with a proportionately greater energy required to point of rupture.

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 suggested new cellular growth, as seen by areas of uptake of methylene blue.10 A metabolically active, moderately well organized, combination of type I and II cartilage was evidenced by safranin-O staining, polarized light microscopic evaluation and immunohistologic staining.10 The dextrose concentration of 12.5% is known to be slightly inflammatory, but was placed in a visible suprapatellar pouch, and would have been diluted rapidly to 10% or less concentration.

No study has compared concentrations of dextrose to determine if concentrations above 12.5% dextrose better stimulate proliferation, and concentrations less than 10% have only been assessed for proliferative effects in vitro. Small clinical studies of varying methodological quality have been systematically reviewed in -fifteen narrative reviews or metanalyses. Table 1 lists the review/metaanalyses by author and year, and by focused or general review. The number of randomized trials is listed along with area of body; e.g., Knee OA (3) indicates that 2 RCTs were included in the review. According to strength of recommendation (SOR) criteria,11 Level A evidence is present for knee osteoarthritis3,12-19 and level B evidence for hand osteoarthritis,3,14,18-20 Osgood-Schlatter disease,3,17-19,21 Achilles tendinopathy,3,17-19,21,22 plantar fasciopathy,3,17,18,21 lateral epicondylosis,3,17-20,23 rotator cuff tendinopathy,3,18-20,24  and temporomandibular dysfunction.25 Proliferation has not been confirmed as a key component of clinical improvement, although it has seldom been directly measured.10,26

3. PERINEURAL INJECTION TREATMENT

Clinical improvement in the absence of proliferation may be due to a sensorineural effect of dextrose on neuropathic pain generators. Clinically, physicians and patients often note pain diminution immediately or within 1-2 days of treatment, a time frame inconsistent with a tissue proliferation effect. To understand what may be happening, 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, or tumor necrosis factor alpha modulate transient receptor potential, 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.27 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.27

The potential action of dextrose in sensorineural effects has been hypothesized. In 2005, Dr. John Lyftogt anecdotally observed that injection of subcutaneous dextrose without local anesthetic over painful sensory nerves (PIT with dextrose) sometimes resulted in prompt (within seconds) elimination of hyperalgesia and allodynia in the area of injection. Results of several case studies suggest pain reduction with injection of subcutaneous dextrose injection over related sensory nerve pathways in Achilles tendinopathy,28 knee, shoulder, and elbow pain,29 and low back pain.30 A rapid neurogenic effect of dextrose on pain-producing C fibers following subcutaneous injection may also explain rapid pain reduction after deeper (enthesis or intraarticular) injection in prolotherapy, since the same pain-producing C fibers are also found in high density on bony cortex.31

The analgesic effect of dextrose injection observed by Dr. Lyftogt was subsequently reported in a double blind RCT comparing D5W to saline injection in the caudal epidural space in participants with back and either buttock or leg pain, resulting in significant analgesia of 15 minutes to 48 hours duration.32 (Table two) Upon continued open label treatment, analgesic effects post-injection were consistent and clinical benefits were cumulative and clinically significant to 1 year follow-up.33

Only one RCT assessing perineural dextrose injection has been performed. Yelland et al. compared subcutaneous dextrose injection to eccentric lengthening exercise (ELE) in Achilles tendinopathy, and showed non-inferiority of dextrose injection to the evidence-based ELE approach to Achilles tendinopathy, and potential additive benefit from combining both treatments.34

Recently published RCTs consistently report clinical benefits compared with injection control, without clear evidence of proliferation, including an RCT comparing dextrose to anesthetic in the treatment of temporomandibular disorder,35 providing increasing evidence of a sensorineural effect of dextrose injection.

4. HYDRODISSECTION EFFECTS USING DEXTROSE

Pain due to nerve entrapment at classic and non-classic locations is being increasingly suspected as a contributor to chronic pain maintenance as ultrasound imaging improves. Bennett observed that non-compressive contact of a ligature with the surface of a rat sciatic nerve consistency results in functional nerve disruption, and an hourglass appearance with prompt appearance of nerve swelling on either side of the ligature.36 The sciatic ligature model, commonly used to create neuropathic pain in research settings, supports the concept that even minimal compression of nerves in fascial layers can result in clinically important neurogenic inflammation and neuropathic pain.4 Use of continuous visualization by ultrasound to inject fluid adjacent to peripheral nerves to separate nerves visibly from all fascial layers is termed hydrodissection. Wu et al. compared hydrodissection of the median nerve in carpal tunnel syndrome to subcutaneous injection with normal saline, reporting benefit from hydrodissection alone.37 (Table two) In other randomized controlled trials, hydrodissection with D5W was superior to either hydrodissection with saline or hydrodissection with triamcinolone in saline.5,38 Thus, dextrose hydrodissection appears to offer both mechanical hydrodissection and sensorineural effects in carpal tunnel syndrome. To emphasize the potential generalizability of benefit 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 26 consecutive participants.39 This high volume hydrodissection used only dextrose, and so had no lidocaine toxicity risk.

5. SUMMARY/CUTTING EDGE ISSUES

Basic science and clinical studies suggest therapeutic effects of dextrose in conditions associated with connective tissue degeneration or insufficiency, neuropathic pain, and in the presence of fascia-based constriction (nerve entrapment). A substantial percentage of those with idiopathic neuropathy may have symptom magnification due to the “double crush” effect of compression of vulnerable nerves, and treatment of those vulnerable nerves to reduce symptoms of neuropathy may be a fertile ground for clinically important research. In addition, since D5W appears to be analgesic and can be used for hydrodissection without anesthetic,39 its use in therapeutic nerve blocks may facilitate diagnostic and therapeutic injection while preventing lidocaine toxicity.39

6. GAPS IN KNOWLEDGE/EVIDENCE BASE

The ideal concentration of dextrose injection for individual therapeutic applications is unclear. As indicated by Figure 1, we know little about the proliferative ability of less than 10% dextrose, as all in vivo work has used concentrations of 10% or more. Dextrose may be more effective when the concentration reaches the level that initiates inflammation (12.5%) but that has not been established. For reduction of neuropathic pain, 5% dextrose is recommended for clinical trials to minimize potential of a proliferative effect of dextrose in a closed space, as clinical effects do not appear to vary from 5-25% in consecutive patient trials28-30 and empirical observations. The mechanism of action of dextrose in each procedure and clinical indication is likely multifactorial due to the complexity of chronic pain, and the nuances of pressure and volume relationships at the tissue level.

The safety of dextrose injection is supported by a growing number of small but methodologically rigorous clinical studies across many pain conditions.3,18 While the level of evidence for prolotherapy for knee osteoarthritis has been reported as “A”, the level of evidence for most published procedures using dextrose is “B”. Larger trials are needed but challenging to conduct given their high cost and relative lack of representation in the university environment. Since 2005 all meta-analyses have reported safety across various indications.40 Discussion of treatment options with patients should include mention of dextrose-based therapies, given the amount of level B evidence in evidence-based literature.41 Each type of therapeutic dextrose injection is 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 information and be sensitive to patient preferences.”41 Further research in these techniques is requisite and will help guide their clinical application.

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Author Disclosure

Dean Reeves, MD
Nothing to Disclose

David Rabago, MD
Nothing to Disclose

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