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.
- 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.
- 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.
- 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.
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.
- Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S, DeBar L, Kerns R, Von Korff M, Porter L, Helmick C. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults – United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67(36):1001-1005.
- Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved Overdose Deaths – United States, 2013-2017. MMWR Morb Motal Wkly Rep. 2018;67(5152):1419-1427.
- Reeves KD, Sit RWS, Rabago D. Dextrose prolotherapy: A narrative review of basic science and clinical research, and best treatment recommendations. . Phys Med Rehabil Clin N Am. 2016;27(4):783-823.
- Lyftogt J. Pain conundrums: which hypothesis? Central nervous system sensitization versus peripheral nervous system autonomy. Australasian Musculoskeletal Medicine. 2008;13(11):72-74.
- Wu YT, Ho TY, Chou YC, Ke MJ, Li TY, Tsai CK, Chen LC. Six-month efficacy of perineural dextrose for carpal tunnel syndrome: A prospective, randomized, double-blind, controlled trial. Mayo Clin Proc. 2017;92(8):1179-1189.
- 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.
- Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. Effects of hypertonic dextrose injections in the rabbit carpal tunnel. J Orthop Res. 2011;29(7):1022-1027.
- Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. The effects of hypertonic dextrose injection on connective tissue and nerve conduction through the rabbit carpal tunnel. Arch Phys Med Rehabil. 2009;90(2):333-339.
- Yoshii Y, Zhao C, Schmelzer JD, Low PA, An KN, Amadio PC. Effects of multiple injections of hypertonic dextrose in the rabbit carpal tunnel: a potential model of carpal tunnel syndrome development. Hand (N Y). 2014;9(1):52-57.
- 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.
- Ebell MH, Siwek J, Weiss BDW, S.H., Susman J, Ewigman BB, M. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician. 2004;69(3):549-556.
- Sit RWS, Chung VCH, Reeves KD, Rabago D, Chan KKW, Chan DCC, Wu X, Ho RST, Wong SYS. Hypertonic dextrose injections (prolotherapy) in the treatment of symptomatic knee osteoarthritis: A systematic review and meta-analysis. Sci Rep. 2016;6:25247.
- Nourani B, Rabago D. Prolotherapy for Knee Osteoarthritis: A Descriptive Review. Curr Phys Med Rehab Rep. 2016;4:42-49.
- Hung CY, Hsiao MY, K.V. C, Han DS, Wang TG. 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;9:847-857.
- 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;4(1-18).
- Krsticevic M, Jeric M, Dosenovic S, Jelicic KA, Puljak L. Proliferative injection therapy for osteoarthritis: a systematic review. Int Orthop. 2017;41(4):671-679.
- Covey CJ, Sineath MHJ, Penta JF, Leggit JC. Prolotherapy: Can it help your patient? J Fam Pract. 2015;64(12):763-768.
- 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;9:139-159.
- Borg-Stein J, Osoaria HL, Hayano T. Regenerative Sports Medicine: Past, Present, and Future (Adapted From the PASSOR Legacy Award Presentation; AAPMR; October 2016). PM&R. 2018;10(10):1083-1005.
- Dwivedi S, Sobel AD, DaSilva MF, Akelman E. Utility of Prolotherapy for Upper Extremity Pathology. J Hand Surg Am. 2019;44(3):236-239.
- Sanderson LM, Bryant A. Effectiveness and safety of prolotherapy injections for management of lower limb tendinopathy and fasciopathy: a systematic review. J Foot Ankle Res. 2015;Oct 20(8):57.
- Morath O, Kubocsh EJ, Taeymans J, Zwingmann J, Konstantinidis L, Südkamp NP, Hirschmüller A. 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.
- Dong W, Goost H, Lin XB, Burger C, Paul C, Wang ZL, Kong FL, Welle K, Jiang ZC, Kabir K. Injection therapies for lateral epicondylalgia: a systematic review and Bayesian network meta-analysis. Br J Sports Med. 2016;50(15):900-908.
- Lin MT, Chiang CF, Wu CH, Huang YT, Tu YK, Wang TG. Comparative Effectiveness of Injection Therapies in Rotator Cuff Tendinopathy: A Systematic Review, Pairwise and Network Meta-analysis of Randomized Controlled Trials. Arch Phys Med Rehabil. 2019;100(2):336-349.
- 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;Jul 19 doi: 10.1111/joor.12698. [Epub ahead of print].
- Rabago D, Kijowski R, Woods M, Patterson JJ, Mundt M, Zgierska A, Grettie J, Lyftogt J, Fortney L. Association between disease-specific quality-of-life and magnetic resonance imaging outcomes in a clinical trial of prolotherapy for knee osteoarthritis. Arch Phys Med Rehabil. 2013;94(11):2075-2082.
- Ji R, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology. 2018;192(2):343-366.
- Lyftogt J. Subcutaneous prolotherapy for Achilles tendinopathy Australasian Musculoskeletal Medicine 2007;12(11):107-109.
- Lyftogt J. Subcutaneous prolotherapy treatment of refractory knee, shoulder and lateral elbow pain. Australasian Musculoskeletal Medicine 2007;12(2):110-112.
- Lyftogt J. Prolotherapy for recalcitrant lumbago. Australasian Musculoskeletal Medicine 2008;13(5):18-20.
- Jimenez-Andrade JM, Mantyh WG, Bloom AP, Freeman KT, Ghilardi JR, Kuskowski MA, Mantyh PW. The effect of aging on the density of the sensory nerve fiber innervation of bone and acute skeletal pain. Neurobiol Aging. 2012;33(5):921-932.
- Maniquis-Smigel L, Reeves KD, Rosen JH, Coleman C, Lyftogt J, Cheng AL, Rabago D. Short term analgesic effects of 5% dextrose epidural injection for chronic low back pain. A randomized controlled trial. Anesth Pain Med. 2017;7(1):e42550.
- Maniquis-Smigel L, Reeves KD, Rosen JH, Coleman C, Lyftogt J, Cheng AL, Rabago D. Analgesic effect and potential cumulative benefit from caudal epidural D5W in consecutive participants with chronic low back and buttock/leg pain. Jnl Alt Compl Med. 2018 12(12):1189-1196.
- Yelland MJ, Sweeting KR, Lyftogt JA, Ng SK, Scuffham PA, Evans KA. Prolotherapy injections and eccentric loading exercises for painful Achilles tendinosis: a randomised trial. Br J Sports Med. 2009;45(5):421-428.
- Louw WF, Burrils F, Reeves KD, Cheng AL, Rabago D. Treatment of temporomandibular dysfunction with dextrose prolotherapy: A randomized controlled trial with long term follow-up Mayo Clinic Proc. 2019;94(5):820-832.
- Bennett GJ, Chung JM, Honore M, Seltzer Z. Models of neuropathic pain in the rat. Curr Protoc Neurosci. 2003;Chapter 9:Unit 9.14.
- Wu YT, Chen SR, Li TY, Ho TY, Shen YP, Tsai CK, Chen LC. Nerve hydrodissection for carpal tunnel syndrome: A prospective, randomized, double-blind, controlled trial. Muscle Nerve. 2019;59(2):174-180.
- Wu YT, Ke MJ, Ho TY, Li TY, Shen YP, Chen LC. Randomized double-blinded clinical trial of 5% dextrose versus triamcinolone injection for carpal tunnel syndrome patients. Ann Neurol. 2018;84(4):601-610.
- Lam SKH, Reeves KD, Cheng AL. Transition from deep regional blocks toward deep nerve hydrodissection in the upper body and torso. Method description and results from a retrospective chart review of the analgesic effect of 5% dextrose water as the primary hydrodissection injectate. Biomed Res Int 2017;7920438 (Available at https://www.hindawi.com/journals/bmri/2017/7920438/).
- Rabago D, Best TM, Beamsley M, Patterson JJ. A systematic review of prolotherapy for chronic musculoskeletal pain. Clin J Sport Med. 2005;15(5):376-380.
- Burns PB, Rohrick RJ, Chung KC. The Levels of Evidence and their role in Evidence-Based Medicine. Plast Reconstr Surg. 2011;128(1):305-310.
K. Dean Reeves, MD
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David Rabago, MD
Nothing to Disclose