Therapeutic Injection of Dextrose: Prolotherapy, Perineural Injection Therapy and

Hydrodissection
Author(s): Dean Reeves, MD, David Rabago, MD
Originally published: October 24, 2019 Last updated: October 24, 2019
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introductionprolotherapyPerineural Injection Treatmenthydrodissection Effects Using
Dextrosesummary/cutting Edge Issuesgaps in Knowledge/evidence Base
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.
Table 1
Table 2
Figure 1
REFERENCES
1. 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.
2. 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.
3. 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.
4. Lyftogt J. Pain conundrums: which hypothesis? Central nervous system
sensitization versus peripheral nervous system autonomy. Australasian
Musculoskeletal Medicine. 2008;13(11):72-74.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. Nourani B, Rabago D. Prolotherapy for Knee Osteoarthritis: A Descriptive
Review. Curr Phys Med Rehab Rep. 2016;4:42-49.
14. 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.
15. 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).
16. 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.
17. Covey CJ, Sineath MHJ, Penta JF, Leggit JC. Prolotherapy: Can it help your
patient? J Fam Pract. 2015;64(12):763-768.
18. 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.
19. 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.
20. Dwivedi S, Sobel AD, DaSilva MF, Akelman E. Utility of Prolotherapy for Upper
Extremity Pathology. J Hand Surg Am. 2019;44(3):236-239.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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].
26. 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.
27. 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.
28. Lyftogt J. Subcutaneous prolotherapy for Achilles tendinopathy Australasian
Musculoskeletal Medicine 2007;12(11):107-109.
29. Lyftogt J. Subcutaneous prolotherapy treatment of refractory knee, shoulder
and lateral elbow pain. Australasian Musculoskeletal
Medicine 2007;12(2):110-112.
30. Lyftogt J. Prolotherapy for recalcitrant lumbago. Australasian Musculoskeletal
Medicine 2008;13(5):18-20.
31. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. Bennett GJ, Chung JM, Honore M, Seltzer Z. Models of neuropathic pain in the
rat. Curr Protoc Neurosci. 2003;Chapter 9:Unit 9.14.
37. 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.
38. 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.
39. 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/).
 40. 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.
41. 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.
Author Disclosure
Dean Reeves, MD
Nothing to Disclose
David Rabago, MD
Nothing to Disclose