What is the efficacy of prolotherapy for joint pain? What does the evidence say about the use of prolotherapy in orthopedics?

Comment by InpharmD Researcher

Several meta-analyses report mixed results on prolotherapy’s effect in osteoarthritis pain, musculoskeletal pain, and pain in the sacroiliac joint, in which limited studies have found a significant difference in pain scores associated with prolotherapy when compared against platelet-rich plasma and corticosteroids. Notably, number of injections, dosage, and duration vary across published literature; these limitations preclude the ability to draw further conclusions on efficacy. See Tables 1 and 2 for studies evaluating prolotherapy for chronic low back pain and musculoskeletal pain.
Background

A 2023 systematic review and meta-analysis evaluated the use of hypertonic dextrose prolotherapy (DPT) in plantar fasciopathy (PF) compared with other non-surgical treatments. Analysis consisted of 8 randomized controlled trials (RCTs; N= 469) that included adult patients with a clinical diagnosis of PF, whose pain intensity was measured after DPT administration. Compared to control saline injections, pooled results favored DPT in reduction of pain (weighted mean difference [WMD] -41.72; 95% confidence interval [CI] -62.36 to -21.08; p<0.01) and function improvement in 12-26 weeks (WMD -39.04; 95% CI -55.24 to -22.85; p<0.01). However, corticosteroid injections were found to be superior to DPT in acute reduction of pain (<12 weeks), with a standardized mean difference (SMD) of 0.77 (95% CI 0.40 to 1.14; p<0.01). Out of the included studies, one RCT observed acute post-injection pain in three patients; no serious adverse events were noted in any trial. Notably, risk of bias ranged from “some concerns” to “high,” and certainty of evidence ranged from very low to moderate due to high heterogeneity among trials. Differences in injection technique, methodology, and injection dosages also varied. Based on the uncertainty of these results, the use of a standardized protocol with longer follow-up is required to substantiate efficacy in patients with PF. [1]

A 2021 meta-analysis (N= 5 RCTs; 319 treated patients) evaluated the efficacy of DPT in managing knee osteoarthritis. Hypertonic dextrose is highlighted as a preferred prolotherapy solution owing to its affordability, availability, and safety profile. This analysis compared the outcomes of DPT treatment against controls receiving non-dextrose interventions. At a mean of 22.8 weeks follow-up, results indicated a statistically significant improvement in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) composite score (WMD 13.77; 95% CI 6.75 to 20.78; p<0.001; I2= 90%), pain (SMD 1.33; 95% CI 0.49 to 2.17; p<0.001; I2= 91%), and knee function (SMD 1.30; 95% CI 0.45 to 2.14; p<0.001; I2= 91%) in favor of DPT compared with control group. These improvements exceeded the minimum clinically important difference, with no adverse events related to dextrose injections reported across the studies. However, the analysis acknowledged several limitations, including a small number of included studies, potential heterogeneity among studies, and the absence of a test for publication bias. Moreover, the varied control groups and the relatively brief follow-up period presented additional challenges. Despite these limitations, the findings suggest that DPT has a positive and significant beneficial effect on knee osteoarthritis in the short term. The study concludes that while DPT shows promise as either an alternative or an adjunct treatment for knee osteoarthritis, further large-scale, prospective international multi-center trials are needed to comprehensively evaluate its efficacy and safety. [2]

Another 2021 meta-analysis aimed to determine the effectiveness of dextrose prolotherapy as a long-term treatment for chronic musculoskeletal pain. The analysis included 10 RCTs (N= 750 participants) comparing the effect of dextrose prolotherapy with alternative therapies such as exercise, saline, platelet-rich plasma, and steroid injection. Data fro the analysis revealed the primary outcome of pain score change during daily life from 6 months to 1 year after dextrose prolotherapy was significantly reduced compared to saline injection (SMD -0.44; 95% CI -0.76 to -0.11, p= 0.008) and exercise (SMD -0.42; 95% CI -0.77 to -0.07, p= 0.02). No significant difference in pain score was associated with prolotherapy when compared to platelet-rich plasma or steroid injection. Despite the confines of study selection, the results advocate for dextrose prolotherapy as a potent treatment for chronic musculoskeletal pain, emphasizing the necessity for further well-conducted RCTs to strengthen the current evidence base. [3]

A 2021 literature review presents an assessment of prolotherapy's efficacy in the management of chronic low back pain (CLBP), drawing from the inclusion of 12 articles. The literature indicates that prolotherapy may offer improvements in pain, functional status, and patient satisfaction for those suffering from CLBP, particularly when conservative treatments have failed. However, the strength of the evidence supporting prolotherapy as a standalone treatment for CLBP is not robust, primarily due to the variable quality of the included studies and the presence of co-interventions in much of the research (See Table 1) with a significant portion of the studies classified as of poor quality in nature. Despite these limitations, some studies suggest that 70-80% of patients experienced clinically significant improvements in pain and disability at a 6-month follow-up. The review highlights the need for more high-quality RCTs to better establish the standard of care for prolotherapy in CLBP patients and to confirm the suggested dose-response effect observed in some research. As the field stands, prolotherapy with dextrose represents a viable option for the management of CLBP in patients where conservative therapies have not yielded sufficient relief, though its use as a singular therapeutic approach remains to be conclusively supported by strong scientific evidence. The review ultimately calls for further, rigorously conducted RCTs to clarify prolotherapy's efficacy and mechanism of action in CLBP treatment, underlining the absence of significant or permanent adverse reactions reported in the studies reviewed. [4]

A systematic review and meta-analysis published in the Journal of Pain Research in 2016 provides a comprehensive overview of the effectiveness of dextrose prolotherapy in managing osteoarthritis pain. Through a comprehensive review, this study aimed to evaluate the efficacy of dextrose prolotherapy, a regenerative injection therapy, by comparing it against traditional treatments such as control injections, exercise, and potentially corticosteroids. The analysis included one single-arm study and five RCTs examining the outcomes of prolotherapy treatment on patients suffering from hand and knee osteoarthritis. Dextrose prolotherapy offered a superior effect compared with local anesthesia (effect size 0.38; 95% CI 0.07 to 0.70) and exercise (effect size 0.71; 95% CI 0.30 to 1.11). Data derived from one study indicated no significant differences in the positive effects of dextrose versus steroid (effect size 0.31; 95% CI -0.18 to 0.80). [5]

Overall, the results indicated that dextrose prolotherapy was significantly more effective in reducing pain compared to baseline levels, local anesthetic injections, and exercise regimens. Despite the positive outcomes, the study did not establish a clear dose-response relationship between the number of dextrose injections and the degree of pain relief, suggesting that the efficacy of the treatment might not linearly increase with more injections. However, the consistency of prolotherapy's effectiveness in both hand and knee osteoarthritis showcases its versatility and reliability as a pain management solution. This review presents a compelling argument for the consideration of dextrose prolotherapy as a viable and potentially superior alternative to conventional treatments for osteoarthritis, highlighting its role in the evolving landscape of pain management strategies. [5]

A 2016 systematic review evaluated the use of dextrose prolotherapy for chronic musculoskeletal pain. A total of 33 studies were included to be evaluated: 14 RCTs, 1 case-control study, and 18 case series (Table 2). Dextrose amounts utilized ranged from 12.5% to 50%, and were given at various timepoints throughout the studies. Results suggest that dextrose prolotherapy may be a promising alternative to surgery for chronic tendinopathy patients who do not respond to conventional rehabilitation exercises; however, varying patient characteristics across studies and methodological diversity limit efficacious outcomes reported with treatment compared to controls. Studies included were also limited to patients with pain for 3 to 6 months, and thus, efficacy in acute musculoskeletal pain (<3 months), as well as patients with chronic pain lasting over 6 months, is uncertain. [6]

References:

[1] Fong HPY, Zhu MT, Rabago DP, Reeves KD, Chung VCH, Sit RWS. Effectiveness of Hypertonic Dextrose Injection (Prolotherapy) in Plantar Fasciopathy: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Arch Phys Med Rehabil. 2023;104(11):1941-1953.e9. doi:10.1016/j.apmr.2023.03.027
[2] Wang J, Liang J, Yao J, et al. Meta-analysis of clinical trials focusing on hypertonic dextrose prolotherapy (HDP) for knee osteoarthritis. Aging Clin Exp Res. 2022;34(4):715-724. doi:10.1007/s40520-021-01963-3
[3] Bae G, Kim S, Lee S, Lee WY, Lim Y. Prolotherapy for the patients with chronic musculoskeletal pain: systematic review and meta-analysis. Anesth Pain Med (Seoul). 2021;16(1):81-95. doi:10.17085/apm.20078
[4] Giordano L, Murrell WD, Maffulli N. Prolotherapy for chronic low back pain: a review of literature. Br Med Bull. 2021;138(1):96-111. doi:10.1093/bmb/ldab004
[5] Hung CY, Hsiao MY, Chang KV, 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. Published 2016 Oct 18. doi:10.2147/JPR.S118669
[6] 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. Published 2016 Jul 7. doi:10.4137/CMAMD.S39160
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the efficacy of prolotherapy for joint pain? What does the evidence say about the use of prolotherapy in orthopedics?

Please see Tables 1-2 for your response.

 

Summaries of the Studies Evaluating Prolotherapy for Chronic Low Back Pain (Giordano et al. 2021)

Citation

Design

Population

Intervention

Follow-up

 Outcome

Ongley et al. (1987)

RCT

N= 81

Sex F: 43—M: 38
Mean age (range) 44 (23–70) 

 (E) n=40: weekly injections of lumbopelvic ligaments with glucose (12.5%) glycerin (12.5%) phenol (1.25%) 0.25% lignocaine, 20 ml in total. 6 injection treatments. (C) n= 41: the same protocol but without glucose and with saline 0.9% 1, 3 and 6 months VAS pain:
(E): 3.78 (entry)—2.13—1.77—1.50 (C) 3.99 (entry)—3.06—2.93—3.08. Roland disability questionnaire
(E): 11.45 (entry)—4.00—4.70—3.43; (C): 11.82 (entry) 8.37—8.49—8.29 

Klein et al. (1993) 

 RCT

N= 80

Sex F: 36—M: 44
Mean age: 46

 (E) n=39:
Weekly injections of glucose (12.5%) glycerin (12.5%) phenol (1.25%) 0.25% lignocaine. 6 injection treatments.
(C) n=40: the same—injections with 0.25% lignocaine		 6 months after intervention  VAS pain:
(E) 4.88 (entry)—2.29
(C) 4.56 (entry)—2.85
Roland disability questionnaire (E) 9.36 (entry)—4.04
(C) 8.25 (entry)—4.38
Dechow et al. (1999) RCT

N= 74

Sex: F: 38—M: 36

Mean age: 46

 (E): Weekly injections of lumbo pelvic ligaments with glucose, glycerin, phenol, lignocaine. 3 injection treatments.
(C): Same but without glucose		 1–3–6 months after intervention

VAS pain:

(E) 5.3 (entry)—5.2—5.1—5.2 (C) 5.3 (entry)—4.8—5.3—4.4 Oswestry disability scale:
(E) 34 (entry), 34—36—36
(C) 33 (entry) 33—34—35
Yelland et al. (2004) RCT

N= 110

Sex: F: 57—M:41
Mean age: 50 

 (E) (n= 54): Fortnightly injections of glucose (20%) and lignocaine (0.2%), 10–30 mls, mean number of injection treatments 7
(C) (n= 56): the same with only saline (0.9%)		 6–12–24 months after commencing intervention  At 12 months, the proportions achieving > 50% reduction in pain from baseline by injection group were glucose-lignocaine: 0.46 vs saline: 0.36. By activity group these proportions were exercise: 0.41 vs normal activity: 0.39. Corresponding proportions for >50% reduction in disability were glucose-lignocaine: 0.42 vs saline 0.36 and exercise: 0.36 vs normal activity: 0.38
Hooper et al. (2004) Retrospective case series

N= 157

Sex: F: 111—M: 46

Mean age: 39.5

 Solution containing 20% dextrose and 0.75% xylocaine Ranging from 2 months to 2.5 years Ninety-one percent (91.0%) of patients reported reduction in level of pain; 84.8% of patients reported improvement in activities of daily living, and 84.3% reported an improvement in ability to work
Miller et al. (2006) Prospective consecutive patients

N= 76

Sex: F: 35—M: 41

Mean age (range): 55 (21–90)

 Bi-weekly disc space injection of 50% dextrose and 0.25% bupivacaine 6 weeks—41 months NRS:
− mean number of treatment: 3.5%
− 43.4% of patients sustained improvement group
− average improvement in numeric pain scores of 71%
Lyftogt et al. (2008) Prospective clinical audit

N= 41

Sex: F: 17—M: 24

Mean age (range): 48 (23–73)

 Hypertonic dextrose 20–40% mixed with lignocaine or ropivacaine
Mean duration of treatment: 8.3 weeks		 1 year VAS pain:
− mean initial: 7.6
− mean last treatment: 1.4
− mean duration of treatment was 8.3 weeks − mean number of treatments was 6.2.
− 95% of patients improved more than 50% and 10% less than 50%.
− 29% of patients reported no pain at the last consultation
Kim et al. (2010) RCT

N= 48

Sex: F: 14—M: 34

Mean age: 59.5 

 Intra-articular 50% dextrose water prolotherapy or 40 mg triamcinolone acetonide injection, with a biweekly schedule and maximum of three injections. Pain and disability scores were assessed at baseline,
2 weeks, and monthly after completion
of treatment, and then at 6, 10 and 15 months		 The cumulative incidence of >50% pain relief at 15 months was 58.7% in the prolotherapy group and 10.2% in the steroid group 

Watson et al. (2010)

 Retrospective case series N= 140
Sex: (F: 89—M: 51) Mean age: 48 		 Initial standard solutions used for injections included P-25-G (phenol 2.5% plus 25% dextrose plus 25% glycerin mixed 50:50 with 1% lidocaine without epinephrine) or 15% dextrose. The number of injection sites varied depending on how many sites were tender 1 year or more Both pain and QoL∗ scores were significantly improved at least 1 year after the last treatment. There were no differences in outcomes as a result of age, response to Xylocaine (lidocaine) injection, insurance coverage, smoking history, or gender
Cusi et al. (2014) Prospective descriptive study

N= 25
Sex: (F: 5—M: 20)

Mean age: 40

 Three injection of hypertonic dextrose into dorsal interosseous ligament under ct control, 6 weeks apart 3–12–24 months

Quebec Back Pain Disability Scale, Roland–Morris, Roland–Morris Multiform Questionnaires.

Functional questionnaires significant improvements for those followed-up at 3, 12 and 24 months. Clinical examination scores showed significant improvement from start to 3, 12 and 24 months
Maniquis et al. (2016) RCT N= 35
Sex: (F: 11—M: 24) Mean Age: 54 		 Injection of 10 ml
of 5% dextrose or 0.9% saline		 15 minutes; and 2, 4, and 48 h and 2 weeks post-injection

NRS pain score:
change at 15 minutes (4.4 vs 2.4 points; 2 h (4.6 vs 1.8_2.8 points;), 4 h (4.6_2.0 vs 1.4 points; and 48 h (3.0 vs 1 points; at 2 weeks (2.1 vs 1.2.

85% (16/19) of dextrose recipients and 19% (3/16) of saline recipients reported 50% pain reduction at 4 h.
Hoffman et al. (2018) Retrospective cohort study N= 103
Sex: (F: 18—M: 85) Mean age: 55		 Three sacroiliac injections (15% dextrose in lidocaine) at 1-month interval Mean follow-up of 117 days The Oswestry disability index:
24 (23%) showed a minimum clinically important improvement despite a median of 2 years with low back pain and a mean pre-intervention ODI of 54 ± 15 points. Much of the improvement was evident after the initial prolotherapy injection.

Abbreviation: RCT, randomized control trial; (E), Experimental group; (C), Control group; VAS, Visual Analog Scale; NRS, Numeric Rating Scale; QoL, Quality of Life Scale; ODI, Oswestry disability index.     
References:

Adapted from:
Giordano L, Murrell WD, Maffulli N. Prolotherapy for chronic low back pain: a review of literature. Br Med Bull. 2021;138(1):96-111. doi:10.1093/bmb/ldab004

Summary of studies of dextrose prolotherapy in chronic musculoskeletal pain
Study/Design Population Intervention Results
Tendinopathies
Topol et al. (2011)
Argentina
Double-blind RCT		 Osgood-Schlatter disease n= 54; athletes aged 9–17 years
Inclusion:
  • Anterior knee pain >3 mo.
  • Replication of pain severity and location to the tibial tuberosity during a single leg squat
  • Nonresponse to 2 mo. physiotherapy

Exclusion:
  • Pain from patellofemoral crepitus or patellar origin
 Active group: dextrose 12.5%, lidocaine 1% Injection control group: lidocaine 1% Noninjection control group: Usual care (supervised exercise)
Injections given at 0, 1, and 2 months (double-blind)
At 3 months, subjects not achieving NPPS = 0 were offered monthly dextrose injections as needed (open-label) 9 lidocaine and 8 usual care patients switched to dextrose at 3 months Outcome measure(s): Mean NPPS scores		 6 month follow-up (double-blind):
  • Greater reduction in pain with dextrose than lidocaine (p= 0.004) and usual care (p< 0.0001)
  • Greater reduction with lidocaine than usual care (p= 0.024)
12 month follow-up (open-label):
NPPS <4 in 100% of dextrose, 92.3% of lidocaine, and 71.4% of usual care patients (dextrose vs. lidocaine, NS; dextrose vs. usual care, p= 0.008; lidocaine vs. usual care, NS)
NPPS of 0 in 84.2% of dextrose, 46.1% of lidocaine, and 14.2% of usual care patients (dextrose vs. lidocaine, p= 0.024; dextrose vs. usual care, p< 0.0001; lidocaine vs. usual care, p= 0.005)
Refai et al. (2011)
Double-blind RCT
Egypt		 TMJ
n= 12
Inclusion:
  • Confirmation of painful subluxation or dislocation of the TMJ
  • Absence of medical condition that could interfere with healing
 Active group: dextrose 10%, mepivacaine 2%
Control group: mepivacaine 2% 4 injections in each TMJ, spaced 6 weeks apart
Outcome measure(s):
  • VAS pain score
  • MMO in cm. between the incisal edges of the upper and lower incisors
  • Frequency of clicking sound
  • Frequency of luxation
 MMO in dextrose and control groups:
  • Baseline: 5.03 and 4.97 (NS)
  • 6 weeks: 4.72 and 4.93 (NS)
  • 18 weeks after first injection: 4.35 and 4.93 (P = 0.043)
  • 3 months after last injection: 4.33 and 4.97 (P = 0.039)
Pain: Steady decrease in both groups, but NS
Luxation frequency: NS
Clicking frequency: NS
Zhou et al. (2014)
Case series		 TMJ
n= 45
Inclusion:
  • Non-neurogenic recurrent dislocation of the TMJ
 Treatment: dextrose 50%, 0.1%
lignocaine
Outcome measure(s):
  • Absence of dislocation or subluxation for ≥6 months after treatment
 At ≥ 6 months post treatment 41/45 (91%) no longer had dislocation or subluxation.
Of the 41 rehabilitated patients
  • 26 (63%) required a single injection
  • 11 (27%) had 2 treatments
  • 4 (10%) needed a third injection.
Yelland et al. (2011)
Double-blind RCT
Austrailia		 Achilles tendinosis n= 43 Treatment: glucose 20%, lignocaine 0.1%, ropivacaine 0.1%
Patients randomly selected for:
  • Eccentric exercises only
  • Prolotherapy only
  • Eccentric and prolotherapy

Outcome measure(s):
  • VISA-A
 At 12 months, proportions achieving the minimum clinically important change for VISA-A
  • ELE-73%
  • Prolotherapy only - 79%
  • Combined treatment - 86%
Mean (95%CI) increases in VISA-A scores at 12 months were:
  • ELE: 23.7 (15.6 to 31.9)
  • Prolotherapy only: 27.5 (12.8 to 42.2)
  • Combined treatment: 41.1 (29.3 to 52.9)
At 6 weeks and 12 months - Increases were significantly less for ELE than for combined treatment.
Compared with ELE, reductions in stiffness and limitation of activity occurred earlier with prolotherapy and reductions in pain, stiffness and limitation of activity occurred earlier with combined treatment.
Maxwell (2007)
Canada
Case series		 Achilles tendinosis n = 32, mean duration 28.6 months
Inclusion:
  • Failure of conservative therapy
  • Pain >3 months

Exclusion:
  • Acute tendinitis
  • Symptoms due to acute trauma, surgery or interventional procedures in past 3 months
 Treatment: dextrose 25%
Patients injected every 6 weeks until symptoms resolved or no improvement was shown; mean injections were 4
Outcome measure(s):
  • VAS pain score
  • US evaluation
 Mean reduction in pain scores from baseline at 12 months:
  • At rest: 88.2% (p< 0.0001)
  • ADL: 84.0% (p< 0.0001)
  • Physical activity: 78.1% (p< 0.0001)
Mean decrease in tendon thickness:
11.7 to 11.1 mm (p< 0.007) at 12 months Tendon neovascularity decreased in 55%
Ryan et al. (2010)
Case series
Canada		 Achilles tendinosis n= 99 (108 tendons), median duration 21 months
Inclusion:
  • Pain at Achilles tendon insertion or midportion >6 months
  • Pain directly at posterior border of the calcaneus or along midportion of the tendon 2–6 cm proximal to its insertion
  • Documented non-response to conservative treatment

Tendon locations of tendinosis:
  • 86 midportion
  • 22 insertion
 Treatment: dextrose 25%
Injection guidance by GS or color Doppler US into abnormal hypoechoic areas and anechoic clefts or foci in the thickened portion of the Achilles tendon 1–3 sites injected per treatment session Patients received a median 5 sessions spaced a mean 5.6 weeks apart
Outcome measure(s):
  • VAS pain score
  • US evaluation

Measurements at baseline, post-test and 28.6 mo. follow-up		 Mean baseline, post-test, and follow-up VAS: Midportion tendinosis (pain improved):
  • At rest: 34.1, 12.6 (p< 0.001), 3.3 (p< 0.001)
  • ADL: 50.2, 21.8 (p< 0.001), 9.5 (p< 0.001)
  • Physical activity: 70.7, 36.7 (p< 0.001), 16.7 (p< 0.001)
Insertional tendinosis (pain improved):
  • At rest: 33.0, 18.0 (NS), 2.7 (p< 0.001)
  • ADL: 51.3, 29.6 (p< 0.05), 10.0 (p< 0.001)
  • Physical activity: 69.6, 39.8 (p< 0.01), 17.7 (p< 0.001)
Baseline and post-test US findings:
  • Midportion tendinosis: Size of hypoechoic region (mm2) 81.60 and 52.1 (p< 0.01)
  • Insertional tendinosis: Intratendinous tear size (mm) 5.3 and 1.6 (p< 0.01)
Greater reduction in grades 2 and 3 echotexture and neovascularization severity in midportion vs. insertional patients
Lyftogt et al. (2005)
Case series
New Zealand		 Achilles tendinopathy n= 16, mean duration 14 months Inclusion: x-ray confirmation Treatment: dextrose 20%
Outcome measure(s):
  • VAS pain score
 At 18-week follow-up:
  • 11/16 pain VAS score of 0
  • 14/16 satisfied with therapy
Scarpone et al. (2008)
United States
Double-blind RCT		 Lateral epicondylitis of the elbow n= 24
Inclusion: ≥6 months duration refractory lateral epicondylosis		 Active group: 50% dextrose/5%
sodium morrhuate/4% lidocaine/0.5%
sensorcaine/saline
Control group: 0.9% saline
Three 0.5 mi injections at the supracondylar ridge, lateral epicondyle and annular ligament at baseline, 4 and 8 weeks.
Outcome measure(s):
  • Resting elbow pain (0–10 Likert scale)
  • Extension and grip strength Each was performed at baseline, 8 and 16 weeks. One-year follow-up included pain assessment and effect of pain on activities of daily living
 Active group vs. Contois:
Improved pain scores (4.5 ± 1.7, 3.6 ± 1.2 and 3.5 ± 1.5 versus 5.1 ± 0.8, 3.3 ± 0.9 and 0.5 ± 0.4 at baseline, 8 and 16 weeks, respectively);
At 16 weeks, differences were significant compared to baseline scores within and between groups (p< 0.001).
Active group improved extension strength compared to Controls (p< 0.01) and grip strength compared to baseline (p< 0.05) Clinical improvement in Active group maintained at 52 wks.
Shin et al. (2002)
South Korea
Case series		 Lateral epicondylitis of the elbow n= 84
Inclusion: US confirmation		 Treatment: dextrose 15%
Patients received 3 injections spaced 2 months apart
Outcome measure(s):
VAS pain score		 Mean pain scores at baseline and 6 mo. were 6.79 and 2.95 (p< 0.01)
9 mo. follow-up (n= 71) pain scores same/improved in 80.2%, increased in 19.7% Greater pain reduction in patients without (7.08 to 2.16) vs. with partial tendinous tear (6.9 to 3.67; p< 0.01)
Park et al. (2003)
Case series
South Korea		 Lateral Epicondylitis of the elbow n= 11
Inclusion:
  • Partial (n= 11) tear or full thickness but incomplete width tear (n= 1) of common extensor tendons
 Treatment: dextrose 15%
Patients received 2–6 injections Outcome measure(s):
Change in:
  • Echogenicity (GS US)
  • Tendon fibrillar pattern (GS US)
  • Vascularity (color Doppler US)
  • Pain (VAS)
 At mean 5.8 month follow-up:
VAS decreased a mean 4.5 points 1 tendon–a few echogenic lines in initially anechoic lesion
3 tendons–most of anechoic lesion filled with fibrillar echogenicity except for a small anechogenic focus
2 tendons–initial anechoic lesion became same sized hypoechoic lesion with diffuse fibrillar pattern
6 tendons– initial anechoic lesion smaller, with diffuse fibrillar pattern
Hypervascularity in 6 of 11 tendons
Ryan et al. (2011)
Case series
Canada		 Overuse patellar tendinopathy n= 47, mean duration 21.8 months
Inclusion:
  • Failure of standard-of-care therapy
  • Confirmation by palpation and US
 Treatment: dextrose 25%
Under US guidance, injections given into abnormal hypoechoic areas and anechoic clefts/foci in the thickened portion of the patellar tendon
Patients received a median 4 injections 6.4 weeks (mean) apart
Outcome measure(s):
  • VAS pain score
  • US evaluation
 Mean pain scores at baseline and 45 weeks:
  • At rest, 38.4 and 18.7 (p< 0.01)
  • ALD: 51.1 and 25.8 (p< 0.01)
Sports activity: 78.1 and 38.8 (p< 0.01) Change in pain scores during rest, ADL and sport activity correlated with change in echotexture severity (rvalues 0.306, 0.379 and 0.428, respectively; p< 0.05)
General improvement in echotexture and neovascularity severity was found
Topol et al. (2008)
Case series
Argentina		 Chronic groin pain
n= 72 athletes, mean duration 11 months
Inclusion:
  • Chronic groin pain from osteitis pubis and/or adductor tendinopathy
  • nonresponse to conservative therapies
 Treatment: dextrose 12.5%
Patients received a mean 2.7 treatments.
Outcome measure(s):
  • VAS pain score
  • NPPS assessment of pain-related athletic avoidance
 Mean scores at baseline and 26 month follow-up (mean):
VAS, 6.47 and 1.18 (p< 0.001)
NPPS, 5.13 and 1.06 (p< 0.001)
At follow-up, 66/72 (91.6%) had fully resumed sport activities; all but 2 of these were pain-free
Topol et al. (2005)
Case series
Argentina		 Chronic groin pain
n= 24, mean duration 15.5 months
Inclusion:
  • Chronic groin pain from osteitis pubis and adductor tendinopathy
 Treatment: dextrose 12.5%
Patients received a mean 2.8 treatments.
Outcome measure(s):
  • VAS pain score
  • NPPS assessment of pain-related athletic avoidance
 Mean scores at baseline and 17 month follow-up (mean):
  • VAS, 6.3 and 1.0 (p< 0.001)
  • NPPS, 5.3 and 0.8 (p< 0.001)
20 of 24 reported an absence of pain at follow-up
Bertrand et al. (2016)
Canada
Double-blind RCT		 Chronic shoulder pain n= 73
Inclusion:
  • Examination findings of rotator cuff tendinopathy
  • US conformation of supraspinatus tendinosis/tear
 Enthesis-Dex group: 25% dextrose, 0.1% lidocaine/saline
Entheis-Saline group: 0.1% lidocaine/saline
Superficial-Saline group: injection 0.5- to 1-cm depth with 0.1% lidocaine/saline All participants received 3 monthly injections to painful entheses at and concurrent programmed physical therapy.
Outcome measure(s):
improvement in maximal current shoulder pain ≥2.8 (twice the minimal clinically important
difference for VAS pain); USPRS; 0-to-10 satisfaction score (10, completely satisfied)		 At 9-month follow-up the Enthesis-Dextros Group:
Maintained greater improvement in pain 59% ≥2.8 VAS compared with Enthesis-Saline (37%; p= 0.088) and Superficial-Saline (27%; p= 0.017).
Had greater satisfaction: 6.7 ± 3.2 compared with Enthesis-Saline (4.7 ± 4.1; p= 0.079) and Superficial-Saline (3.9 ± 3.1; p= 0.003).
USPRS findings were not different between groups (p= 0.734).
Lee et al. (2015)
South Korea
Retrospective case
controlled series		 Chronic shoulder pain n= 151
Inclusion:
  • Non-traumatic refractory rotator cuff disease
  • Unresponsive to 3 months of aggressive conservative treatment
 Active group: dextrose 16.5%.
Control group: conservative treatment Outcome measure(s):
  • VAS score of shoulder pain level for the past 1 week;
  • SPADI score
  • Isometric strength of the shoulder abductor
  • AROM of shoulder
  • Maximal tear size on ultrasonography
  • Number of analgesic ingestions per day
 Compared with the control group, the active group showed significant improvement at 1-year follow-up in:
  • VAS score
  • SPADI score
  • Isometric strength of shoulder abductor
  • Shoulder AROM of flexion, abduction, and external rotation
Ryan et al. (2009)
Canada
Case series		 Plantar fasciitis
n= 20, median 21 months duration
Inclusion:
  • Symptoms >6 months
  • Non-response to conservative treatment
Exclusion: acute plantar foot pain, surgery or interventional procedures in last 6 months		 Treatment: dextrose 25%
Injections into plantar fascia
Injections were given at 6 week intervals; median of 3 treatments per patient
Outcome measure(s):
VAS pain score		 Mean pain scores at baseline and 18 week follow-up:
  • At rest, 3.7 and 1.0 (p< 0.001)
  • With walking, 7.5 and 2.5 (p< 0.001)
  • With running, 9.2 and 3.9 (p< 0.001)
No change in mean pain score from 18 week to 11.8 month (mean) follow-up
Osteoarthritis and Degenerative Conditions
Rabago et al. (2011)
United States
3-way double-blind RCT		 Knee osteoarthritis n= 89
Inclusion:
  • ARA criteria moderate-severe knee osteoarthritis
  • >3 months duration

Active group: dextrose 15% and dextrose 25%
Injection control group: saline
Noninjection control group: exercise instruction

Injections at 1, 5, and 9 weeks, and weeks 13 and 17 as needed.
Extra-articular injections at periarticular tendon and ligament insertions (dextrose 15%), with 1 intra-articular injection (dextrose 25%) through an infero-medial approach.
Patients received a mean 4.3 injection sessions
Outcome measure(s):
OA-related pain, function and stiffness (WOMAC)
Knee pain severity and frequency (KPS)

WOMAC composite score: no significant difference between groups
WOMAC score, adjusted for gender, age and BMI: greater reduction in mean dextrose (15.32) than saline (7.68) (p< 0.05) and exercise (8.25) (p< 0.05) scores

Mean KPS scores in dextrose subjects showed greater improvement per injected knee relative to baseline status (p< 0.001) and compared to both control groups (p< 0.05)
Reeves & Hassanein (2000)
United States
Double-blind RCT		 Knee osteoarthritis with/without ACL laxity
n= 77
Inclusion:
  • ≥ grade 2 joint narrowing or ≥ grade 2 osteophytic change in any knee compartment
  • pain duration ≥6 months
 Active group: 10% dextrose, xylocaine 0.075%
Control group: xylocaine 0.075%
Tibiofemoral injections
Patients received 3 bimonthly injections; dextrose-injected patients then received 3 further bimonthly injections under open-label conditions
Outcome measure(s):
  • VAS pain and swelling scores
  • Goniometric measurement of joint flexion
  • KT1000 measurement of ADD
  • US
 6 month follow-up (dextrose vs. control): Greater improvement in dextrose vs. control group in pain, swelling, buckling episodes, and knee flexion range (p= 0.015 for all) 12 month follow-up (dextrose vs. baseline): Improvement found in lateral patellofemoral cartilage thickness (p= 0.019) and distal femur width in mm (p= 0.021).
Knees w/ joint laxity showed improved knee flexion range (+12.8 degrees, P = 0.005) and ADD (57%, p= 0.025).
8/13 dextrose-treated knees with ACL laxity at baseline no longer lax at 1 year
Reeves & Hassanein (2003)
United States
Case series		 ACL laxity in patients with knee osteoarthritis
n= 18
Inclusion:
  • Laxity with ADD ≥2 mm measured by KT1000 arthrometer
  • Duration >6 months
 Treatment: dextrose 10% and dextrose 25%
Injections of dextrose 10% at months 0, 2, 4, 6, and 10, dextrose 25% at month 12, then dextrose 10% or 25% every 2–4 months through month 36 according to patient preference
Outcome measure(s):
  • VAS pain and swelling scores
  • Goniometric measurement of joint flexion
  • KT1000 measurement of ADD
 VAS at baseline and 12 months:
  • Pain during rest, 2.31 and 1.56 (NS)
  • With walking, 4.19 and 2.50 (p= 0.004)
  • With stair use, 5.88 and 4.06 (p= 0.022)
  • Swelling, 2.75 and 1.31 (NS)
VAS at baseline and 36 months:
  • Pain at rest, 2.31 and 1.25 (NS)
  • With walking, 4.19 and 2.38 (p= 0.002)
  • With stair use, 5.88 and 3.82 (p= 0.007)
  • Swelling, 2.75 and 1.00 (p= 0.017)
Biomechanical assessments:
Flexion range: 111.88, 125.94 at 12 months (p= 0.001), 122.38 at 36 months (p= 0.002) ADD: 2.88, 1.32 at 12 months (p= 0.023), 0.82 at 36 months (p= 0.002)
At 36 months, normal ADD in 10 of 14 knees
Dumais et al. (2012)
Randomized Crossover Study
Canada		 Chronic knee osteoarthritis
  • Pain duration ≥6 months
  • Age ≥18 years
  • Able to execute exercises
 Treatment: dextrose 20%, lidocaine 0.5%
Random assignment:
Group A: exercise therapy for 32 weeks in combination with injections inside the
knee joint on weeks 0, 4, 8, and 12 Group B: exercise therapy for 32 weeks in combination with injections inside the knee joint on weeks 24, 28, and 32 (Group B)
Outcome measure(s):
Change in WOMAC scores between weeks 0 and 16; and weeks 20 and 36		 Group A:
  • 0–16 weeks - significant change in WOMAC indicating decrease in symptoms (mean ± standard deviation: –21.8 ± 12.5, p< 0.001).
  • 20–30 weeks - no significant change in WOMAC scores (–1.2 ± 10.7, p= 0.65).
Group B:
  • 0–16 weeks - no significant change in WOMAC scores (–6.1 ± 13.9, p= 0.11).
  • 20–30 weeks - significant change in WOMAC indicating decrease in symptoms (–9.3 ± 11.4, p= 0.006).
>36 weeks - WOMAC scores improved in both groups by 47.3% (A) and 36.2% (B). The improvement attributable to RIT alone corresponds to a 11.9-point (or 29.5%) decrease in WOMAC scores.
Eslamian & Amouzandeh (2015)
Iran
Case series		 Moderate knee osteoarthritis n= 24
Inclusion: female		 Treatment: dextrose 20%
Injections given at baseline, 4 weeks, 8 weeks
Patients were followed for 24 weeks.
Outcome Measure(s):
  • VAS pain scale
  • AROM
  • WOMAC
Measurements made at baseline, 4, 8, and 24 weeks later.		 At baseline:
  • Mean AROM (105.41 ± 11.22°)
  • Mean VAS scale at rest (8.83 ± 1.37)
  • Mean VAS scale at activity (9.37 ± 1.31)
Week 24:
  • Mean AROM increased by 8°
  • Mean VAS scale at rest decreased in 45.89% (p< 0.001)
  • Mean VAS scale at activity decreased in 44.23%, (p< 0.001)
  • Total WOMAC decreased by 30.5 ± 14.27 points (49.58%) (p< 0.001)
Improvements of all parameters were considerable until week 8, and were maintained throughout the study period.
Hashemi et al. (2015)
Iran
Double-blind RCT		 Mild to moderate knee osteoarthritis
n= 80
Inclusion: Diagnosis of knee osteoarthritis (clinical examination and anteroposterior standing radiography)		 Active Group 1: dextrose 12.5%, lidocaine 1%
Active Group 2: 15 g/mL of ozone-oxygen mixture, lidocaine 1%
Injections given 3 times at 7 to 10 day intervals.
Outcome Measure(s):
  • VAS pain scale
  • WOMAC
 Active Groups 1 and 2:
  • Mean VAS decreased (p< 0.001)
  • WOMAC increased (p< 0.001
  • No significant difference between the two groups
Reeves & Hassanein (2000)
United States
Double-blind RCT		 Osteoarthritic finger joints n= 27; average pain duration >4 years
Inclusion:
  • Moderate osteophytosis
  • Moderate joint space narrowing
  • Mild osteophytosis plus mild joint space narrowing
  • Pain duration ≥6 months
 Active group: dextrose 10%, xylocaine 0.075%
Control group: xylocaine 0.075%
Injections performed 0, 2, and 4 months after enrollment, data obtained 6 months after first injection
After 6 months, patients in both groups offered bimonthly dextrose 10% injection
Patient attrition: 4/13 active, 3/14 control group
Outcome measure(s):
  • VAS pain scale
  • Goniometric measurement of joint flexion
  • X-ray imaging of joint repair
 6 month follow-up:
  • Greater improvement in dextrose vs. control groups in pain with movement (p= 0.027); other comparisons NS
  • Greater improvement in flexion range in dextrose vs. control group (p= 0.003)
12 month follow-up:
  • Dextrose group showed difference from baseline in joint narrowing (p= 0.006)
  • All other comparisons NS
Jahangiri et al. (2014)
Iran
Double-blind RCT		 Osteoarthritic finger joints n= 60
Inclusion:
  • >40 years of age
  • history of pain in first carpometacarpal joint >3 months
  • Pain intensity VAS >30 at baseline
  • radiographic evidence of OA
 Active group: dextrose 20%, lidocaine 2%
Control group: 40 mg methylprednisolone acetate (0.5 mL), lidocaine 2%
Outcome measure(s):
  • VAS pain score
  • Hand function and strength of lateral pinch grip
  • Measured at baseline, 2 and 6 months after the treatment
 At 1 and 2 month follow-up results were more favorable among control group than active group participants.
At 6 months outcome was more favorable for active group [mean difference in VAS = 1.1 (95% CI 0.2-2.0), p= 0.02].
After 6 months of treatment, both study and control groups increased functional level, but study group seemed to be more effective [mean difference in total function score = 1.0 (95% CI 0.2-1.8), p= 0.01]
Spinal and pelvic pain
Miller et al. (2006)
Case series		 Discogenic leg pain n = 76, mean duration 39 months
Inclusion:
  • Moderate to severe degenerative disc disease without herniation
  • Concordant pain reproduction with CT discography
  • Normal neurological exam
  • Nonresponse to 6 months of conservative treatment
 Treatment: dextrose 25%
Dextrose solution injected into disc space; patients received a mean
3.5 injections into a mean 1.7 discs
Outcome measure(s):
  • Mean NRS pain rating
 n= 37 non-responders (<20% pain reduction); n= 6 temporary (<2 months) responders
Of 33 sustained responders, mean pain scores at baseline, 2 month, and 18-month follow-up:
8.9 ± 1.4), 2.5 ± 2.0, and 2.6 ± 2.2
Mean overall pain improvement: 71%
Khan et al. (2008)
India
Case series		 Coccygodynia
n= 37
Inclusion:
  • Nonresponse to conservative therapy for >6 months
Exclusion: Posttraumatic and post-delivery coccygodynia, sacro-coccygeal subluxation, coccygeal spicule, organic bony pathology on radiograph		 Treatment: dextrose 25%
2 injections into sacro-coccygeal joint 15 days apart; those with VAS pain score >4 given 3rd injection 4 weeks later
Outcome measure(s):
VAS pain scores		 Baseline pain score: 8.5*
Pain score after 1st injection: 3.4
Pain score after 2nd injection: 2.5
n= 7 little-no improvement
n= 30 good pain relief
*patients w/ previous steroid injection (n= 27) had baseline pain score 8.8
Kim WM, et al. (2010)
South Korea (in English)
Double-blind RCT		 Sacroiliac joint pain n = 48
Inclusion:
  • Pain origin confirmed by pain reduction ≥50% to intraarticular SI joint block with levobupivacaine 0.25%
  • Following SI block response, non-response to 1 month of medical treatment
Exclusion: Cancer, fractures, inflammatory arthritis, infection, fibromyalgia, active litigation		 Active group: dextrose 25%, levobupivacaine 0.25%
Control group: triamcinolone 40 mg, levobupivacaine 0.25%
Biweekly intraarticular injections into intra-articular SI, up to 3 injections Outcome measure(s):
NRS pain scores
Oswestry (2 weeks only)		 2-week follow-up:
Significant improvement in both groups, no significant difference between active and control
15 month follow-up:
Cumulative incidence of ≥50% pain reduction:
Dextrose: 58.7% (95% CI 37.9%–79.5%)
Steroid: 10.2% (95% CI 6.7%-27.1%)
Between-groups difference p< 0.005
Kim HS, e al. (2007)
South Korea
Double-blind RCT		 Iliac crest pain syndrome n= 44 Active group: dextrose 20%, 1% lidocaine
Control group: triamcinolone, lidocaine Weekly injection for 4 weeks
Outcome measure(s):
  • Mean change from baseline in VAS pain
  • Oswestry
  • Pressure threshold (algometer, kg/cm2)
 3 month follow-up:
Both groups improved in pain, disability and pressure threshold scores (p< 0.05)
No significant difference between groups on any measure at any follow-up interval
Hooper et al. (2011)
Canada
Case series		 Chronic cervical, thoracic or lumbar pain
n= 71 litigants (mean pain duration 2.1 years)
n= 76 non-litigants (mean pain duration 6.3 years)
Inclusion:
  • Demonstration of laxity on stress testing in spinal, iliolumbar, or sacroiliac ligaments
  • Pain >6 months
  • Nonresponse to conventional therapies
 Active treatment: dextrose 20% Injections into the facet capsules of the cervical, thoracic, lumbar spine Patients received weekly injections for up to 3 weeks, and 1 month later if needed
Outcome measure(s):
  • NDI
  • PSFS
  • RMDQ
 At baseline, litigants compared to non- litigants:
  • Higher disability scores (p= 0.001)
  • More multiple regions affected
  • More cervical and thoracic regions affected (p< 0.0001)
  • Shorter mean symptom duration (p< 0.0001)

1-year follow-up:
Both litigants and non-litigants improved in all disability scales (p< 0.001).
Percentage of litigants vs. non-litigants reporting improvement:
  • Impression of change scales for symptoms (91/92%) and function (90/90%)
  • Improved ability to work (76/75%)
  • Willingness to repeat treatment (91/93%)
  • Ability to decrease medication (82/81%)
  • Decreased need for other treatment (80/84%)
  • Litigants showed greater improvement in treatment of the thoracic spine (p< 0.05)
Centeno et al. (2005)
United States
Case series		 Neck pain
n= 6
Inclusion:
  • ≥50% pain reduction and >2.7 mm absolute cervical translation with 2-day cervical immobilization
  • Post-MVA cervical instability, neck pain and disability
  • Pain/disability >6 months
  • Failure to respond to conservative therapy Exclusion: previous neck injury, connective tissue disease, arthritis or diabetes I or II
 Treatment: dextrose 12.5%
Injections targeted instability sites including the spinous processes, lamina, and posterior elements
Outcome measure(s):
  • Mean changes from baseline in VAS pain scores
  • Radiographic findings
 Pain scores, baseline and 1 month: 5.75 and 3.83 (p= 0.04)
Significant correlation between changes in pain scores and translation (rho = 0.88, p= 0.02),
Significant correlation between changes in flexion and translation (rho = 0.94, p< 0.01)
Lee et al. (2009)
South Korea
Case series		 Low back and pelvic pain
n= 22, mean duration
39.8 months
Inclusion:
  • Sacroiliac pain confirmed by ≤50% pain reduction with local anesthetic block
 Treatment: Dextrose 25%
Injections every other week for 3 weeks
Outcome measure(s):
  • Mean changes from baseline in NRS pain scale
  • Oswestry
 Mean (range) NRS scores: (p< 0.01)
Baseline: 6 (4–8)
10 weeks: 1 (0–3)
Mean (SD) Oswestry scores (p< 0.01)
Baseline: 34.1 ± 15.5
10 weeks: 12.6 ± 9.8
Mean duration of pain reduction ≥50% was 12.2 months
Myofascial Pain Syndrome
Kim MY, et al. (1997)
South Korea
Double-blind RCT		 Myofascial pain syndrome
n= 64		 Active group: dextrose 5%
Control group: lidocaine 0.5%
Control group: saline
Outcome measure(s):
  • Mean changes from baseline at 7 days in VAS pain score
  • Pressure threshold (algometer, kg/cm2)
 Change in VAS pain score:
Dextrose: 6.87 and 2.39 (p< 0.01)
Saline: 6.50 and 3.85 (NS)
Lidocaine: 6.95 and 4.05 (NS)
Pressure threshold tolerance:
Dextrose: 1.79 and 2.49 (p< 0.05)
Saline: 1.70 and 1.91 (NS)
Lidocaine: 1.75 and 2.07 (NS)
Abbreviations: ACL, anterior cruciate ligament; ADD, anterior displacement difference; ADL, activities of daily living; AROM, active range of motion; BMI, body mass index; CI, confidence interval; CT, computerized tomography; GS, gray scale; KPS, Knee Pain Scale; MMO, maximum mouth opening; MVA, motor vehicle accident; NDI, Neck Disability Index; NPPS, Nirschl Pain Phase Scale; NRS, Numeric Rating Scale; NS, not significant; OA, osteoarthritis; Oswestry, Oswestry Disability Index; PEDro, Physiotherapy Evidence Database; PRS, Pain Rating Scale; PSFS, Patient Specific Functional Scale; RMDQ, Roland-Morris Disability Questionnaire; SD, standard deviation; SI, sacro-iliac; SPADI, Shoulder Pain and Disability Index; TMJ, temporomandibular joint; US, ultrasound; USPRS, Ultrasound Shoulder Pathology Rating Scale; VAS, Visual Analog Scale; VISA-A, Victorian Institute of Sports Assessment; WOMAC, Western Ontario Macmaster University Osteoarthritis Index
References:

Adapted from:
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. Published 2016 Jul 7. doi:10.4137/CMAMD.S39160