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Effects of Hypertonic Dextrose Injection (Prolotherapy) in Lateral Elbow Tendinosis: A Systematic Review and Meta-analysis

Open AccessPublished:February 28, 2022DOI:https://doi.org/10.1016/j.apmr.2022.01.166

      Abstract

      Objective

      To systematically review the effectiveness of hypertonic dextrose prolotherapy (DPT) on pain intensity and physical functioning in patients with lateral elbow tendinosis (LET) compared with other active non-surgical treatments.

      Data Sources

      Systematic search of Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Web of Science, PubMed, Dimensions, Global Health, NHS Health Technology Assessment, Allied and Complementary Medicine, and OVID nursing database from inception to June 15, 2021, without language restrictions.

      Study Selection

      Two reviewers independently identified parallel or crossover randomized controlled trials that evaluated the effectiveness of DPT in LET. The search identified 245 records; data from 8 studies (354 patients) were included.

      Data Extraction

      Two reviewers independently extracted data and assessed included studies. The Cochrane Risk of Bias 2 tool was used to evaluate risk of bias. The Grading of Recommendation Assessment, Development, and Evaluation approach was used to assess quality of the evidence.

      Data Synthesis

      Pooled results favored the use of DPT in reducing tennis elbow pain intensity compared with active controls at 12 weeks postenrollment, with a standardized mean difference of −0.44 (95% confidence interval, −0.88 to −0.01, P=.04) and of moderate heterogeneity (I2=49%). Pooled results also favored the use of DPT on physical functioning compared with active controls at 12 weeks, with Disabilities of the Arm, Shoulder and Hand scores achieving a mean difference of −15.04 (95% confidence interval, −20.25 to −9.82, P<.001) and of low heterogeneity (I2=0.0%). No major related adverse events have been reported.

      Conclusions

      DPT is superior to active controls at 12 weeks for decreasing pain intensity and functioning by margins that meet criteria for clinical relevance in the treatment of LET. Although existing studies are too small to assess rare adverse events, for patients with LET, especially those refractory to first-line treatments, DPT can be considered a nonsurgical treatment option in carefully selected patients. Further high-quality trials with comparison with other injection therapies are needed.

      Keywords

      List of abbreviations:

      CI (confidence interval), DASH (Disabilities of the Arm, Shoulder and Hand), DPT (hypertonic dextrose prolotherapy), GRADE (Grading of Recommendation Assessment, Development, and Evaluation), LET (lateral elbow tendinosis), MCID (minimal clinically important difference), MD (mean difference), NRS (numerical rating scale), RCT (randomized controlled trial), RoB (Risk of Bias), SMD (standardized mean difference), VAS (visual analog scale)
      Lateral elbow tendinosis (LET), also known as tennis elbow, lateral epicondylitis, or lateral epicondylalgia, has a significant disease burden of 2.5 to 3.5 per 1000.
      • Sanders Jr, TL
      • Maradit Kremers H
      • Bryan AJ
      • Ransom JE
      • Smith J
      • Morrey BF.
      The epidemiology and health care burden of tennis elbow: a population-based study.
      It is most commonly seen in the middle-aged population,
      • Shiri R
      • Viikari-Juntura E
      • Varonen H
      • Heliövaara M.
      Prevalence and determinants of lateral and medial epicondylitis: a population study.
      with a higher prevalence among industrial workers
      • Walker-Bone K
      • Palmer KT
      • Reading I
      • Coggon D
      • Cooper C.
      Occupation and epicondylitis: a population-based study.
      and amateur tennis players.
      • Kitai E
      • Itay S
      • Ruder A
      • Engel J
      • Modan M.
      An epidemiological study of lateral epicondylitis (tennis elbow) in amateur male players.
      Although most cases are self-limiting with symptoms resolving in 12 months, up to 20% are refractory to conservative care,
      • Buchbinder R
      • Green SE
      • Struijs PA.
      Tennis elbow.
      with considerable individual morbidity, substantial health care resource utilization, and lost time from work.
      • Sanders TL
      • Maradit Kremers H
      • Bryan AJ
      • Ransom JE
      • Morrey BF
      Health care utilization and direct medical costs of tennis elbow: a population-based study.
      Exercise-based rehabilitation, such as eccentric, isometric, and concentric loading exercises, are the primary LET treatment.
      • Bisset LM
      • Vicenzino B.
      Physiotherapy management of lateral epicondylalgia.
      However, a recent review has shown that the magnitude of the effect is small compared with other passive interventions.
      • Karanasios S
      • Korakakis V
      • Whiteley R
      • Vasilogeorgis I
      • Woodbridge S
      • Gioftsos G.
      Exercise interventions in lateral elbow tendinopathy have better outcomes than passive interventions, but the effects are small: a systematic review and meta-analysis of 2123 subjects in 30 trials.
      Other second-line interventions such as corticosteroid injections,
      • Coombes BK
      • Bisset L
      • Vicenzino B.
      Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomised controlled trials.
      shock wave therapy,
      • Xiong Y
      • Xue H
      • Zhou W
      • et al.
      Shock-wave therapy versus corticosteroid injection on lateral epicondylitis: a meta-analysis of randomized controlled trials.
      laser therapy,
      • Dingemanse R
      • Randsdorp M
      • Koes BW
      • Huisstede BM.
      Evidence for the effectiveness of electrophysical modalities for treatment of medial and lateral epicondylitis: a systematic review.
      bracing,
      • Kroslak M
      • Pirapakaran K
      • Murrell GA.
      Counterforce bracing of lateral epicondylitis: a prospective, randomized, double-blinded, placebo-controlled clinical trial.
      and newer options such as platelet-rich plasma
      • Simental-Mendía M
      • Vilchez-Cavazos F
      • Álvarez-Villalobos N
      • et al.
      Clinical efficacy of platelet-rich plasma in the treatment of lateral epicondylitis: a systematic review and meta-analysis of randomized placebo-controlled clinical trials.
      and autologous whole blood injection
      • Tsikopoulos K
      • Tsikopoulos A
      • Natsis K.
      Autologous whole blood or corticosteroid injections for the treatment of epicondylopathy and plantar fasciopathy? A systematic review and meta-analysis of randomized controlled trials.
      have been evaluated in many randomized trials but there is no definitive evidence or consensus on which should be considered as the priority in LET.
      • Sims SEG
      • Miller K
      • Elfar JC
      • Hammert WC.
      Non-surgical treatment of lateral epicondylitis: a systematic review of randomized controlled trials.
      ,
      • Niedermeier SR
      • Crouser N
      • Speeckaert A
      • Goyal KS.
      A survey of fellowship-trained upper extremity surgeons on treatment of lateral epicondylitis.
      Hypertonic dextrose prolotherapy (DPT) is an injection therapy used to treat chronic painful musculoskeletal conditions.
      • Rabago D
      • Nourani B.
      Prolotherapy for osteoarthritis and tendinopathy: a descriptive review.
      ,
      • Hauser RA
      • Lackner JB
      • Steilen-Matias D
      • Harris DK.
      A systematic review of dextrose prolotherapy for chronic musculoskeletal pain.
      The historical understanding posits that DPT facilitates healing and subsequent pain control by initiating a temporary inflammatory reaction with related tissue proliferation.
      • Jensen K
      • Rabago D
      • Best TM
      • Patterson JJ
      • Vanderby R.
      Early inflammatory response of knee ligaments to prolotherapy in a rat model.
      • Jensen KT
      • Rabago D
      • Best TM
      • Patterson JJ
      • Vanderby R.
      Longer term response of knee ligaments to prolotherapy in a rat injury model.
      • Yoshii Y
      • Zhao C
      • Schmelzer JD
      • Low PA
      • An K-N
      • Amadio PC.
      The effects of hypertonic dextrose injection on connective tissue and nerve conduction through the rabbit carpal tunnel.
      • Yoshii Y
      • Zhao C
      • Schmelzer JD
      • Low PA
      • An K-N
      • Amadio PC.
      Effects of multiple injections of hypertonic dextrose in the rabbit carpal tunnel: a potential model of carpal tunnel syndrome development.
      Recent literature also suggests possible direct sensorineural effects of DPT on neuralgic pain.
      • Wu YT
      • Ho TY
      • Chou YC
      • et al.
      Six-month efficacy of perineural dextrose for carpal tunnel syndrome: a prospective, randomized, double-blind, controlled trial.
      The role of DPT in LET has been evaluated in a growing number of methodologically higher quality clinical trials, which reported beneficial effects on pain and function using standardized outcomes,
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      yet the findings have not been synthesized. In a recent meta-analysis, a conclusion that injection therapy did not improve pain and functional outcomes but increased risk of adverse events in LET was made without including DPT in the analysis.
      • Kim YJ
      • Wood SM
      • Yoon AP
      • Howard JC
      • Yang LY
      • Chung KC.
      Efficacy of nonoperative treatments for lateral epicondylitis: a systematic review and meta-analysis.
      Therefore, we conducted this systematic review of randomized controlled trials (RCTs) to assess and analyze the effectiveness of DPT in LET.

      Methods

      Study design

      We followed the statement on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for RCTs.
      • Moher D
      • Liberati A
      • Tetzlaff J
      • Altman DG.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      The protocol has been registered in the PROSPERO registry (CRD42021265178).

      Eligibility criteria

      This review included parallel or crossover RCTs that evaluated the efficacy or effectiveness of DPT in LET regardless of blinding.
      • Shea BJ
      • Reeves BC
      • Wells G
      • et al.
      AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both.
      For crossover RCTs, only data before the crossover period were used.
      • Wellek S
      • Blettner M.
      On the proper use of the crossover design in clinical trials: part 18 of a series on evaluation of scientific publications.

      Information sources

      Potential studies were identified by searching electronic databases, including Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Web of Science, PubMed, Dimensions, Global Health, NHS Health Technology Assessment, Allied and Complementary Medicine, and OVID nursing database. A systematic search of all databases was conducted from their inception to June 15, 2021, with no language limitations. Reference lists of relevant studies were also screened for additional possible studies.

      Search strategy

      The strategy had 2 components including terms for DPT and LET. Keywords for population were “Tennis Elbow” [MeSH] OR “Elbow Tendinopathy” [MeSH] OR lateral epicondyle*[all fields] OR lateral humeral epicondylitis*[all fields]; keywords for intervention were “Prolotherapy” [MeSH] OR dextrose [all fields] OR prolotherapy [all fields]. Search keys are summarized in appendix 1 (available online only at http://www.archives-pmr.org/).

      Types of participants

      This study included participants with a diagnosis of LET, defined as pain over the lateral humeral epicondyle provoked by palpation and resisted wrist/middle finger extension or gripping and with or without confirmatory hypoechoic lesions on ultrasonography.
      • Speers CJ
      • Bhogal GS
      • Collins R.
      Lateral elbow tendinosis: a review of diagnosis and management in general practice.

      Types of interventions

      For inclusion, DPT had to be administered to at least 1 group within the trial. Co-interventions were allowed as long as they were uniform across all groups such that the effects of DPT could be isolated; for example, studies comparing DPT plus dry needling with dry needling alone would be included but studies comparing DPT plus dry needling with DPT alone would not be included.

      Types of comparison controls

      Comparison groups were classified into active and inactive controls according.
      • Higgins JP
      • Thomas J
      • Chandler J
      • et al.
      Cochrane handbook for systematic reviews of interventions.
      Inactive control was defined as no treatment, standard care, or a waiting list control, and these included watchful waiting, bracing, and usual care. Active control was defined as the use of different injection solutions or a different kinds of therapies, which included exercise,
      • Karanasios S
      • Korakakis V
      • Whiteley R
      • Vasilogeorgis I
      • Woodbridge S
      • Gioftsos G.
      Exercise interventions in lateral elbow tendinopathy have better outcomes than passive interventions, but the effects are small: a systematic review and meta-analysis of 2123 subjects in 30 trials.
      manual therapy,
      • Hoogvliet P
      • Randsdorp MS
      • Dingemanse R
      • Koes BW
      • Huisstede BM.
      Does effectiveness of exercise therapy and mobilisation techniques offer guidance for the treatment of lateral and medial epicondylitis? A systematic review.
      dry needling,
      • Navarro-Santana MJ
      • Sanchez-Infante J
      • Gómez-Chiguano GF
      • et al.
      Effects of trigger point dry needling on lateral epicondylalgia of musculoskeletal origin: a systematic review and meta-analysis.
      shock wave,
      • Xiong Y
      • Xue H
      • Zhou W
      • et al.
      Shock-wave therapy versus corticosteroid injection on lateral epicondylitis: a meta-analysis of randomized controlled trials.
      laser,
      • Dingemanse R
      • Randsdorp M
      • Koes BW
      • Huisstede BM.
      Evidence for the effectiveness of electrophysical modalities for treatment of medial and lateral epicondylitis: a systematic review.
      injections of corticosteroids,
      • Coombes BK
      • Bisset L
      • Vicenzino B.
      Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomised controlled trials.
      platelet-rich plasma injection,
      • Simental-Mendía M
      • Vilchez-Cavazos F
      • Álvarez-Villalobos N
      • et al.
      Clinical efficacy of platelet-rich plasma in the treatment of lateral epicondylitis: a systematic review and meta-analysis of randomized placebo-controlled clinical trials.
      autologous whole blood injection,
      • Tsikopoulos K
      • Tsikopoulos A
      • Natsis K.
      Autologous whole blood or corticosteroid injections for the treatment of epicondylopathy and plantar fasciopathy? A systematic review and meta-analysis of randomized controlled trials.
      and normal saline.
      • Gao B
      • Dwivedi S
      • DeFroda S
      • et al.
      The therapeutic benefits of saline solution injection for lateral epicondylitis: a meta-analysis of randomized controlled trials comparing saline injections with nonsurgical injection therapies.

      Outcome measures

      The primary outcome of interest was pain reduction in LET, measured by visual analog scale (VAS 0-100 mm), numerical rating scale (NRS 0-10), or algometry. Secondary outcomes included handgrip strength in kilograms,
      • Stratford PW
      • Norman GR
      • McIntosh JM.
      Generalizability of grip strength measurements in patients with tennis elbow.
      Patient-Related Tennis Elbow Evaluation (PRTEE) score and its subscales,
      • Macdermid J.
      Update: The Patient-Rated Forearm Evaluation Questionnaire is now the Patient-Rated Tennis Elbow Evaluation.
      and Disabilities of the Arm, Shoulder and Hand (DASH).
      • Franchignoni F
      • Vercelli S
      • Giordano A
      • Sartorio F
      • Bravini E
      • Ferriero G.
      Minimal clinically important difference of the Disabilities of the Arm, Shoulder and Hand outcome measure (DASH) and its shortened version (QuickDASH).

      Study selection and data extraction

      All potential studies from the search process were imported into the Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia; www.covidence.org). Two reviewers (M.T.Z., R.W.S.S.) independently screened electronically retrieved titles and abstracts for potentially eligible trials and evaluated potential relevant full texts and determined study eligibility. For eligible studies, data were extracted independently by MTZ and RWSS using a data extraction form. The extracted information included authors, publication year, follow-up duration, number of participants and their characteristics, features of interventions and controls, treatment outcomes. Discrepancies in study selection and data extraction were resolved by a third reviewer (DR).

      Risk of bias assessment

      The Cochrane Risk of Bias 2 (RoB 2) tool was used to evaluate the following 5 RoB domains: bias arising from randomization process, deviation from intended interventions, missing outcome data, measurement of outcome, and selection of the reported results.
      • Sterne JA
      • Savović J
      • Page MJ
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      The RoB was assessed independently by 2 reviewers (M.T.Z., R.W.W.S.); any discrepancy was resolved by a third reviewer (V.C.H.C.).

      Quality of evidence

      The Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach was used to assess the quality of the evidence across studies for pain intensity, DASH and Patient-Related Tennis Elbow Evaluation cumulative score, and grip strength separately. Evidence was downgraded 1 place if (1) risk of bias was evident (majority of trials were at moderate or high risk of bias), (2) there was evidence of unexplained inconsistency (I2>50%), (3) there was evidence of indirectness in population or outcome, (4) there was evidence of imprecision (wide 95% confidence interval [CI], >0.8 for standardized mean difference [SMD] and > minimal clinically important difference [MCID] for mean difference [MD]), or (5) there was publication bias (visual inspection of funnel plots when there were at least 10 trials in the meta-analysis). When there were fewer than 10 trials, evidence consists of a small number of studies (≤2) with a small number of participants (≤100). The quality of evidence was classified into 4 categories: very low, low, moderate, and high.

      Statistical analysis

      All meta-analyses were conducted using Review Manager (RevMan v5.4)a software.
      • Keijsers R
      • Kuijer PPFM
      • Koenraadt KLM
      • et al.
      Effectiveness of standardized ultrasound guided percutaneous treatment of lateral epicondylitis with application of autologous blood, dextrose or perforation only on pain: a study protocol for a multi-center, blinded, randomized controlled trial with a 1 year follow up.
      Pairwise meta-analysis was performed using a random effects model, taking into account possible variations in effect sizes across trials.
      • Borenstein M
      • Hedges LV
      • Higgins JP
      • Rothstein HR.
      A basic introduction to fixed-effect and random-effects models for meta-analysis.
      For continuous outcomes measured using different scales, data were summarized as SMDs with 95% CIs. The magnitude of the SMD was determined using the standard approach: small, SMD=0.2; medium, SMD=0.5; and large, SMD=0.8.
      • Cohen J.
      Statistical power analysis for the behavioral sciences.
      Weighted mean difference was used to measure outcomes sharing the same unit of measure, and its potential clinical significance was interpreted based on the MCID. The MCID for pain intensity was 1.65 on the 11-point NRS and 16.55 on 100-mm VAS,
      • Bahreini M
      • Safaie A
      • Mirfazaelian H
      • Jalili M.
      How much change in pain score does really matter to patients?.
      the MCID for PRTEE cumulative score among participants with LET was 7/100 or 22% of baseline PRTEE score,
      • Poltawski L
      • Watson T.
      Measuring clinically important change with the Patient-Rated Tennis Elbow Evaluation.
      the MCID for grip strength was 17 kg for patients with LET,
      • Bobos P
      • Nazari G
      • Lu Z
      • MacDermid JC.
      Measurement properties of the hand grip strength assessment: a systematic review with meta-analysis.
      and the MCID for the DASH cumulative score was 10.83 points.
      • Franchignoni F
      • Vercelli S
      • Giordano A
      • Sartorio F
      • Bravini E
      • Ferriero G.
      Minimal clinically important difference of the Disabilities of the Arm, Shoulder and Hand outcome measure (DASH) and its shortened version (QuickDASH).
      I2 was calculated to quantify the degree of heterogeneity across studies. I2 <25%, 25%-50%, and >50% indicate low, moderate, or high heterogeneity, respectively.
      • Higgins JP
      • Thompson SG
      • Deeks JJ
      • Altman DG.
      Measuring inconsistency in meta-analyses.
      Funnel plots were constructed, where possible, to explore publication bias.

      Results

      Eligible studies

      The search strategy retrieved 245 citations from all databases after excluding 99 duplicates. After screening based on the titles and abstracts, we retrieved 27 full texts for further assessment. Of these, 19 were excluded for the following reasons: no eligible data (n=6), duplicate (n=5), a narrative review (n=4), trial registration only (n=2), not an RCT (n=1), and conference abstract only (n=1). Finally, 8 full texts met the inclusion criteria and were included for descriptive synthesis,
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      ,
      • Ahadi T
      • Jamkarani ME
      • Raissi GR
      • Mansoori K
      • Razavi SZE
      • Sajadi S.
      Prolotherapy vs radial extracorporeal shock wave therapy in the short-term treatment of lateral epicondylosis: a randomized clinical trial.
      • Carayannopoulos A
      • Borg-Stein J
      • Sokolof J
      • Meleger A
      • Rosenberg D.
      Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial.
      • Rabago D
      • Lee KS
      • Ryan M
      • et al.
      Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial.
      • Scarpone M
      • Rabago DP
      • Zgierska A
      • Arbogast G
      • Snell E.
      The efficacy of prolotherapy for lateral epicondylosis: a pilot study.
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      among which 5 were included in the quantitative synthesis procedure
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      ,
      • Scarpone M
      • Rabago DP
      • Zgierska A
      • Arbogast G
      • Snell E.
      The efficacy of prolotherapy for lateral epicondylosis: a pilot study.
      ,
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      (fig 1). Among the 3 that were not included in the quantitative synthesis, 1 study had no available data for extraction at 12-16 weeks,
      • Ahadi T
      • Esmaeili Jamkarani M
      • Raissi GR
      • Mansoori K
      • Emami Razavi SZ
      • Sajadi S
      Prolotherapy vs radial extracorporeal shock wave therapy in the short-term treatment of lateral epicondylosis: a randomized clinical trial.
      and 2 studies had complex intervention components in addition toDPT.
      • Carayannopoulos A
      • Borg-Stein J
      • Sokolof J
      • Meleger A
      • Rosenberg D.
      Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial.
      ,
      • Scarpone M
      • Rabago DP
      • Zgierska A
      • Arbogast G
      • Snell E.
      The efficacy of prolotherapy for lateral epicondylosis: a pilot study.
      There were no discrepancies in study selection and data extraction.
      Fig 1
      Fig 1Flowchart of studies selected according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

      Characteristics of included trials

      Detailed descriptions of the characteristics of the 8 included studies are summarized in table 1. Study sample sizes ranged from 24 to 120, with a total of 354 individuals. The study period ranged from 8 weeks to 52 weeks postenrollment. The injection frequency ranged from a single injection to 4 injections, weekly to 4 weeks apart, with dextrose concentration varying from 12.5% to 50%.
      Table 1Characteristics of the 8 included studies.
      StudySample SizeSample AnalyzedIntervention GroupControl Group(s)Mean Age (SD)Female (%)Injection Site(s)Dextrose Vol/Inj.(mL)Injection FrequencyOutcomesAssessment Time PointDuration
      Ahadi et al
      • Ahadi T
      • Esmaeili Jamkarani M
      • Raissi GR
      • Mansoori K
      • Emami Razavi SZ
      • Sajadi S
      Prolotherapy vs radial extracorporeal shock wave therapy in the short-term treatment of lateral epicondylosis: a randomized clinical trial.
      3330Gp A (n=15): 20% dextroseGp B (n=15): shock wave therapy weekly (once weekly for 3 weeks)46.94 (8.3)69.60%Maximal tenderness point3Single inj.VAS pain severity (0-10)

      Grip strength

      Quick DASH

      PPT
      0, 4, 8 wk8 wk
      Akcay et al
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      6050Gp A (n=23): 15% dextroseGp B (n=27): 1.5 cc saline (0.9% NaCl)Gp A: 48.1 (8.9)

      Gp B: 46.7 (8.3)
      74.00%Lateral epicondyle, annular ligament, and supracondylar ridge1.50, 4, 8 weeksVAS pain intensity (0-10 cm)

      PRTEE

      DASH (0-100)

      Pain-free handgrip strength
      0, 4, 8, 12 wk12 wk
      Apaydin et al
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      3232Gp A (n=16): 15% dextroseGp B (n=16): 30 mg/2 mL 1500 kDa high-molecular-weight hyaluronic acid44.5 (1.1)81.25%Gp A: the tenderest point of the lateral epicondyle, the annular ligament, lateral collateral ligament, and tender areas of the extensor tendon.

      Gp B: the most sensitive point in the lateral epicondyle
      5Gp A: 0, 3, 6 weeks

      Gp B: 0 wk
      VAS (0-10 cm)

      Q-DASH (0-100)

      Pain-free grip strength
      0, 6, 12 wk12 wk
      Bayat et al
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      3028Gp A (n=14): 16% dextrose (containing 2.5 mL dextrose 20% and 1 mL lidocaine 2%)Gp B (n=14): corticosteroid (1 mL 40 mg/mL methylprednisolone and 2 mL 1% lidocaine)Gp A: 46.2 (6.4)

      Gp B: 50.7 (7.5)
      60.71%The point of maximal tenderness3Single injectionVAS (0-10 cm)

      Quick DASH (0-100)
      0, 4, 12 wk12 wk
      Carayannopoulos et al
      • Carayannopoulos A
      • Borg-Stein J
      • Sokolof J
      • Meleger A
      • Rosenberg D.
      Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial.
      2417Gp A (n=8): 1.0 mL of procaine, 0.9 mL of P2G (phenol 1.2%, glycerine 12.5%, and dextrose 12.5% in sterile water) plus 0.1 mL sodium morrhuateGp B (n=9): 1.0 mL of procaine and 1.0 mL of DepoMedrolTotal: 46 (range 35-57)

      Gp A: 49 (56.2)

      Gp B: 46 (5.3)
      64.71%Lateral epicondyle of the humerus (first to the radial side of the annular ligament at the margin between the radial head and the ulna; second to the attachment of the common extensor tendon at the lateral epicondyle; third to the radial collateral ligament at the tubercle of the radius)20, 4 wkVAS (0-10 cm)

      QVAS

      DASH (0-100)

      Pain-free and maximum grip strength
      0, 4, 12, 24 wks24 wk
      Rabago et al
      • Rabago D
      • Lee KS
      • Ryan M
      • et al.
      Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial.
      3127Gp A (n=8): 20 % dextrose (4 mL of 50% dextrose+4 mL of 0.9% saline+2 mL of 1% lidocaine)

      Gp B (n=9): 10% dextrose and morrhuate (1 mL of 5% morrhuate sodium+1.5 mL of 50% dextrose+2 mL of 1% lidocaine+2.5 mL of 0.9% saline)
      Gp C (n=10): waitlist48.2 (7.8)35.00%Lateral epicondyle

      The bone along a short segment of the tendon and the annular ligament at the areas of palpated tenderness and ultrasound-documented pathology
      101, 4, 8 wkPRTEE (0-100)

      Pain-free grip strength
      0, 4, 8, 16, 32 wk32 wk
      Scarpone et al
      • Scarpone M
      • Rabago DP
      • Zgierska A
      • Arbogast G
      • Snell E.
      The efficacy of prolotherapy for lateral epicondylosis: a pilot study.
      2420Gp A (n=10): 10.7% dextrose (solution consisting of 50% dextrose, 5% sodium morrhuate, 4% lidocaine, and 0.5% sensorcaine). The study pharmacist mixed the following 35 mL sterile solution: 7.5 mL 50% dextrose, 5 mL of 5% sodium morrhuate, 2.5 mL 4% lidocaine, 2.5 mL 0.5% sensorcaine, and 17.5 mL normal saline. The solution is 10.7% dextrose and contains 14.7% sodium morrhuate by volume)Gp B (n=10): 0.9% saline45.7 (10.7)50.00%Supracondylar ridge

      Lateral epicondyle

      Annular ligament
      0.53 injections; 0, 4, 8 wkNRS resting elbow pain (0-10 Likert scale)

      Resting grip strength

      Isometric resistance strength
      0, 8, 16, 52 wk52 wk
      Yelland et al
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      120102Gp A (n=35): 20% dextrose 20% glucose+0.4% lignocaineGp B (n=34): physiotherapy

      Gp C (n=33): combined treatment (prolotherapy+physiotherapy)
      49.3 (7.8)43.33%Tenderness points in lateral epicondylalgia; that is, over the lateral epicondyle, supracondylar ridge, radial head, lateral collateral and annular ligaments, and the common extensor tendon and musculotendinous junction0.5-1.04 injections; 4-weeks apart (0.4,8.12 wk)PRTEE

      GIC

      NRS pain severity at rest (0-10)

      NRS the worst pain severity (0-10)

      Pain-free grip strength

      EQ-5D-3 L
      0, 6, 12, 26, 52 wk52 wk
      Abbreviations: EQ-5D-3L, EuroQol-5 Dimension 3-level version; GIC, global impression of change; Gp, group; PPT, pressure pain threshold; PRTEE, Patient-Rated Tennis Elbow Evaluation; QVAS, Quadruple Visual Analog Scale.

      Risk of bias assessment

      Overall, 87.5% of outcomes were scored as having “some concerns” (7/8), and 12.5% of outcomes were rated as having high risk of bias (1/8; fig 2). In the domain of “bias arising from randomization process,” 1 study had low bias
      • Carayannopoulos A
      • Borg-Stein J
      • Sokolof J
      • Meleger A
      • Rosenberg D.
      Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial.
      and 7 had some bias.
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      ,
      • Ahadi T
      • Jamkarani ME
      • Raissi GR
      • Mansoori K
      • Razavi SZE
      • Sajadi S.
      Prolotherapy vs radial extracorporeal shock wave therapy in the short-term treatment of lateral epicondylosis: a randomized clinical trial.
      ,
      • Rabago D
      • Lee KS
      • Ryan M
      • et al.
      Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial.
      • Scarpone M
      • Rabago DP
      • Zgierska A
      • Arbogast G
      • Snell E.
      The efficacy of prolotherapy for lateral epicondylosis: a pilot study.
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      In the domain of “bias due to deviations from intended interventions,” 7 studies had low bias
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      ,
      • Ahadi T
      • Jamkarani ME
      • Raissi GR
      • Mansoori K
      • Razavi SZE
      • Sajadi S.
      Prolotherapy vs radial extracorporeal shock wave therapy in the short-term treatment of lateral epicondylosis: a randomized clinical trial.
      ,
      • Rabago D
      • Lee KS
      • Ryan M
      • et al.
      Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial.
      • Scarpone M
      • Rabago DP
      • Zgierska A
      • Arbogast G
      • Snell E.
      The efficacy of prolotherapy for lateral epicondylosis: a pilot study.
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      and 1 had some bias.
      • Carayannopoulos A
      • Borg-Stein J
      • Sokolof J
      • Meleger A
      • Rosenberg D.
      Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial.
      In the domain of “bias due to missing outcome data,” all 8 studies had low bias.
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      ,
      • Ahadi T
      • Jamkarani ME
      • Raissi GR
      • Mansoori K
      • Razavi SZE
      • Sajadi S.
      Prolotherapy vs radial extracorporeal shock wave therapy in the short-term treatment of lateral epicondylosis: a randomized clinical trial.
      • Carayannopoulos A
      • Borg-Stein J
      • Sokolof J
      • Meleger A
      • Rosenberg D.
      Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial.
      • Rabago D
      • Lee KS
      • Ryan M
      • et al.
      Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial.
      • Scarpone M
      • Rabago DP
      • Zgierska A
      • Arbogast G
      • Snell E.
      The efficacy of prolotherapy for lateral epicondylosis: a pilot study.
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      In the domain of “bias in measurement of outcome,” 7 had low bias
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      ,
      • Ahadi T
      • Jamkarani ME
      • Raissi GR
      • Mansoori K
      • Razavi SZE
      • Sajadi S.
      Prolotherapy vs radial extracorporeal shock wave therapy in the short-term treatment of lateral epicondylosis: a randomized clinical trial.
      • Carayannopoulos A
      • Borg-Stein J
      • Sokolof J
      • Meleger A
      • Rosenberg D.
      Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial.
      • Rabago D
      • Lee KS
      • Ryan M
      • et al.
      Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial.
      ,
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      and 1 study had high bias.
      • Scarpone M
      • Rabago DP
      • Zgierska A
      • Arbogast G
      • Snell E.
      The efficacy of prolotherapy for lateral epicondylosis: a pilot study.
      In the domain “bias in selection of reported outcome”, 7 had some bias
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      ,
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      ,
      • Ahadi T
      • Jamkarani ME
      • Raissi GR
      • Mansoori K
      • Razavi SZE
      • Sajadi S.
      Prolotherapy vs radial extracorporeal shock wave therapy in the short-term treatment of lateral epicondylosis: a randomized clinical trial.
      • Carayannopoulos A
      • Borg-Stein J
      • Sokolof J
      • Meleger A
      • Rosenberg D.
      Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial.
      • Rabago D
      • Lee KS
      • Ryan M
      • et al.
      Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial.
      • Scarpone M
      • Rabago DP
      • Zgierska A
      • Arbogast G
      • Snell E.
      The efficacy of prolotherapy for lateral epicondylosis: a pilot study.
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      and 1 had low bias.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      Details of response options for signaling questions in 5 domains and overall domain are summarized in appendix 2 (available online only at http://www.archives-pmr.org/).
      Fig 2
      Fig 2Quality assessment of included studies.

      DPT vs active controls on tennis elbow pain intensity at 12 weeks

      In this comparison, 4 RCTs (n=183) were eligible for pooling.
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      ,
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      VAS and NRS were reported, with SMDs calculated in the random effects meta-analyses. Pooled results favored the use of DPT in reducing tennis elbow pain intensity compared with active control, with SMD=−0.44 (95% CI, −0.88 to −0.01, P=.04) and moderate heterogeneity (I2=49%; fig 3a).
      Fig 3
      Fig 3(a) Dextrose vs active controls on pain intensity (including VAS and NRS score) at 12 weeks. (b) Dextrose vs active controls on DASH cumulative score at 12 weeks. (c) Dextrose vs active controls on PRTEE cumulative score at 12 weeks. (d) Dextrose vs active controls on grip strength via dynamometer at 12-16 weeks.

      DPT vs active controls on DASH cumulative score at 12 weeks

      In this comparison, 3 RCTs (n=110) were eligible for pooling. Pooled results favored the use of DPT compared with active control, with MD=−15.04 (95% CI, −20.25 to −9.82, P<.001) and low heterogeneity (I2=0%; fig 3b).

      DPT vs active controls on PRTEE cumulative score at 12 weeks

      In this comparison, 2 RCTs (n=123) were eligible for pooling.
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      ,
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      The same scale PRTEE scores were reported, with MDs calculated in the random effect meta-analyses. Pooled results suggested no significant effect of DPT on improving PRTEE score, with MD=2.35 (95% CI, −9.81 to 14.51, P=.70) and moderate heterogeneity (I2=42%; fig 3c).

      DPT vs active controls on grip strength at 12-16 weeks

      Two RCTs (n=105) were eligible for pooling; a dynamometer was used in 1 trial to assess grip strength, and another trial did not describe the measurement method.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      ,
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      Pooled results suggested no significant effect of DPT on improving grip strength, with SMD=−0.06 (95% CI, −1.00 to 0.88, P=.90) and high heterogeneity (I2=80%; fig 3d).

      Adverse events

      Injection side effects were reported in 7 of the 8 included trials. One trial reported that a DPT participant developed neuropraxia of the posterior interosseous nerve after the fourth treatment, but symptoms resolved in 3 months and there were no further negative effects; another DPT participant developed painful bruising over the forearm after the second treatment that resolved in 2 weeks.
      • Yelland M
      • Rabago D
      • Ryan M
      • et al.
      Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.
      Two trials reported mild to moderate self-limiting post-injection pain.
      • Carayannopoulos A
      • Borg-Stein J
      • Sokolof J
      • Meleger A
      • Rosenberg D.
      Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial.
      ,
      • Rabago D
      • Lee KS
      • Ryan M
      • et al.
      Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial.
      The other 4 trials reported no adverse events in the DPT group throughout the study period.
      • Akcay S
      • Gurel Kandemir N
      • Kaya T
      • Dogan N
      • Eren M
      Dextrose prolotherapy versus normal saline injection for the treatment of lateral epicondylopathy: a randomized controlled trial.
      ,
      • Bayat M
      • Raeissadat SA
      • Babaki MM
      • Rahimi-Dehgolan S.
      Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis?: a randomized clinical trial.
      ,
      • Ahadi T
      • Jamkarani ME
      • Raissi GR
      • Mansoori K
      • Razavi SZE
      • Sajadi S.
      Prolotherapy vs radial extracorporeal shock wave therapy in the short-term treatment of lateral epicondylosis: a randomized clinical trial.
      ,
      • Scarpone M
      • Rabago DP
      • Zgierska A
      • Arbogast G
      • Snell E.
      The efficacy of prolotherapy for lateral epicondylosis: a pilot study.
      Adverse events were not reported in 1 study.
      • Apaydin H
      • Bazancir Z
      • Altay Z.
      Injection therapy in patients with lateral epicondylalgia: hyaluronic acid or dextrose prolotherapy? A single-blind, randomized clinical trial.
      Overall, there were no significant related adverse events of DPT in the included trials.

      Quality of evidence with GRADE approach

      The overall quality of evidence presented in this review ranges from very low to moderate based the assessment with the GRADE approach (appendix 3, available online only at http://www.archives-pmr.org/). The assessment showed low certainty for DPT compared with active controls in reducing pain intensity and moderate certainty in improving DASH cumulative score. The assessment showed very low to low certainty on PRTEE cumulative score and grip strength.

      Discussion

      This study showed that DPT is superior to other active controls in reducing elbow pain, with a small to medium effect size and moderate heterogeneity at 12 weeks postenrollment, with evidence from low- to moderate-quality studies. We also found that DPT improved the DASH score by 15.04 points, exceeding the MCID of 10.83 points for this measure in LET.
      • Franchignoni F
      • Vercelli S
      • Giordano A
      • Sartorio F
      • Bravini E
      • Ferriero G.
      Minimal clinically important difference of the Disabilities of the Arm, Shoulder and Hand outcome measure (DASH) and its shortened version (QuickDASH).
      No statistically significant improvement was reported in PRTEE score and grip strength. Statistical comparison with inactive controls was not possible because only 1 trial used waitlist as the control group.
      • Rabago D
      • Lee KS
      • Ryan M
      • et al.
      Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial.
      Compared to the standard treatment of LET, DPT achieved a larger effect size than corticosteroid injection, which has demonstrated a statistically significant SMD of 0.38 in reducing pain intensity in LET at around 12 weeks.
      • Gaujoux-Viala C
      • Dougados M
      • Gossec L.
      Efficacy and safety of steroid injections for shoulder and elbow tendonitis: a meta-analysis of randomised controlled trials.
      However, the effect size of DPT is smaller than eccentric strengthening exercise, which has a statistically significant SMD of 1.12 in pain reduction.
      • Chen Z
      • Baker NA.
      Effectiveness of eccentric strengthening in the treatment of lateral elbow tendinopathy: a systematic review with meta-analysis.
      Platelet-rich plasma is a recommended injection therapy for LET and has been shown to be more effective than corticosteroids over time.
      • Huang K
      • Giddins G
      • Wu LD.
      Platelet-rich plasma versus corticosteroid injections in the management of elbow epicondylitis and plantar fasciitis: an updated systematic review and meta-analysis.
      However, no RCT has been conducted comparing DPT and platelet-rich plasma in LET. Therefore, we suggest that DPT can be considered as an adjunctive therapy to exercise and an alternative injection therapy to corticosteroids in LET. Its effectiveness as compared to platelet-rich plasma needs to be confirmed in future trials.
      The mechanism of DPT in decreasing musculoskeletal pain, including LET pain and other soft tissue conditions, is likely due to its tissue proliferation and sensorineural analgesic effects. In vitro study has shown that exposure of tenocytes to DPT elicited an inflammatory response through the upregulation of pro-inflammatory markers, including interleukin 8, cyclooxygenase 2, and prostaglandin 2, and downregulation of anti-inflammatory marker growth factor-beta. This suggested the possible mechanism of DPT on initiating the wound-healing cascades.
      • Ekwueme EC
      • Mohiuddin M
      • Yarborough JA
      • et al.
      Prolotherapy induces an inflammatory response in human tenocytes in vitro.
      A rodent study of medial collateral ligaments injected with dextrose reported a statistically significant increased cross-sectional area of dextrose-injected medial collateral ligaments by 30% and 90% compared with saline and uninjured controls.
      • Jensen KT
      • Rabago D
      • Best TM
      • Patterson JJ
      • Vanderby R.
      Longer term response of knee ligaments to prolotherapy in a rat injury model.
      In a rabbit model, injection of DPT into the connective tissue in the carpal tunnel produced thickening of the collagen bundles and increased energy absorption when compared with saline controls.
      • Yoshii Y
      • Zhao C
      • Schmelzer JD
      • Low PA
      • An K-N
      • Amadio PC.
      The effects of hypertonic dextrose injection on connective tissue and nerve conduction through the rabbit carpal tunnel.
      ,
      • Yoshii Y
      • Zhao C
      • Schmelzer JD
      • Low PA
      • An K-N
      • Amadio PC.
      Effects of multiple injections of hypertonic dextrose in the rabbit carpal tunnel: a potential model of carpal tunnel syndrome development.
      Dextrose solution hyperpolarizes nerves by opening their potassium channels, thereby decreasing signal transmission in nociceptive pain fibers.
      • Burdakov D
      • Jensen LT
      • Alexopoulos H
      • et al.
      Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose.
      In addition, glucose solutions may work by blocking transient receptor potential vanilloid type 1, thus reduce the action potentials and the release of substance P and calcitonin gene-related peptide, which theoretically could minimize neuropathic pain.
      • Veronesi B
      • Oortgiesen M.
      Neurogenic inflammation and particulate matter (PM) air pollutants.
      ,
      • Lyftogt J.
      Subcutaneous prolotherapy treatment of refractory knee, shoulder, and lateral elbow pain.
      Strengths of the current study include timely conduct of a study to review an area that is rapidly emerging, is clinically important, and has disparate findings. We used a rigorous methodology that conformed to best practice guidelines.

      Study limitations

      There were several limitations of the current study. The number of studies included and total participant sample size were small, and quantitative syntheses included a small number of studies in most comparisons. For the same reason, we were unable to generate funnel plots to assess publication bias.
      • Sterne JA
      • Sutton AJ
      • Ioannidis JP
      • et al.
      Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.
      The time frame of 12 to 16 weeks available for data pooling was short; thus, longer term effects remain uncertain. There was high heterogeneity across trials; this could be partially explained by variation in the number, frequency, volume, and concentrations of dextrose solutions used and the nature of different active controls.

      Conclusions

      Our systematic review and meta-analysis found that DPT outperformed active controls for improving pain intensity and function and met criteria for clinical relevance in the treatment of LET. Hence, for patients with LET, especially those who are refractory to exercise therapy, DPT can be considered as an appropriate nonsurgical treatment option. Further high-quality trials with longer term follow-up, adequate sample size, and direct comparison with other injection therapies are needed. Future research of the mechanism of action will further inform the assessment of DPT in LET.

      Supplier

      a. Review Manager version 5.4; The Cochrane Collaboration.

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