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Comparative effectiveness of dextrose
prolotherapy versus control injections and
exercise in the management of osteoarthritis pain:
a systematic review and meta-analysis
This article was published in the following Dove Press journal:
Journal of Pain Research
18 October 2016
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Chen-Yu Hung 1 Background: Increasing evidence has supported the use of dextrose prolotherapy for patients
Ming-Yen Hsiao 2,3 with osteoarthritis. However, the real benefits may be affected by differences in injection pro-
Ke-Vin Chang 1,2 tocols, comparative regimens, and evaluation scales.
Der-Sheng Han 1,2 Methods: PubMed and Scopus were searched from the earliest record until February 2016.
One single-arm study and five randomized controlled trials were included, comprising 326
Tyng-Guey Wang 2,3
participants. We estimated the effect sizes of pain reduction before and after serial dextrose
Department of Physical Medicine
injections and compared the values between dextrose prolotherapy, comparative regimens, and
and Rehabilitation, National Taiwan
University Hospital, Bei-Hu Branch, exercise 6 months after the initial injection.
Taipei, Taiwan; 2National Taiwan Results: Regarding the treatment arm using dextrose prolotherapy, the effect sizes compared
University College of Medicine,
Taipei, Taiwan; 3Department of
with baseline were 0.65 (95% confidence interval [CI], 0.14–1.17), 0.84 (95% CI, 0.40–1.27),
Physical Medicine and Rehabilitation, 0.85 (95% CI, 0.60–1.10), and 0.87 (95% CI, 0.53–1.21) after the first, second, third, and fourth
National Taiwan University Hospital, or more injections, respectively. The overall effect of dextrose was better than control injections
Taipei, Taiwan
(effect size, 0.36; 95% CI, 0.10–0.63). Dextrose prolotherapy had a superior effect compared
with local anesthesia (effect size, 0.38; 95% CI, 0.07–0.70) and exercise (effect size, 0.71; 95%
Video abstract CI, 0.30–1.11). There was an insignificant advantage of dextrose over corticosteroids (effect
size, 0.31; 95% CI, –0.18 to 0.80) which was only estimated from one study.
Conclusion: Dextrose injections decreased pain in osteoarthritis patients but did not exhibit a
positive dose–response relationship following serial injections. Dextrose prolotherapy was found
to provide a better therapeutic effect than exercise, local anesthetics, and probably corticosteroids
when patients were retested 6 months following the initial injection.
Keywords: dextrose, prolotherapy, knee, hand, osteoarthritis

Osteoarthritis is a chronic degenerative disorder that causes pain, stiffness, and limited
Point your SmartPhone at the code above. If you have a range of motion in affected joints.1 Causes of osteoarthritis include cartilage degra-
QR code reader the video abstract will appear. Or use: dation, subchondral bone outgrowths, synovial hypertrophy, and altered ligament
integrity.2 Injection therapies are most commonly administered when pain or func-
tional limitations of osteoarthritis are significant despite oral medication or exercise.3
Correspondence: Ke-Vin Chang While injection of corticosteroids is the most common regimen for musculoskeletal
Department of Physical Medicine
and Rehabilitation, National Taiwan
disorders, it merely provides short-term improvement of symptoms while posing the
University Hospital, Bei-Hu Branch, risk of aggravating cartilage damage and producing tissue atrophy.4 Administration
No. 87, Neijiang Street, Wanhua
of hyaluronic acid is another common approach to replenishing dysfunctional syno-
District, Taipei 108, Taiwan
Email vial fluid in joints affected by osteoarthritis. However, according to the results of a

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12–14 A total score 2000. the most a maximal score of 9 points. measurement tools. To assess the effectiveness from their earliest records until February 2016. we used the pain Methods subscale from Western Ontario and McMaster Universities Two electronic databases. and reference groups to the pooled SD. was also checked for pertinent regardless of the affected In terms of the effect size of dextrose prolotherapy sites.5 changes in functional outcome measurements.13 A positive value excluded. Studies that scored and tendon insertions (entheses) and adjacent joint spaces. Pooled SD was gener- before and after interventions. Pooled SD equaled the square subject headings and text words for searches. – 1) + (participant numbers in the control group – 1)]}. was used to evaluate the qual- commonly used solution. we designed a meta-analysis The first priority of pain measurement extraction was the to evaluate the effect of using dextrose prolotherapy in the pain score during movement/walking because of a stronger treatment of osteoarthritis. fewer than 3 points were regarded to have poorly designed with the goal of reducing pain and ostensibly promoting Journal of Pain Research 2016:9 Dovepress . tion. we used the standardized mean difference between the cal Trials. Therefore. Case series lacking a treatment)2]/[(participant numbers in baseline – 1) + (par- predestinated therapeutic protocol and a follow-up plan were ticipant numbers after treatment – 1)]}.10 However. PubMed and Scopus. association with patient’s function. dextrose. dosage and inter. ated from the square root of {[(participant numbers in the dextrose group – 1)*(standard deviation of pain reduction in Data extraction and quality assessment the dextrose group)2 + (participant numbers in the control Two authors (C-YH and M-YH) independently assessed all group – 1)*(standard deviation of changes in pain in the the relevant literature and extracted the following data from control group)2]/[(participant numbers in the dextrose group selected studies: patient demographics.8 The proposed mechanism by which dextrose pro. increasing evidence has supported the use of dextrose prolo- therapy for patients with osteoarthritis. degenerative cartilage disorders. exposure. root of {[(participant numbers in baseline – 1)*(standard We included single-arm prospective studies. comparability. evaluation intervals. (2) they should involve adults receiving serial dextrose compared with other injection treatments. was first examined in the treatment ity of selection.9 In recent years. Data synthesis and analysis tude of benefit of prolotherapy may be affected by variations The main outcome was determined by the severity of pain. of the difference between baseline and posttreatment pain The key terms encompassed prolotherapy. The inclusion criteria for studies and RCTs were of the effect size indicated a decrease in pain compared with as follows: (1) they should involve adult participants with baseline.7. and were entered as medical – Painposttreatment)/pooled SD. this approach offers only a val of dextrose administrations. and (3) they should be studies providing quanti.12. the composite volume of solution into multiple sites of painful ligament scores of which ranged from 0 to 5 points. The quality Regenerative therapy involves the injection of a small of the RCTs was appraised by the Jadad scale. and clinically irrelevant benefit. Discrepancies in opinions between the two creating a hyperosmolar environment to induce cell rupture evaluators were resolved by discussion or a ruling by the and release platelet-derived growth factor. cartilage. which has tissue repair and growth. 11–15 The of dextrose prolotherapy compared with the baseline condi- Cochrane Collaboration Central Register of Controlled Clini. and outcome in of osteoarthritis in randomized controlled trials (RCTs) in single-arm and quasi-experimental studies.Hung et al Dovepress recent large-scale meta-analysis. less than 4 points was assumed to signify a study that was lotherapy alleviates joint degenerative disorders includes low in quality. and osteoarthritis. were explored Arthritis Index as the substitute. baseline and status after treatment in the treatment arm using which includes bibliographies of included trials and related dextrose prolotherapy. studies with deviation of pain scales in baseline)2 + (participant numbers non-randomized assignment to control or active treatment after treatment – 1)*(standard deviation of pain scales after (quasi-experimental studies). injection techniques.12–14 The Newcastle–Ottawa Scale.dovepress. and RCTs. corresponding author. to the standard deviation (SD) of pooled results. and therapeutic derived from the visual analog scale or knee pain scale. (Pain reductiondextrose tative measurement of functional change or pain reduction – Pain reductionreference)/pooled SD.13 848 submit your manuscript | www. Cochrane Systematic Reviews (ClinicalTrials. If pain score with move- ment/walking was not available in the trial.12.6 Hyperosmolar dextrose. (Painbaseline degeneration. Data were calculated from the ratio systematic reviews. the magni. we used the ratio injections to the involved joints in at least one treatment arm of the difference in reduction of pain between the dextrose of a study. in treatment protocols.

18 was assessed by the subgroup analysis. Cochran’s Q methods. due to lack of quantitative fied by the involved joints and difference in control groups pain evaluation in patients with patellar chondro-arthropathy.05 was considered final meta-analysis included one single-arm follow-up trial23 statistically significant. eleven studies were screened for eligibility (Figure 1).19 one RCT targeting nonspecific chronic low back as the tendency for positive trials to be published and the pain without definite radiologic evidence of lumbar spine tendency for negative and null trials not to be published. Studies included in studies with duplicated qualitative synthesis data from a published RCT (n=6) (n=2) Included Studies included in quantitative synthesis (meta-analysis) (n=6) Figure 1 Flow diagram of the evaluation process for the inclusion or exclusion of studies. defined ropoietin. and five RCTs. (n=11) single injection of dextrose comparing with Eligibility erythropoietin (n=1).20 and two observational studies analyzing data All analyses were performed using Stata 10. College Station. USA).24–26 four of which probed knee osteoarthri- Flow Diagram Records identified through Additional records identified Identification database searching through other sources (n=170) (n=0) Records after duplicates Records excluded by title removed and abstract Screening (n=93) (n=82) Full-text articles excluded: Full-text articles assessed lack of quantitative pain for eligibility evaluation (n=1). and the heterogeneity was determined by I-square and ture. Adapted from Moher et al. We excluded one single-arm trial. Journal of Pain Research 2016:9 submit your manuscript | www. The funnel plot and one RCT comparing single injection of dextrose with eryth- Egger test were used to examine the publication bias.dovepress. nonspecific chronic low back pain without definite radiologic evidence (n=1).17 osteoarthritis.22 The LP. randomized controlled trial.31 Abbreviation: 849 Dovepress .0 (StataCorp from a published RCT exploring knee osteoarthritis.7. TX. Study search and patient characteristics The random effect model was used to pool the effect Of the 170 non-duplicate citations identified from the litera- sizes.21.8.Dovepress Dextrose prolotherapy for osteoarthritis A positive value of the effect size indicated a favorable result Results after dextrose prolotherapy.16 Whether the effect sizes were modi. and p < 0.

52 (0. 1.24.013) 0.36) 4.26 and two of which examined hand osteoarthritis.56 Rabago et al23 0.3%) of whom were females.98) 100.33) 5.96. domization” in Jadad scale since appropriate randomization respectively (Figure 2).40 Dumais et al26 1.07. the two with other injected solutions was 0.65 (0. 1.40. all 0.7.0 months.24) 3.53. The effect size of dextrose prolotherapy compared points).27) 22.99) 6. The preparations and injection details of implementing the dextrose injection at different time points.84 (95% CI. In the aspect of “blinding”.22 (–0.26 each retrieved study are summarized in Table 2.47) 3. third. confidence interval. 0. Ages ranged from 56.36 (95% CI.60.50 (0. 0. p=0.40– Rabago et al24 Journal of Pain Research 2016:9 Dovepress .31 Reeves and Hassanein8 1. p=0. In the aspect of “an account of all patients”. 1. which was the last follow-up point available in most a blinded design of intervention and evaluation (earning 0 studies.10–0. and fourth or more injections.45.10) 6. 2. second.97) 6.5 years.20.49. 1.26) 5.07. 2. CI.8.4 Pooled effect sizes to 64.85 (95% CI.87 (0.25 three used sequential administrations (earning 1 point).16) 6. 1.8.47) 6.53–1. 0.18 (0.25 Rabago et al24 0.69 (0. As regards the quality assessment.87 (95% CI. The duration from the onset of symptoms to Regarding the treatment arm using dextrose prolotherapy.25 studies conducted by Reeves and Hassanein.8%.00) 3.21) the RCTs obtained a maximal 2 points in the aspect of “ran. findings in each trial. 1. 0.050) 0.10).54 (0.27. 190 (58.75 3rd dose Reeves and Hassanein7 0.08 Subtotal (I-squared = 61. 1.24 and the one by Dumais et al26 had descriptions RCTs.43 (–0.21) 22.27). The results of the quality assessment are of local anesthetics.46 (–0.62.43) 6.56 Dumais et al26 1.7.8 the one by Regarding the comparative injection regimens in the five Rabago et al.94 Rabago et al23 0.76 (0. 0. after the first.73 (0. the being registered in the study was from 10. 1.98 (0. one used two serial saline injections followed by one of the outcome of all the patients at the end of the studies shot of corticosteroids. and fourth or more injections.84 (0.31 Rabago et al24 0. 2.66 Rabago et al24 0.7 to 108. 0.60–1.65 (95% confi- The diagnosis of osteoarthritis was verified by radiographic dence interval [CI]. 0. effect sizes compared with baseline were 0. 0. 0. 1.94 (0.58 (0. 850 submit your manuscript | www.63) ES of pain reduction % ES (95% CI) weight 1st dose Rabago et al23 0. second.80 (0.10) 32.08.09) 6.25) 6. p=0.85 (0. 2. all the dextrose prolotherapy and other injected solutions.08 Subtotal (I-squared = 17.73 2nd dose Rabago et al23 0.17) 22.71 (0.73.13 4th dose or more Reeves and Hassanein7 0.7%.2%.Hung et al Dovepress tis7.013) 0. The meta-analysis enrolled a total of 326 participants.22.00 –5 0 5 Figure 2 Forest plot of the effect of pain reduction from baseline after the first.17). p=0.08.56 Dumais et al26 1. we RCTs had appropriate blinding methods (maximal 2 points) extracted the data closest to the sixth month after the first except the study by Dumais et al26 which did not mention injection.31 Dumais et al26 1.80 (0. and 0.1%. 1.14–1.52 (0. Abbreviations: ES.01) 6. In terms of the comparisons between methods were mentioned. 0.4%.302) 0. 1.36.30) 3. 1.66 (0.08 Jahangiri et al25 0.39 Overall(I-squared = 47.23.24 and one used a crossover design by listed in Table 1.86 Jahangiri et al25 0.08 Jahangiri et al25 0. 0.14.86 Subtotal (I-squared = 35.71) 6.27.202) 0.dovepress. 1. 2. p=0.31 Subtotal (I-squared = 72.94) (0.76. third. effect size.

IV: 5. 18 (8 M. rest.dovepress.4 years ± 42. 12 months with a Hassanein7 control groups. III: from Brief Pain weeks 24 group B (dextrose 11.5 ± 9.Intention. or with grip. flare osteophytic change goniometrically measured flexion.3 6 months or more Kellgren–Lawrence No Not WOMAC.9 years 10.2 months space narrowing. and 32 in Rating Scale. VAS. with joint 12 months with a flare Hassanein8 proximal control: 14 control: placebo: 50 moderate joint movement and of pain at the interphalangeal. participants narrowing or frequency of postinjection 58% males grade 2 or more leg buckling. 8 F).com (Continued) 851 Dextrose prolotherapy for osteoarthritis . 64. grade I: 1.2 ± grade I: 2. Wong.2 years. radiographic measures of joint narrowing and osteophytosis. and 28 on weeks 20. group B: impairment period both legs at 18 (11 M. 59 ± 117 months. and (6 M. combination simple descriptive with exercise): intensity scale. osteophytosis. 4 weeks in with diffuse 12 in combination group B: 56. III: and functional a 36-week edema of with exercise): 10. Baker Faces Pain 28. Every One patient 3a et al26 on weeks 0. and ± 12. 4. and KT1000- measured anterior displacement difference Dumais Knee OA Group A (dextrose Group A: 57. 13 (5 M. Table 1 Summary of studies that investigated the therapeutic effect of dextrose prolotherapy on patients with osteoarthritis Study Disease Enrolled sample Average age Symptom Severity of OA Double. IV: 5 Inventory.9 ± 9. II: 1. score: group A: mentioned pain intensity. 10 F) numeric distress scale.Outcome Follow. II: 1. 7 F).6 years. Adverse Quality number duration on radiographs blind to-treat measure(s) up timing event assessment Dovepress Randomized control trial Reeves Thumb and finger OA Dextrose: Dextrose: Dextrose: Moderate Yes Yes VAS for pain at 6 and One patient 5a and (distal interphalangeal. 24. and combined pain score of all the aforementioned Dovepress submit your manuscript | www. 8 F) 63. 8. joint thumb at the trapeziometacarpal mild osteophytosis flexion range in 12th month Journal of Pain Research 2016:9 joints) plus mild joint space degrees follow-up narrowing Reeves Knee OA Overall 77 patients 63 years for 6 months or more Either grade 2 Yes Not VAS for pain 6 and One patient 5a and in the dextrose and all knee OA or more joint mentioned and swelling.

3 in ± 7 years ± 71.8 ± 7. and 26. 14.9 ± Dextrose: 10. WOMAC. 2. or subluxation Single-arm prospective study Rabago Knee OA 36 (15 M.7 years. 56.3 ± moderate joint 6 months transient 9.Intention. mentioned procedure-related 5. visual analog scale. M. Baseline. 21 F) 63.7 Moderate Yes Not VAS. 19 F).6 months grade I–II: 9. osteophytosis.0 grade I–II: 11.4 exercise: 60.8 ± 62. Journal of Pain Research 2016:9 Dovepress . Health Assessment Questionnaire Disability Index. not self-limiting bruising Jahangiri First carpometacarpal Dextrose: 30 (7 M. female. control: 56. Western Ontario and McMaster Universities Arthritis Index.4 III–IV: 9.Outcome Follow. control: ± 7. NA. 21 F) exercise: 56. injection or subchondral sclerosis. bQuality scores derived from the Newcastle–Ottawa Scale. All patients 5a et al24 (11 M.9 years. control: 30 (9 9. score: dextrose: mentioned procedure-related 5.5 months. Dextrose: 63. 12.3 ± 10. KPS.7 years 81. KPS. male. III–IV: pain severity. exercise: ± 6.8 control: 108. mentioned 1. No 4b et al23 score: grade I–II: 8.9 months Kellgren–Lawrence NA Not WOMAC. and 52 patient satisfaction weeks Notes: aQuality scores derived from the Jadad scale. KPS.dovepress. 12. 79. with mild- Dovepress control: 29 (9 M. 21 F) 60 ± 8. VAS. Table 1 (Continued) 852 Study Disease Enrolled sample Average age Symptom Severity of OA Double. 9.4 years. control: I–II: 12.1 years control: 11. knee pain scale.3 months space narrowing. 9. and 26. III–IV: dextrose 14 group and 5 in saline group with submit your manuscript | www.9 months. Baseline. and 52 to-moderate 20 F). exercise: pain. HAQ-DI Baseline. Three 4a et al25 joint OA 23 F). patient satisfaction weeks postinjection 31 (10 M. Adverse Quality Hung et al number duration on radiographs blind to-treat measure(s) up timing event assessment Rabago Knee OA Dextrose: 30 Dextrose: Dextrose: Kellgren–Lawrence Yes Not WOMAC. or increases mild osteophytosis in pain at plus mild joint the site of space narrowing.2 ± 72. Abbreviations: OA.7 months. ± 99. HAQ-DI. F. osteoarthritis. grade III–IV: 23 pain severity. and patients with M.

5 mL of 1% lidocaine. resistance was felt label period) Reeves and 3 (3 basic 9 mL 2 months 10% dextrose and 0.5 mL of 15% necessary) (6. the other group extra-articular: the at each of 8 sites articular: 15% receiving injections on osteotendinous in the collateral dextrose and 0. increase as each ligament-bone saline) tolerated to 5 sessions injection per week.25–0.75 mL of 50% knee exercises.9% saline with injection through an from WOMAC 2 additional articular: 0. 24. 8. 10 repetitions daily Rabago 3 (3 basic Intra-articular: 4 weeks Intra-articular: 25% Control: intra-articular: Intra-articular Pain subscale et al24 doses with 6 mL.5 mL of 50% dextrose 5 mL of 1% lidocaine. of 0. begin solution was injected dextrose mixed with 3 sessions per using a peppering with 4. extra.075% lidocaine bacteriostatic water inserted at the joint walking additional site in bacteriostatic line of all symptomatic injections water DIP. technique with a 1% lidocaine and 10 repetitions per 25-guage needle at 11. straight leg raise. dextrose and 0.9 was inserted toward movement with 0.9% saline with injection: up to 15 physicians up to 22. 15 repetitions per exercise Jahangiri 3 1 mL 1 month 0. junction of both ligaments lidocaine Both receiving 32 weeks insertion sites of the of exercise (isometric collateral ligaments quadriceps exercises.5 mL of 2% metacarpal in the lidocaine in the 3rd month snuffbox (Continued) Journal of Pain Research 2016:9 submit your manuscript | www.075% lidocaine in A 27-gauge Pain during Hassanein7 doses but 0. 8.Dovepress Dextrose prolotherapy for osteoarthritis Table 2 Summary of the preparations and injection details of prolotherapy in the retrieved trials Study Total Volume per Interval Regimen Comparison Injection technique Pain number of dose of measurement injection injection extracted for doses analysis Randomized controlled trial Reeves and 3 (3 basic 0. and 32.5 mL) mixed the base of the first with 0. extra. extra. followed by the ulnar side of the lidocaine a single dose of 40 mg extensor pollicis brevis methylprednisolone and just proximal to acetate (0. 3 times daily.dovepress. PIP.6% weeks 20. and 853 Dovepress . anterior approach. and thumb were CMC joints laterally allowed in and medially until firm the open.9% exercise.5 mL extra-articular: 4. subdermal injections thought 15% dextrose Exercise: 10 at-home and 0.075% lidocaine bacteriostatic water needle through movement additional in bacteriostatic an inferomedial injections water approach to inject the were tibiofemoral joint allowed at 6. leg was identified extension exercises with quadriceps roll. of 1% lidocaine).25 mL of 0. from WOMAC articular: 1 mL lidocaine.5% injections on weeks 0. 4.5 mL of week. dextrose (5 mL 5 mL of 0. inferomedial approach. and 10 months) Dumais 4 Intra-articular: 4 weeks Intra-articular: 20% One group receiving Intra-articular: Pain subscale et al26 5 mL.5 mL of 2% % saline.5 mL of 20% 2 monthly placebo A 25-gauge needle Pain during et al25 dextrose mixed injections of 1 mL of 0. 1 session daily. and sitting end- range knee extension).075% lidocaine in A 27-gauge needle was Pain during Hassanein8 doses but each injection 0. injections at each ligament– mixed with 5 mL extra-articular: 18 mL extra-articular if the bone insertion. 28.5 mL at 2 months 10% dextrose and 0.

not applicable.25 mL of 0.18 to 0.30–1. However. distal interphalangeal. 95% treatment of symptomatic osteoarthritis. (Figure 3A).9% ligament–bone injection saline) Abbreviations: DIP.24. 95% CI.8. WOMAC. extra. PIP. lidocaine).28 Since 2013. The subgroup to the placebo effect and could not be used as true effectiveness analysis further showed that the effect of prolotherapy did of a treatment and was only used as a surrogate approach for not differ between hand and knee osteoarthritis. 0. osteoarthritis and chronic tendinopathy.5 mL articular: 15% and 0. Therefore. but the number of clinical positive compared with the reference regimen and exercise trials investigating its effectiveness is still limited.38. The inconsistency might asymmetry were detected in terms of the effect size compar.dovepress. 15 subdermal injections physicians up to 22. –0. a quantitative analysis was required Discussion to examine the dose–response relationship and true effect of Our meta-analysis included one single-arm study and five dextrose prolotherapy in the treatment of osteoarthritis. There was no difference in the effect sizes regarding the use three more RCTs have been published regarding the use of of dextrose prolotherapy compared with control injection dextrose injection for hand and knee osteoarthritis. proximal interphalangeal. Western Ontario and McMaster Universities Arthritis Index. Dextrose prolotherapy was more effective Journal of Pain Research 2016:9 Dovepress . ences in injection techniques. dextrose (5 mL through an inferomedial from WOMAC 2 additional articular: 0. evaluation of a potential dose–response relationship (Figure 2). 0. a narrative review investigated the same indicated moderately superior treatment effect of dextrose to 854 submit your manuscript | www.75 mL solution was injected necessary) of 50% dextrose using a peppering mixed with 4. Sit et al The subgroup analysis showed that dextrose prolotherapy conducted a meta-analysis regarding the use of dextrose in the had a superior effect to local anesthesia (effect size. approach. their pretreated baseline levels.5 mL technique with a of 1% lidocaine and 25-guage needle at each 11. we did not identify The purpose was to examine whether additional injections a positive dose–response relationship following serial dex.19.6 In 2016. 0. extra- injections at each ligament– 5 mL of 1% articular injection: up to if the bone insertion. extra. The values of the effect size back pain.71 issue. disclosing a favorable trend of prolotherapy in treating (95% CI. their analysis did roids (effect size. mentioning a poten- CI. NA.Hung et al Dovepress Table 2 (Continued) Study Total Volume per Interval Regimen Comparison Injection technique Pain number of dose of measurement injection injection extracted for doses analysis Single-arm prospective study Rabago 3 (3 basic Intra-articular: 4 weeks Intra-articular: 25% NA Intra-articular injection Pain subscale et al23 doses with 6 mL.31.07–0. differ- ing dextrose prolotherapy and other injected solutions.5 mL of 50% dextrose. No publication of these studies showed a superior effect of dextrose adminis- bias (p=0. not include patients with hand osteoarthritis. In our study. a at 6 months following the first injection. and volumes and selections of injected joints.80) (Figure 3C). carpometacarpal.11) (Figure 3B). determined by the Begg’s test) and funnel plot tration over the reference regimen. while that compared with exercise was 0. However. CMC.70) and an insignificant advantage over corticoste. and the comparison between dextrose and exercise was within clinical trials using prolotherapy in the treatment of chronic expectations because injection and needling carry a strong musculoskeletal pain and found a potential benefit of prolo. which usually leads to superior response therapy on osteoarthritis but an inconsistent outcome on low to the noninvasive treatment. 0. placebo effect. We were aware that the effect size derived from the com- than local anesthetics injection and exercise. and found that dextrose injection reduced pain in We selectively analyzed the serial changes between the patients with hand and knee osteoarthritis compared with baseline and posttreatment status within the dextrose group.5 mL of 15% thought dextrose (6. case series. tial positive effect of prolotherapy. In 2005.27 In 2011. RCTs. The result from systematic review summarized case reports. Dextrose prolotherapy has been used for treating mus. and had an parison with the pretreatment condition was overestimated due insignificant advantage over corticosteroids. have arisen from heterogeneity in enrolled participants.25 Two between knee and hand joints (Figure 3D). could reduce more pain or sustain the duration of symptomatic trose injections. the effect of dextrose prolotherapy was culoskeletal pain for decades.

29 Corticosteroids was existed in the patient populations. although the injection volumes of Fourth.18.42) 25 Jahangiri et al 0.13.96) Subtotal (I-squared=0. (B) the pooled result comparing dextrose and exercise. and (C) the subgroup analysis based on different comparative injectates and (D) the affected joints.520) 0.25.63) –2 0 2 –2 0 2 Not favored Favor dextrose Not favored Favor dextrose C. 0. 0. OA. analysis. Comparison with injections B. 1. 0.801) 0. 1. local anesthetics and corticosteroids.65) 8 Reeves and Hassanein 0.25.80) 0.11) Overall ( 855 Dovepress .70) Hand OA Corticosteroid Reeves and Hassanein8 0.30. In our subgroup because the data were not available in each retrieved trial. 0.0%. Third.18.22 (–0. Different joints ES (95%CI) ES (95%CI) Lidocaine Knee OA Reeves and Hassanein7 0.Dovepress Dextrose prolotherapy for osteoarthritis A.06. which considered the Journal of Pain Research 2016:9 submit your manuscript | www.70) Dumais et al26 0. p=0. Second.42) Rabago et al 0.13. 1. the subgroup analysis did not reveal a significant appeared to be more effective than the use of corticosteroids difference between hand and knee osteoarthritis.96) Jahangiri et al25 0.28.25. and heterogeneity ment responsiveness using binary data. First.42) 24 24 Rabago et al 0.80) Jahangiri et al25 0. although previous research proposed that the benefit ticosteroids. 0. Furthermore.45 (–0. the treat- eligible for meta-analysis was limited. Fifth.31 (–0. knees in a previous meta-analysis.97 (0. p=0.801) 0. and outcome assessment.0%. Different injectates D. 0.36 (0.349) 0.625) 0. osteoarthritis. CI.0%.0%. p=0.30 Although dextrose prolotherapy large joints.96) Rabago et al24 0. 0.31 (–0. these theo- trial) using corticosteroids as reference.36 (0.0%.801) 0.68) Subtotal (I-squared=0.70) Reeves and Hassanein 7 0.71 (0.4 and the effect did not last we did not analyze effect sizes of functional improvements for more than 3 months after administration.38 (0. 0. Our data implied that ries could not be proved by our meta-analysis since there dextrose prolotherapy was potentially more effective than an were few data about the measurement of cartilage thickness anti-inflammatory (corticosteroids) regimen or placebo (local and intra-articular cytokine level in the retrieved articles. This subject should be Our study had several limitations. 1.64 (–0. hyaluronic acid and platelet-rich plasma are known to dextrose for small joints differed remarkably from those for counteract osteoarthritis. p=0. Abbreviations: ES.45 (–0.07) Rabago et al 0. 0.70) 8 24 Reeves and Hassanein 0. p=0. 1. effect size.63) –2 0 2 –2 0 2 Not favored Favor dextrose Not favored Favor dextrose Figure 3 Forest plot of comparisons of the effect size between dextrose prolotherapy and the reference treatments: (A) the pooled result from four randomized controlled trials comparing dextrose with other injections.18.80) Overall (I-squared=0. injection protocols.01. 0. 0. confidence interval.31 (–0. Comparison with exercise ES (95%CI) ES (95%CI) 7 Reeves and Hassanein 0.05. 0.33 (–02.45 (–0. p=0.64 (–0.10. Subtotal (I-squared=0. 0.13.63) Overall (I-squared=0. known to provide short-term pain relief for osteoarthritic comparative regimens.22 (–0. and local anesthetics. 0.36 (0.22 (–0.56 (0. the number of trials investigated in future prospective studies.82) Overall (I-squared=0.41 (–0.13. The reason for lacking statistical significance of dextrose prolotherapy derived from its chondo-protective might be attributed to insufficient study numbers (only one effect or modulation of intra-articular cytokines.31 (–0.06. anesthetics).64 (–0. p=0. dextrose showed an insignificant benefit over cor. the comparison with commonly used regimens like hyaluronic acid or platelet-rich plasma was Study limitations lacking in our literature search.474) 0.0%. 0.dovepress.07.

25. et al. Ann Fam Med. Han DS. Dextrose and morrhuate sodium thritis. Patterson J. The effect of prolotherapy did cuff repair: a meta-analysis of randomized controlled trials. Com- Conclusion parative effectiveness of platelet-rich plasma injections for treating knee joint cartilage degenerative pathology: a systematic review and Compared with pretreatment baseline. et al. Am J Sports Med. Patterson JJ. A systematic review double-blind study of dextrose prolotherapy for osteoarthritic thumb of prolotherapy for chronic musculoskeletal pain. Chung VCh.5(3):351–361. 2009. Chang KV. Chien KL. and prob. 2015. 8. prospective. Sci Rep. Mundt M. Verma A. J Clin Epidemiol. Hung CY. Rabago D. Zakany R. Altern Ther Health Med. Hassanein K.94(11):2075–2082. Am Fam Physician. 2000. 20. Clin J Sport Med. 2013. J R. Woods M. Slobogean GP. 2006. Jevsevar D. 2014. Mundt M. Ziaeefard (Beihu 10501). 2015. 2012. J Bone Joint Surg Am.18(4):408–414. Vora A. Rabago D.95(3):562–575. Zgierska AE. prolotherapy. Effectiveness of bisphosphonate analogues and functional electrical a positive dose–response relationship following serial injec. Effectiveness corticosteroids should be cautious because the finding was of intra-articular hyaluronic acid for ankle osteoarthritis treatment: a systematic review and meta-analysis. Cummins DS. from National Taiwan University Hospital. Effect of regenerative injection controlled study of dextrose prolotherapy for knee osteoarthritis with or therapy on function and pain in patients with knee osteoarthritis: a without ACL laxity. whole blood and platelet-rich plasma. 2014. Matta C. The epidemiology and impact of pain in osteoarthritis. tions (prolotherapy) for knee osteoarthritis: results of a single-arm 4. Chang KV. J Grad Med Educ. injections (prolotherapy) for knee osteoarthritis: a prospective open- 3. Dextrose prolotherapy was found to provide a better patients. Deeks JJ. derived from only a single study. 15. Akgun I. roid. Therefore. 2013. we used the effect sizes 11. Patterson JJ. Wang TG. A (prolotherapy) in the treatment of symptomatic knee osteoarthritis: a systematic review of four injection therapies for lateral epicondylosis: systematic review and meta-analysis.21(9):1145–1153. Borg-Stein J. Chen WS. Musumeci G.84(11):1208–1210. et al. Han DS. 24. Reeves KD.94(5):951–960. Gee T. Hung CY. Mobasheri A. PM first carpometacarpal joint: a double-blind randomized clinical Journal of Pain Research 2016:9 Dovepress . Chien KL. Entezary SR. 23. Aliwarga F. Orthop Sci. and finger (DIP.80(3):237–244. 2004. 2013. 18. a clinical trial of prolotherapy for knee osteoarthritis. et al. Rabago D. Rahimzadeh P. Rabago D. Finally. Measuring inconsis- Acknowledgments tency in meta-analyses. Dextrose prolotherapy for 5. Spine (Phiia Pa 1986). Chang KV. Regenerative injection therapy for corticosteroid local injection for the treatment of osteoarthritis in the osteoarthritis: fundamental concepts and evidence-based review. Fleiss JL. Zgierska A. Wang TG. PIP. Nguyen R. Reeves KD. Dumais A. Lai MS. decreased pain in osteoarthritis patients but did not exhibit 14. Giustini D. 2014. The statistical basis of meta-analysis. therapy injections. hyaluronic acid. Rabago D. not differ between hand and knee osteoarthritis 16. 2014. and exercises for chronic low-back pain: a randomized trial. definition. Viscosupplementa. knee osteoarthritis: a randomized controlled trial. placebo-controlled 27. Arch Phys Med Rehabil. uncontrolled study with 1-year follow-up. Sprague IS. Schluter PJ. Chondrosenescence: Rehabil. polidocanol. 26.6:25247. Hypertonic dextrose injections 9. Hung CY. Ayhan E. Stat Methods Med Res. Maturitas. Feinn R. Prolo- The authors report no conflicts of interest in this work. Ryan M. Imani F. Benoit C. et al. Best TM. Rabago D. References 21. 2015. tion for osteoarthritis of the knee: a systematic review of the evidence. Chang KV. Slobogean BL. Using effect size—or why the P value is not Sports Med. platelet rich plasma) for the knee osteoarthritis. Pain Med. M. Kesmezacar H.2(2):121–145. Crane D.Hung et al Dovepress standard outcome ­variable in pain medicine. Hauser RA. Chien KL. Rabago D.8(11): therapeutic effect than exercise. Wang TG. 2013. specific quality of life and magnetic resonance imaging outcomes in arthritis Cartilage. Early ably corticosteroids when patients were retested 6 months versus delayed passive range of motion exercise for arthroscopic rotator following the initial injection.62(12):1261–1267. Bellamy N. local anesthetics. 856 submit your manuscript | www. in the included studies.43(7):471–481.4(5 Suppl):S104–S109. Faiz SH. retrieved from continuous variables like changes in pain MEDLINE. 2012. 28. Chen WS. Campbell J. Reeves KD. Osteo. PLoS One.13(8):990–999. saline injections. Moghaddam FR. Prolotherapy for chronic musculoskeletal pain. Clin Med ence Council (104-2314-B-002-022-MY2) and by funding Insights Arthritis Musculoskelet Disord. Sit RW. Neogi T. Higgins JP.4(3):279–282. 2003.6(2):68–74.15(3):376–380. Fortney L. 13.11(3):229–237. Sullivan GM. Kijowski R. Randomized. 2000. EMBASE. BMJ. Association between disease- 1.19(5):737–743. and trapeziometacarpal) joints: evidence of clinical 2005. is not reported 10. Thompson SG. 2012. and Cochrane index most primary studies but or function instead in the quantitative analysis. Han DS.43(5):1265–1273. McKernon M. 2014. dextrose injections meta-analysis. discussion 16. enough. e81124. Outcomes of prolotherapy in chondromalacia patella patients: improvements in pain level and function. et al. randomized crossover study.327(7414):557–560. Arch Phys Med Rehabil. Beamsley M. efficacy. stimulation on attenuating post-injury osteoporosis in spinal cord injury tions. Zgierska A. Glasziou PP.20(5):383–391. 1993. Hassanein K. Patterson J. Altman DG. J Altern Complement Med. 2012. Bourne R. Yelland M. Jahangiri A. Arch Phys Med 2.6(4):311–320. Randomized prospective double-blind placebo. J Altern Complement Med.(2):CD005328. Mulpuri K. Hypertonic dextrose versus 6. hallmarks and potential role in the pathogenesis of osteoar.7:13–20. label trial. Najafi S.29(1):9–16. 2016. 77–80.19(8):696–702. Wells G. J Res Med Sci. Hypertonic dextrose injec- World J Orthop.dovepress. 7. 2013. J Altern Complement Med. Zeisig E. Intraarticular injections (corticoste. Cochrane Database Syst Rev. not abstracts included in orthopedic meta-analyses. 22. Nasiri AA. This research was supported by grants from the National Sci. Investigation the efficacy of intra-articular prolotherapy with erythropoietin and dextrose and intra-articular pulsed radiofrequency on pain level reduction and range of motion improvement in primary Disclosure osteoarthritis of knee.97(24):2047–2060. Bei-Hu branch 19. Chen WS. 2009. the interpretation of the effect of dextrose compared with 12. 17. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Hsiao MY. Br J 29. Brown GA. Bogduk N. Chen WS. Yelland MJ. Dumais R. 2011. Robinson V. Donnelly P. Best TM.a systematic review and meta-analysis. 2014.

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