Efficacy of intra-articular hypertonic dextrose prolotherapy versus normal saline for knee osteoarthritis: a protocol for a triple-blinded randomized controlled trial

Regina Wing Shan Sit, Ricky Wing Keung Wu, Kenneth Dean Reeves, David Rabago, Dicken Cheong Chun Chan, Benjamin Hon Kei Yip, Vincent Chi Ho Chung, Samuel Yeung Shan Wong, Regina Wing Shan Sit, Ricky Wing Keung Wu, Kenneth Dean Reeves, David Rabago, Dicken Cheong Chun Chan, Benjamin Hon Kei Yip, Vincent Chi Ho Chung, Samuel Yeung Shan Wong

Abstract

Background: Knee Osteoarthritis (KOA) is a very common condition with prevalence rising with age. It is a major contributor to global disability and has a large socioeconomic burden worldwide. Conservative therapies have marginal effectiveness, and surgery is reserved for severe symptomatic KOA. Dextrose Prolotherapy (DPT) is an evidence-based injection-based therapy for chronic musculoskeletal conditions including KOA. The standard "whole joint" injection method includes intra-articular injection and multiple extra-articular injections at soft tissue bony attachments. The procedure is painful and requires intensive procedural training often unavailable in conventional medical education, which potentially limits access. Intra-articular injection offers the possibility of a less painful, more accessible treatment. The aim of this project is to assess the clinical efficacy of intra-articular injection of DPT versus normal saline (NS) for KOA.

Method: Seventy-six participants with KOA will be recruited from the community. We will conduct a single center, parallel group, superiority randomized controlled trial comparing DPT and NS injections, with blinding of physician, participants, outcome assessors and statisticians. Each group will receive injections at week 0, 4, 8 and 16. The primary outcome will be the Western Ontario McMaster University Osteoarthritis Index pain scale (WOMAC), and secondary outcomes include WOMAC composite score, the WOMAC function and stiffness subscale, the Visual Analogue Score of pain, objective physical function tests (the 30 s chair stand, 40- m fast paced walk test, the Timed up and go test) and the EuroQol-5D (EQ-5D). All outcomes will be evaluated at baseline, and 16, 26 and 52 weeks. All analyses will be conducted on an intention-to-treat basis using linear mixed regression models.

Discussion: This paper presents the rationale, design, method and operational aspects of the trial. The findings will determine whether IA DPT, an inexpensive and simple injection, is a safe and effective non-surgical option for KOA. The results can be translated directly to clinical practice, with potentially substantial impact to patient care.

Trial registration: The trial ( ChiCTR-IPC-15006617 ) is registered under Chinese Clinical Trials Registry on 17th June 2015.

Keywords: Dextrose prolotherapy; Knee osteoarthritis; Normal saline; Randomized controlled trial; Study protocol.

Conflict of interest statement

Ethics approval and consent to participate

The study complies with the Declaration of Helsinki, and has been approved by the Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee. (CREC no. 2014.059). Written inform consent was obtained from all participants.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study flow chart
Fig. 2
Fig. 2
Suprapetella pouch injection under USG guidance

References

    1. Felson DT. Osteoarthritis of the knee. N Engl J Med. 2006;354(8):841–848. doi: 10.1056/NEJMcp051726.
    1. Felson DT. Epidemiology of osteoarthritis. In: Brandt KDDM, Lohmander LS, editors. Osteoarthritis. Oxford, England: Oxford university press; 2003. pp. 9–16.
    1. Woo J, Leung J, Lau E. Prevalence and correlates of musculoskeletal pain in Chinese elderly and the impact on 4-year physical function and quality of life. Public Health. 2009;123(8):549–556. doi: 10.1016/j.puhe.2009.07.006.
    1. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part II. Arthritis & Rheumatism. 2008;58(1):26–35. doi: 10.1002/art.23176.
    1. Gupta S, Hawker GA, Laporte A, Croxford R, Coyte PC. The economic burden of disabling hip and knee osteoarthritis (OA) from the perspective of individuals living with this condition. Rheumatology (Oxford, England) 2005;44(12):1531–1537. doi: 10.1093/rheumatology/kei049.
    1. Sayer EC, Li LC, Kopec JA, Esdaile JM, Cibere J. The effect of disease site (knee, hip, hand, foot, lower back or neck) on employment due to osteoarthritis. PLoS One 2010;DOI: 10.1371/journal.pone.0010470.
    1. Hutton I, Gamble G, Mclean G, Butcher H, Gow P, Dalbeth N. Obstacles to action in arthritis: a community case-control study. Int J Rheum Dis. 2009;12(2):107–117. doi: 10.1111/j.1756-185X.2009.01392.x.
    1. Samson DJ, Grant MD, Ratko TA, Bonnell CJ, Ziegler KM, Aronson N. Treatment of primary and secondary osteoarthritis of the knee. Evid. Rep. Technol. Assess. 2007;157:1–157.
    1. Altman RD. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum. 2000;43:1905–1915. doi: 10.1002/1529-0131(200009)43:9<1905::AID-ANR1>;2-P.
    1. Little CV, Parsons T. Herbal therapy for treating osteoarthritis. The Cochrane database of systematic reviews. 2001;1:Cd002947.
    1. Morelli V, Naquin C, Weaver V. Alternative therapies for traditional disease states: osteoarthritis. Am Fam Physician. 2003;67(2):339–344.
    1. Carr AJ, Robertsson O, Graves S, et al. Knee replacement. Lancet (London, England) 2012;379(9823):1331–1340. doi: 10.1016/S0140-6736(11)60752-6.
    1. Felson DT. Osteoarthritis: priorities for osteoarthritis research: much to be done. Nature Rev Rheumatol. 2014;10(8):447. doi: 10.1038/nrrheum.2014.76.
    1. Conaghan PG, Kloppenburg M, Schett G, Bijlsma JW. Osteoarthritis research priorities: a report from a EULAR ad hoc expert committee. Annals of the rheumatic diseases. 2014;73(8):1442-5.
    1. Felson DT. The sources of pain in knee osteoarthritis. Curr Opin Rheumatol. 2005;17(5):624–628. doi: 10.1097/01.bor.0000172800.49120.97.
    1. Hawker GA, Gignac MA, Badley E, et al. A longitudinal study to explain the pain-depression link in older adults with osteoarthritis. Arthritis Care & Res. 2011;63(10):1382–1390. doi: 10.1002/acr.20298.
    1. Hochman J, Davis A, Elkayam J, Gagliese L, Hawker G. Neuropathic pain symptoms on the modified painDETECT correlate with signs of central sensitization in knee osteoarthritis. Osteoarthr Cartil. 2013;21(9):1236–1242. doi: 10.1016/j.joca.2013.06.023.
    1. Rabago D, Slattengren A, Zgierska A. Prolotherapy in primary care. Prim Care. 2010;37:65–80. doi: 10.1016/j.pop.2009.09.013.
    1. Reeves KD, Sit RW, Rabago DP. Dextrose Prolotherapy: A Narrative Review Of basic science, clinical research, and best treatment recommendations. Phys Med Rehabil Clin N Am. 2016;27(4):783–823. doi: 10.1016/j.pmr.2016.06.001.
    1. Maniquis-Smigel L, Reeves KD, Lyftogt J, Rabago D. Analgesic Effect of Caudal 5% Dextrose in Water in Chronic Low Back Pain (Abs) Arch. Phys. Med. Rehabil. 2015;96(10):e103.
    1. Rabago D, Zgierska A, Fortney L, et al. Hypertonic dextrose injections (Prolotherapy) for knee osteoarthritis: results of a single-arm uncontrolled study with 1-year follow-up. J Altern Complement Med. 2012;18(4):408–414. doi: 10.1089/acm.2011.0030.
    1. Rabago D, Patterson JJ, Mundt M, et al. Dextrose prolotherapy for knee osteoarthritis: a randomized controlled trial. Ann Fam Med. 2013;11(3):229–237. doi: 10.1370/afm.1504.
    1. Dumais R, Benoit C, Dumais A, et al. Effect of regenerative injection therapy on function and pain in patients with knee osteoarthritis: a randomized crossover study. Pain Med. 2012;13(8):990–999. doi: 10.1111/j.1526-4637.2012.01422.x.
    1. Hassan F, Trebinjac S, Murrell WD, Maffulli N. The effectiveness of prolotherapy in treating knee osteoarthritis in adults: a systematic review. Br Med Bull. 2017:1–18.
    1. Nourani B, Rabago D. Prolotherapy for knee osteoarthritis: a descriptive review. Current Physical Medicine and Rehabilitation Reports. 2016;4(1):42–49. doi: 10.1007/s40141-016-0111-z.
    1. Sit RW, Chung VC, Reeves KD, Rabago D, Chan KK, Chan DC, Wu X, Ho RS, Wong SY. Hypertonic dextrose injections (prolotherapy) in the treatment of symptomatic knee osteoarthritis: a systematic review and meta-analysis. Sci Rep. 2016;6:25247.
    1. Hung C-Y, Hsiao M-Y, Chang K-V, Han D-S, Wang T-G. Comparative effectiveness of dextrose prolotherapy versus control injections and exercise in the management of osteoarthritis pain: a systematic review and meta-analysis. J Pain Res. 2016;9:847–857. doi: 10.2147/JPR.S118669.
    1. Reeves KD, Hassanein K. Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Altern Ther Health Med. 2000;6(2):68.
    1. Eslamian F, Amouzandeh B. Therapeutic effects of prolotherapy with intra-articular dextrose injection in patients with moderate knee osteoarthritis: a single-arm study with 6 months follow up. Ther Adv Musculoskelet Dis. 2015;7(2):35-44.
    1. Topol GA, Podesta LA, Reeves KD, Giraldo MM, Johnson LL, Grasso R, Jamín A, Clark T, Rabago D. Chondrogenic effect of intra-articular hypertonic-dextrose (prolotherapy) in severe knee osteoarthritis. PM&R. 2016;8(11):1072-82.
    1. Hashemi SM, Madadi F, Razavi S, Nikooseresht M, Nasiripour S. Intra-articular hyaluronic acid injections Vs. dextrose prolotherapy in the treatment of osteoarthritic knee pain. Tehran University of Medical Sciences. 2012;70(2).
    1. Hashemi M, Jalili P, Mennati S, et al. The effects of prolotherapy with hypertonic dextrose versus prolozone (intraarticular ozone) in patients with knee osteoarthritis. Anesth Pain Med. 2015;5(5).
    1. McAlindon TE, Driban JB, Henrotin Y, et al. OARSI clinical trials recommendations: design, conduct, and reporting of clinical trials for knee osteoarthritis. Osteoarthr Cartil. 2015;23(5):747–760. doi: 10.1016/j.joca.2015.03.005.
    1. Dobson F, Hinman RS, Roos EM, et al. Recommended performance-based tests to assess physcial function in people diagnosed with hip or knee osteoarthritis. Osteoarthr Cartil. 2013;21(18):1042–1052. doi: 10.1016/j.joca.2013.05.002.
    1. Fransen M, Edmonds J. Reliability and validity of the EuroQol in patients with osteoarthritis of the knee. Rheumatology. 1999;38(9):807–813. doi: 10.1093/rheumatology/38.9.807.
    1. Chan A-W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200–207. doi: 10.7326/0003-4819-158-3-201302050-00583.
    1. Aigner T, Rose J, Martin J, Buckwalter J. Aging theories of primary osteoarthritis: from epidemiology to molecular biology. Rejuvenation Res. 2004;7(2):134–145. doi: 10.1089/1549168041552964.
    1. Altman RD. Criteria for classification of clinical osteoarthritis. J Rheumatol Suppl. 1991;27:10–12.
    1. Randolph TG, Rollins JP, Walter CK. Allergic reactions following the intravenous injection of corn sugar (dextrose). Arch Surg. 1950;61(3):554-64.
    1. Guharoy S, Barajas M. Probable anaphylactic reaction to corn-derived dextrose solution. Vet Hum Toxicol. 1991;33(6):609–610.
    1. Kernan WN, Viscoli CM, Makuch RW, Brass LM, Horwitz RI. Stratified randomization for clinical trials. J Clin Epidemiol. 1999;52(1):19–26. doi: 10.1016/S0895-4356(98)00138-3.
    1. Schulz KF, Grimes DA. Allocation concealment in randomised trials: defending against deciphering. Lancet. 2002;359(9306):614–618. doi: 10.1016/S0140-6736(02)07750-4.
    1. Bang H, Ni L, Davis CE. Assessment of blinding in clinical trials. Control Clin Trials. 2004;25(2):143–156. doi: 10.1016/j.cct.2003.10.016.
    1. Qu NN, Li KJ. Study on the reliability and validity of international physical activity questionnaire (Chinese Vision, IPAQ) Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi. 2004;25(3):265–268.
    1. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16(4):494–502. doi: 10.1136/ard.16.4.494.
    1. Maricar N, Parkes MJ, Callaghan MJ, Felson DT, O'Neill TW. Where and how to inject the knee—a systematic review. Semin Arthritis Rheum. 2013;43(2):195–203. doi: 10.1016/j.semarthrit.2013.04.010.
    1. Hart S. Using an aseptic technique to reduce the risk of infection. Nurs Stand. 2007;21(47):43–48. doi: 10.7748/ns.21.47.43.s53.
    1. Saltzman BM, Leroux T, Meyer MA, et al. The therapeutic effect of intra-articular normal saline injections for knee osteoarthritis: a meta-analysis of evidence level 1 studies. Am J Sports Med. 2017;45(11):2647–2653. doi: 10.1177/0363546516680607.
    1. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15(12):1833–1840.
    1. Dobson F, Hinman RS, Hall M, Terwee CB, Roos EM, Bennell KL. Measurement properties of performance-based measures to assess physical function in hip and knee osteoarthritis: a systematic review. Osteoarthr Cartil. 2012;20(12):1548–1562. doi: 10.1016/j.joca.2012.08.015.
    1. Yang KA, Raijmakers N, Van Arkel E, et al. Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial. Osteoarthr Cartil. 2008;16(4):498–505. doi: 10.1016/j.joca.2007.07.008.
    1. Akaike H. Likelihood of a model and information criteria. J Econ. 1981;16(1):3–14. doi: 10.1016/0304-4076(81)90071-3.
    1. Van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res. 2007;16(3):219–242. doi: 10.1177/0962280206074463.
    1. Rubin DB. Multiple imputation for nonresponse in surveys. Vol 81: john Wiley & sons; 2004.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner