Glucopuncture: Series of Regional Multiple Glucose 5% Injections

Glucose and dextrose injections have been used for decades in prolotherapy [1-26]. Prolotherapy - also known as proliferation therapy - is an injection technique which uses high concentrations of dextrose (more than 10% net concentration). Lidocaine is added to make the injections less painful. One of the aims of such hypertonic injections is to create an inflammatory reaction and / or stimulate formation of scar tissue in ligaments [27]. It is postulated that these dextrose injections stimulate tissue repair through growth factors and modulate pain modulation through agonism of TRPV1 receptor. As an increased matrix metalloproteinase (MMP) activity plays a major role in degradation of articular cartilage in patients with osteoarthritis, it is interesting to realize that glucose decreases IL-1β-induced MMP-1 expression in chondrocytes [28].

In prolotherapy, injections are given mainly into joint cavities, entheses, tendons and ligaments. It is suggested that prolotherapy can be as efficient as corticosteroid injections in the treatment of, for example, lateral epicondylosis [29,30], failed rotator cuff repair surgery [31] and chronic rotator cuff lesions [32]. It is also an interesting treatment modality in the treatment of osteoarthritis [33,34].

Over the last decade, low concentrations of dextrose 5% have become more popular [35-38]. These injections are administered into muscles, in the epidural liquid, near peripheral nerves [39], around tendons and in the skin. As the clinical effect is usually temporary, the sessions need to be repeated on a regular basis to achieve clinical effect. Although treatment protocols vary a lot, most physicians are using series of weekly injections of glucose 5% without adding local anesthetics in the treatment of osteoarthritis, carpal tunnel syndrome, back pain, sports injuries, whiplash, failed back surgery syndrome, regional pain syndrome and neuropathic pain.

Glucose is a monosaccharide which functions as a precursor for many carbohydrates found in organisms. It is considered as the prime energy source for cellular health. One glucose molecule result in 38 ATP molecules during the aerobic respiration. The conversion of ATP into ADP releases 30.6kJ/mol energy to the cells. In other words, glucose can be considered as a provider of energy to the cell metabolism.

When tissues are damaged because of trauma, overuse or other causes, the cells need to regenerate as quickly as possible. This tissue regeneration requires an additional amount of energy. When energy supply is limited, complete recovery of the tissue may be slow or even impossible, leading to poor tissue healing. It is postulated that injecting glucose in the extracellular space of the damaged tissue may enhance ATP supply to the cells and as a result support and speed up local recovery. However, there is no strong evidence for this hypothesis so far. Only one study seems to support (partially) this ATP-based theory. In this recent study the authors have illustrated that injecting ATP in the spinal cord stimulates regeneration of primary sensory axons [40].

In the last decade, more findings about injections of low concentrations of glucose have been published. A prospective, randomized, double-blind, controlled trial illustrated a six-month efficacy of perineural dextrose for carpal tunnel syndrome [41]. Dextrose 5% injections also seem to be beneficial for patients with chronic low back pain (failed back surgery syndrome) [42]. Epidural injection of 5% dextrose is reported to reduce pain temporary, but a waning pain control at 2 weeks suggests the need to assess the effect of serial dextrose epidural injections [43]. Caudal epidural injection of 10mL of D5W (without anesthetic) every 2 weeks for 4 treatments and then as needed for 1 year resulted in a consistent pattern of post injection analgesia [44]. This suggests a potential sensorineural effect of serial dextrose injections on neurogenic pain, probably by targeting the peptidergic nociceptors. One proposed mechanism of action suggests that dextrose binds to presynaptic calcium channels and inhibits the release of substance P and CGRP, thereby decreasing neurogenic inflammation [37].

These observations generate the idea that glucose 5% injections (without anesthetic) might be an inexpensive and safe option in the treatment of sports injuries, carpal tunnel syndrome, musculoskeletal pain, whiplash, regional pain syndrome and osteoarthritis. In contrast to cortisone, longer series of such injections every week or every two weeks have little or no side effects. The downside of Glucopuncture is that more sessions are needed to attain symptom resolution when compared to cortisone injections or to PRP injections [45,46], although one study showed that intraarticular glucose injections in the sacroiliac joint produced longer lasting effects than those of steroid injections [47]. In other words, steroid injections provide probably better results on the short run while glucose injections may be superior when it comes to long term results.

Glucose in a five percent water solution (G5W) is a sterile liquid which can be injected without adding a local anesthetic. Adverse reactions are not well documented but appear to be extremely rare (e.g., itching, allergic dermatitis). Temporary injection site tenderness and bruising are the most frequently reported side effects. Injections are given intracutaneously, subcutaneously, in joints and into muscles. Glucose 5% can also be injected around tendons, ligaments, and peripheral nerves. Usually multiple injections (5 to 10 injections) are given in the zone of tissue repair or in the pain zone (the zone which the patient points out as the painful area). Needles frequently used are 30G (1/2”), 27G (3/4” or 1 1/2”) and 23G (3”). The total volume injected varies from 5 to 15ml in each treatment zone. In acute cases, injections are given once or twice a week, and one to five sessions might be necessary. In chronic cases, five to ten sessions (first once a week and then every two weeks) might be needed to attain tissue repair and / or lasting pain relief.

When glucose (or dextrose) is injected in normal healthy tissue, the influence on cell metabolism is minimal. But it is hypothesized that when glucose is injected in tissues which lack energy supply, the added extracellular glucose may lead to more ATP production in the cell and thus support the natural repair processes in those damaged cells. When injected into a muscle tear, the muscle fibers seem to heal quicker and better [48]. As a result, it seems an interesting option to use injections of G5W in trigger points for the treatment of myofascial pain. Glucose injections are also applied in peripheral nerves. Especially chronic inflamed nerves seem to react well to Glucopuncture. Even the peripheral nerve endings in the skin and under the skin recover quicker from neural inflammation when injected with glucose 5%. More clinical research might illustrate the hypothesis that chronic regional pain syndrome [49] might be treated successfully and safely with subcutaneous (SC) or intracutaneous (IC) glucose injections.

Glucopuncture is a new term to describe regional multiple injections with glucose 5%. It is hypothesized that a series of sessions of multiple injections of glucose 5% supports the repair of damaged tissue such as muscles, tendons, ligaments, cartilage, and peripheral nerves. This injection technique can be applied as a single or as an adjuvant modality in the treatment of sports injuries, posttraumatic pain, osteoarthritis, neuropathic pain, and myofascial pain. More clinical and fundamental research in this area is necessary to verify the mechanism of action, safety, and long-term results of this technique.

1. Reeves KD, Sit RW, Rabago DP (2016) Dextrose prolotherapy: a narrative review of basic science, clinical research, and best treatment recommendations. Phys Med Rehabil Clin N Am 27(4): 783-823.
2. Distel LM, Best TM (2011) Prolotherapy: a clinical review of its role in treating chronic musculoskeletal pain. PM R 3(6 Suppl 1): S78-81.
3. Ganji R (2018) Dextrose prolotherapy for improvement of rotator cuff lesions: ready for clinical use? Hong Kong Med J 24(4): 429-430.
4. Hauser RA, Lackner JB, Steilen MD, Harris DK (2016) A systematic review of dextrose prolotherapy for chronic musculoskeletal pain. Clin Med Insights Arthritis Musculoskelet Disord 9: 139-159.
5. Topol GA, Podesta LA, Reeves KD, Marcia MG, Lanny LJ, et al. (2016) Chondrogenic effect of intra-articular hypertonic dextrose (prolotherapy) in severe knee osteoarthritis. PM R 8(11): 1072-1082.
6. Rabago D, Kijowski R, Woods M, Patterson JJ, Mundt M, et al. (2013) Association between disease-specific quality of life and magnetic resonance imaging outcomes in a clinical trial of prolotherapy for knee osteoarthritis. Arch Phys Med Rehabil 94(11): 2075-2082.
7. Rabago D, Nourani B (2017) Prolotherapy for osteoarthritis and tendinopathy: a descriptive review. Curr Rheumatol Rep 19(6): 34.
8. Rabago D, Kansariwala I, Marshall D, Nourani B, Stiffler JM, et al. (2019) Dextrose prolotherapy for symptomatic knee osteoarthritis: feasibility, acceptability, and patient-oriented outcomes in a pilot-level quality improvement project. J Altern Complement Med 25(4): 406-412.
9. Kim BK, Shin JY, Seo KM (2001) The effect of prolotherapy for the chronic pain of musculoskeletal system. The Journal of the Korean Academy of Rehabilitation Medicine 25: 128-133.
10. Kim MY, Na YM, Moon JH (1997) Comparison on treatment effects of dextrose water, saline, and lidocaine, and saline for trigger point injections. J Korean Acad Rehabil Med 21: 967-973.
11. Chou Y, Chiou HJ, Wang HK, Lai YC (2020) Ultrasound-guided dextrose injection treatment for chronic myofascial pain syndrome: a retrospective case series. J Chin Med Assoc 83(9): 876-879.
12. Lin CL, Huang CC, Huang SW (2019) Effects of hypertonic dextrose injection in chronic supraspinatus tendinopathy of the shoulder: a randomized placebo-controlled trial. Eur J Phys Rehabil Med 55(4): 480-487.
13. Lee DH, Kwack KS, Rah UW, Yoon SH (2015) Prolotherapy for refractory rotator cuff disease: retrospective case-control study of 1-year follow-up. Arch Phys Med Rehabil 96(11): 2027-2032.
14. Louw WF, Reeves KD, Lam SKH, Cheng AL, Rabago D (2019) Treatment of temporomandibular dysfunction with hypertonic dextrose injection (prolotherapy): a randomized controlled trial with long-term partial crossover. Mayo Clin Proc 94(5): 820-832.
15. Arias VPI, Tovilla ZCA, Legorreta RBG, Wajid BF, Dory MR, et al. (2019) Prolotherapy for knee osteoarthritis using hypertonic dextrose vs other interventional treatments: systematic review of clinical trials. Adv Rheumatol 59(1): 39.
16. Catapano M, Zhang K, Mittal N, Sangha H, Onishi K, et al. (2020) Effectiveness of dextrose prolotherapy for rotator cuff tendinopathy: a systematic review. PM R 12(3): 288-300.
17. Hsieh PC, Chiou HJ, Wang HK, Lai YC, Lin YH (2019) Ultrasound-guided prolotherapy for acromial enthesopathy and acromioclavicular joint arthropathy: a single-arm prospective study. J Ultrasound Med 38(3): 605-612.
18. Bayat M, Raeissadat SA, Mortazavian BM, Rahimi DS (2019) Is dextrose prolotherapy superior to corticosteroid injection in patients with chronic lateral epicondylitis? a randomized clinical trial. Orthop Res Rev 11: 167-175.
19. Bertrand H, Reeves KD, Bennett CJ, Bicknell S, Cheng AL (2016) Dextrose prolotherapy versus control injections in painful rotator cuff tendinopathy. Arch Phys Med Rehabil 97(1):17-25.
20. Hooper RA, Ding M (2004) Retrospective case series on patients with chronic spinal pain treated with dextrose prolotherapy. J Altern Complement Med 10(4): 670-674.
21. Fullerton BD (2018) Prolotherapy for the thoracolumbar myofascial system. Phys Med Rehabil Clin N Am 29(1): 125-138.
22. Ongley MJ, Inklebarger J (2020) The diagnosis and management of upper gluteal pain. Journal of Prolotherapy 12: e1009-e1014.
23. Sit RW, Chung VCh, Reeves KD, David R, Keith KC et al. (2017) Hypertonic dextrose injections (prolotherapy) in the treatment of symptomatic knee osteoarthritis: A systematic review and meta-analysis. Sci Rep 6: 25247.
24. Nagori SA, Jose A, Gopalakrishnan V, Roy ID, Chattopadhyay PK, et al. (2018) The efficacy of dextrose prolotherapy over placebo for temporomandibular joint hypermobility: A systematic review and meta-analysis. J Oral Rehabil 45(12): 998-1006.
25. Rhatomy S, Evlin M, Rizki R (2020) Dextrose prolotherapy for muscle, tendon and ligament injury or pathology: a systematic review. Annual Research & Review in Biology 2020: 43-62.
26. Ozkan O, Torgutalp SS, Karacoban L, Donmez G, Korkusuz F (2020) Do pain and function improve after dextrose prolotherapy or autologous platelet-rich plasma injection in longstanding groin pain? Monten J Sports Sci Med 9(2): 5-12.
27. Hackett GS, Hemwall GA, Montgomery GA (1993) Ligament and tendon relaxation treated by prolotherapy. Oak Park, USA
28. Wu TJ, Lin CY, Tsai CH, Huang YL, Tang CH (2018) Glucose suppresses il-1β-induced mmp-1 expression through the fak, mek, erk, and ap-1 signaling pathways. Environ Toxicol 33(10):1061-1068.
29. Carayannopoulos A, Borg SJ, Sokolof J, Meleger A, Rosenberg D (2011) Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial. PM R 3(8): 706-715.
30. Yelland M, Rabago D, Ryan M, Shu KN, Dinusha V, et al. (2019) Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomized clinical trial. BMC Musculoskelet Disord 20(1): 509.
31. Akpancar S, Örsçelik A, Seven MM, Koca K (2019) The effectiveness of prolotherapy on failed rotator cuff repair surgery. Turk J Phys Med Rehabil 65(4): 394-401.
32. Seven MM, Ersen O, Akpancar S, Ozkan H, Turkkan S, et al. (2017) Effectiveness of prolotherapy in the treatment of chronic rotator cuff lesions. Orthop Traumatol Surg Res 103(3): 427-433.
33. Works, Cynthia MD; Miller, Jesse DO (2020) Is prolotherapy effective in reducing pain and improving function in patients with knee OA? Evidence-Based Practice: 23(3): 19-20.
34. Gül D, Orsçelik A, Akpancar S (2020) Treatment of osteoarthritis secondary to developmental dysplasia of the hip with prolotherapy injection versus a supervised progressive exercise control. Med Sci Monit 26: e919166.
35. Köroğlu Ö, Orscelik A, Karasimav Ö, Demir Y, Solmaz İ (2019) Is 5% dextrose prolotherapy effective for radicular low back pain? Gulhane Medical Journal 61(3): 123-127.
36. Lyftogt J (2007) Subcutaneous prolotherapy for achilles tendinopathy: the best solution? Australasian Musculoskeletal Medicine p. 107-109.
37. Weglein AD (2001) Neural prolotherapy. Journal of Prolotherapy 3(2): 639-643.
38. Paprottka KJ, Lehner A, Fendler WP, Harun I, Axel R, et al. (2016) Reduced periprocedural analgesia after replacement of water for injection with glucose 5% solution as the infusion medium for 90y-resin microspheres. J Nucl Med 57(11): 1679-1684.
39. Chen SR, Shen YP, Ho TY, Chen LC, Wu YT (2018) Ultrasound-guided perineural injection with dextrose for treatment of radial nerve palsy: A case report. Medicine (Baltimore) 97(23): e10978.
40. Wu D, Lee S, Luo J, Xia H, Gushchina S, et al. (2018) Intraneural injection of atp stimulates regeneration of primary sensory axons in the spinal cord. J Neurosci 38(6): 1351-1365.
41. Wu YT, Ho TY, Chou YC, Ming JK, Tsung YL, et al. (2017) Six-month efficacy of perineural dextrose for carpal tunnel syndrome: a prospective, randomized, double-blind, controlled trial. Mayo Clin Proc 92(8): 1179-1189.
42. Solmaz İ, Akpancar S, Örsçelik A, Yener KÖ, Gül D (2019) Dextrose 5% injections for failed back surgery syndrome: a consecutive case series. Eur Spine J 28(7): 1610-1617.
43. Maniquis SL, Dean RK, Jeffrey RH, Lyftogt J, Cassie GC, et al. (2016) Short term analgesic effects of 5% dextrose epidural injections for chronic low back pain: a randomized controlled trial. Anesth Pain Med 7(1): e42550.
44. Maniquis SL, Reeves KD, Rosen HJ, John L, Cassie GC, et al. (2018) Analgesic effect and potential cumulative benefit from caudal epidural d5w in consecutive participants with chronic low-back and buttock/leg pain. J Altern Complement Med 24(12): 1189-1196.
45. Wu YT, Ke MJ, Ho TY, Li TY, Shen YP, et al. (2018) Randomized double-blinded clinical trial of 5% dextrose versus triamcinolone injection for carpal tunnel syndrome patients. Ann Neurol 84(4): 601-610.
46. Shen YP, Li TY, Chou YC, Tsung YH, Ming JK, et al. (2019) Comparison of perineural platelet-rich plasma and dextrose injections for moderate carpal tunnel syndrome: A prospective randomized, single-blind, head-to-head comparative trial. J Tissue Eng Regen Med 13(11): 2009-2017.
47. Kim WM, Lee HG, Jeong CW, Kim CM, Yoon MH (2010) A randomized controlled trial of intra-articular prolotherapy versus steroid injection for sacroiliac joint pain. J Altern Complement Med (12): 1285-1290.
48. Tsai SW, Hsu YJ, Lee MC, Huang HE, Huang CC, et al. (2018) Effects of dextrose prolotherapy on contusion-induced muscle injuries in mice. Int J Med Sci 15(11): 1251-1259.
49. Thor JA, Mohamed HNH, Halil H, Suhaimi A (2017) Perineural injection therapy in the management of complex regional pain syndrome: a sweet solution to pain. Pain Med 18(10): 2041-2045.