Research Supports the Use of Naturopathic Medicine

IV vitamin C may support patients with renal disease.

Effect of Intravenous Vitamin C on Cytokine Activation and Oxidative Stress in End-Stage Renal Disease Patients Receiving Intravenous Iron Sucrose

Conner, T. A., McQuade, C., Olp, J., & Pai, A. B. (2012). Effect of intravenous vitamin C on cytokine activation and oxidative stress in end-stage renal disease patients receiving intravenous iron sucrose. Biometals, 25(5), 961-969. doi:10.1007/s10534-012-9562-6

Reticuloendothelial blockade in hemodialysis patients prevents optimal intravenous (IV) iron utilization. Vitamin C has emerged as a potential therapy to improve anemia treatment by enhancing iron mobilization. However, Vitamin C can act as a pro-oxidant in the presence of iron. This was a prospective, open-label, crossover study. Thirteen patients with end-stage renal disease on hemodialysis and four healthy controls were assigned to receive 100 mg of IV iron sucrose (IS) or 100 mg of IV IS co-administered with 300 mg of IV Vitamin C (IS + C) in random sequence. Both IS and IS + C induced serum cytokine activation accompanied by lipid peroxidation, however, IS + C induced higher plasma concentrations of F2-isoprostanes, IL-1, IL-10, and TNF-α post-infusion. Long-term safety studies of IV iron co-administered with Vitamin C are warranted.

IV vitamin C may support patients with iron deficiency/anemia

Intravenous Ascorbic Acid in Hemodialysis Patients with Functional Iron Deficiency: A Clinical Trial

Giancaspro, V., Nuzziello, M., Pallotta, G., Sacchetti, A., & Petrarulo, F. (2000). Intravenous ascorbic acid in hemodialysis patients with functional iron deficiency: a clinical trial. J Nephrol, 13(6), 444-449.

Recent studies suggest that intravenous ascorbic acid (IVAA) may circumvent rHuEpo resistance. The aim of our study was to show the effects of IVAA on FID and whether this results in a better correction of anemia in HD patients with stable hemoglobin (Hb) concentration and FID. Twenty-seven HD patients with serum ferritin >300 microg/l, transferrin saturation (TS) <20% and hemoglobin (Hb) <10 g/dL were selected andrandomly divided into two groups to enter a cross-over trial with IVAA. In group I IV vitamin C 500 mg was administered three times a week for three months and discontinued in the next three months of the study. Vitamin C was not given the first three months in group II (control group, first three months of the study), who then received 500 mg IV three times a week for the next three months. IVAA may partially correct FID and consequently help rHuEpo hyporesponsive anemia.

IV vitamin C is efficacious, safe and well-tolerated as a treatment for sepsis

Phase I Safety Trial of Intravenous Ascorbic Acid in Patients with Severe Sepsis

Fowler, A. A., 3rd, Syed, A. A., Knowlson, S., Sculthorpe, R., Farthing, D., DeWilde, C., . . . Natarajan, R. (2014). Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. Journal of translational medicine, 12, 32. doi:10.1186/1479-5876-12-32

Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis. Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury.

High-dose IV vitamin C is safe and well-tolerated for cancer patients

Phase I Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of High-Dose Intravenous Ascorbic Acid in Patients with Advanced Cancer

Stephenson, C. M., Levin, R. D., Spector, T., & Lis, C. G. (2013). Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol, 72(1), 139-146. doi:10.1007/s00280-013-2179-9

This phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy. Five cohorts of three patients received i.v. ascorbic acid administered at 1 g/min for 4 consecutive days/week for 4 weeks, starting at 30 g/m² in the first cohort. For subsequent cohorts, dose was increased by 20 g/m² until a maximum tolerated dose was found. Ascorbic acid administered i.v. at 1 g/min for 4 consecutive days/week for 4 weeks produced up to 49 mM ascorbic acid in patient’s blood and was well tolerated. The recommended dose for future studies is 70-80 g/m².

IV vitamin C may reduce chemotherapy-associated toxicity in cancer patients

High-Dose Parenteral Ascorbate Enhanced Chemosensitivity of Ovarian Cancer and Reduced Toxicity of Chemotherapy

Ma, Y., Chapman, J., Levine, M., Polireddy, K., Drisko, J., & Chen, Q. (2014). High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med, 6(222), 222ra218. doi:10.1126/scitranslmed.3007154

This study investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.

IV vitamin C is a safe and effective treatment for patients with septic shock

Pharmacokinetic Data Support 6-Hourly Dosing of Intravenous Vitamin C to Critically Ill Patients with Septic Shock

Hudson, E. P., Collie, J. T., Fujii, T., Luethi, N., Udy, A. A., Doherty, S., . . . Bellomo, R. (2019). Pharmacokinetic data support 6-hourly dosing of intravenous vitamin C to critically ill patients with septic shock. Crit Care Resusc, 21(4), 236-242.

Twenty-one patients with septic shock enrolled in a randomised trial of high dose vitamin C therapy in septic shock. Patients received 1.5 g intravenous vitamin C every 6 hours. Plasma samples were obtained before and at 1, 4 and 6 hours after drug administration, and vitamin C concentrations were measured by high performance liquid chromatography. The findings established that intravenous vitamin C (1.5 g every 6 hours) corrects vitamin C deficiency and hypovitaminosis C and provides an appropriate dosing schedule to achieve and maintain normal or elevated vitamin C levels in septic shock.

Evidence supports the use of vitamin C IV in the treatment of shingles (herpes zoster)

Intravenous Vitamin C in the Treatment of Shingles: Results of a Multicenter Prospective Cohort Study

Schencking, M., Vollbracht, C., Weiss, G., Lebert, J., Biller, A., Goyvaerts, B., & Kraft, K. (2012). Intravenous vitamin C in the treatment of shingles: results of a multicenter prospective cohort study. Med Sci Monit, 18(4), Cr215-224. doi:10.12659/msm.882621

Vitamin C is an immune-relevant micronutrient, which is depleted in viral infections and this deficiency seems to play a critical role in the pathogenesis of herpes infections and in the development of postherpetic neuralgia. The objective of this observational multicenter study was to evaluate the utilization, safety and efficacy of intravenously administrated vitamin C in patients with shingles. Between April 2009 and December 2010 16 general practitioners recorded data of 67 participants with symptomatic herpes zoster who received vitamin C intravenously for approximately 2 weeks in addition to standard treatment. The assessment of pain (VAS) and the dermatologic symptoms of shingles such as hemorrhagic lesions and the number of efflorescences were investigated in a follow-up observation phase of up to 12 weeks. The data presented here provide evidence that concomitant use of intravenously administered ascorbic acid may have beneficial effects on herpes zoster-associated pain, dermatologic findings and accompanying common complaints. To confirm our findings, randomized, placebo-controlled clinical studies are necessary.

IV vitamin C improved responsiveness to conventional treatments for hemodialysis

Effect of Intravenous Ascorbic Acid in Hemodialysis Patients with EPO-Hyporesponsive Anemia and Hyperferritinemia

Attallah, N., Osman-Malik, Y., Frinak, S., & Besarab, A. (2006). Effect of intravenous ascorbic acid in hemodialysis patients with EPO-hyporesponsive anemia and hyperferritinemia. Am J Kidney Dis, 47(4), 644-654. doi:10.1053/j.ajkd.2005.12.025

Although erythropoietin (EPO)-hyporesponsive anemia in hemodialysis patients most commonly results from iron deficiency, the contributory role of chronic inflammation and oxidative stress in its pathogenesis is poorly understood. We conducted an open-label prospective study to assess the effect of vitamin C, an antioxidant, on EPO-hyporesponsive anemia in hemodialysis patients with unexplained hyperferritinemia. 20 patients to receive standard care and 300 mg of intravenous vitamin C with each dialysis session (group 1) and 22 patients to receive standard care only (group 2). Study duration was 6 months. Monthly assessment included Hb level, mean corpuscular volume, iron level, iron-binding capacity, ferritin level, TSAT, and Hb content in reticulocytes. In addition, biointact parathyroid hormone, aluminum, C-reactive protein (CRP), and liver enzymes were measured every 3 months. In hemodialysis patients with refractory anemia and hyperferritinemia, vitamin C improved responsiveness to EPO, either by augmenting iron mobilization from its tissue stores or through antioxidant effects.

Patients with severe allergies may benefit from vitamin C IV

Intravenous Infusion of Ascorbic Acid Decreases Serum Histamine Concentrations in Patients with Allergic and Non-Allergic Diseases

Hagel, A. F., Layritz, C. M., Hagel, W. H., Hagel, H. J., Hagel, E., Dauth, W., . . . Raithel, M. (2013). Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases. Naunyn Schmiedebergs Arch Pharmacol, 386(9), 789-793. doi:10.1007/s00210-013-0880-1

In the present study, we systematically investigated for the first time the effect of 7.5 g of intravenously administered ascorbic acid on serum histamine levels (as detected by ELISA) in 89 patients (19 with allergic and 70 with infectious diseases). When all patients were grouped together, there was a significant decline in histamine concentration from 0.83 to 0.57 ng/ml×m2 body surface area (BSA, p<0.0001). The decrease in serum histamine concentration in patients with allergic diseases (1.36 to 0.69 ng/ml×m2 BSA, p=0.0007) was greater than that in patients with infectious diseases (0.73 to 0.56 ng/ml×m2 BSA, p=0.01). Furthermore, the decline in histamine concentration after ascorbic acid administration was positively correlated with the basal, i.e., pre-therapeutic, histamine concentration. Intravenous infusion of ascorbic acid clearly reduced histamine concentrations in serum and may represent a therapeutic option in patients presenting with symptoms and diseases associated with pathologically increased histamine concentration.

Vitamin C IV may benefit patients undergoing conventional treatment for pancreatic cancer

Phase I Evaluation of Intravenous Ascorbic Acid in Combination with Gemcitabine and Erlotinib in Patients with Metastatic Pancreatic Cancer

Monti, D. A., Mitchell, E., Bazzan, A. J., Littman, S., Zabrecky, G., Yeo, C. J., . . . Levine, M. (2012). Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLOS ONE, 7(1), e29794. doi:10.1371/journal.pone.0029794

Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy. 14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease. These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration.

Patients with atrial fibrillation may benefit from vitamin C IV treatment

Vitamin C Intravenous Treatment in the Setting of Atrial Fibrillation Ablation: Results from the Randomized, Double-Blinded, Placebo-Controlled CITRUS-AF Pilot Study

Trankle, C. R., Puckett, L., Swift-Scanlan, T., DeWilde, C., Priday, A., Sculthorpe, R., . . . Koneru, J. N. (2020). Vitamin C Intravenous Treatment In the Setting of Atrial Fibrillation Ablation: Results From the Randomized, Double-Blinded, Placebo-Controlled CITRIS-AF Pilot Study. J Am Heart Assoc, 9(3), e014213. doi:10.1161/jaha.119.014213

Ascorbic acid (AA) has shown promise in reducing inflammation but is untested in this population. We sought to test the feasibility, safety, and preliminary effects on inflammatory biomarkers in the CITRIS-AF pilot study. Patients scheduled to undergo AF ablation (N=20) were randomized 1:1 to double-blinded treatment with AA (200 mg/kg divided over 24 hours) or placebo. C-reactive protein and interleukin-6 levels were obtained before the first infusion and repeated at 24 hours and 30 days. Pain levels within 24 hours and early recurrence of AF within 90 days were recorded. igh-dose AA is safe and well tolerated at the time of AF ablation and may be associated with a blunted rise in C-reactive protein, although consistent findings were not seen in interleukin-6 levels. Further studies are needed to validate these findings and explore the potential benefit in improving clinically relevant outcomes.

Patients suffering from severe burns benefited widely from vitamin C IV

Reduction of Resuscitation Fluid Volumes in Severely Burned Patients Using Ascorbic Acid Administration: A Randomized, Prospective Study

Tanaka, H., Matsuda, T., Miyagantani, Y., Yukioka, T., Matsuda, H., & Shimazaki, S. (2000). Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg, 135(3), 326-331. doi:10.1001/archsurg.135.3.326

This study hypothesised that high-dose ascorbic acid (vitamin C) therapy (66 mg/kg per hour) attenuates postburn lipid peroxidation, resuscitation fluid volume requirements, and edema generation in severely burned patients. hirty-seven patients with burns over more than 30% of their total body surface area (TBSA) hospitalized within 2 hours after injury were randomly divided into ascorbic acid and control groups, ascorbic acid was infused during the initial 24-hour study period in the intervention group. Adjuvant administration of high-dose ascorbic acid during the first 24 hours after thermal injury significantly reduces resuscitation fluid volume requirements, body weight gain, and wound edema. A reduction in the severity of respiratory dysfunction was also apparent in these patients.

Anti-cancer action of vitamin C IV inhibits pancreatitis cancer growth

High Dose Parenteral Ascorbate Inhibited Pancreatitis Cancer Growth and Metastasis: Mechanisms and Phase I/IIa Study

Polireddy, K., Dong, R., Reed, G., Yu, J., Chen, P., Williamson, S., . . . Chen, Q. (2017). High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanisms and a Phase I/IIa study. Sci Rep, 7(1), 17188. doi:10.1038/s41598-017-17568-8

There is increasing interest in using high-dose intravenous ascorbate (IVC) in treating this disease partially because of its low toxicity. IVC bypasses bioavailability barriers of oral ingestion, provides pharmacological concentrations in tissues, and exhibits selective cytotoxic effects in cancer cells through peroxide formation. Here, we further revealed its anti-pancreatic cancer mechanisms and conducted a phase I/IIa study to investigate pharmacokinetic interaction between IVC and gemcitabine. Pharmacological ascorbate induced cell death in pancreatic cancer cells with diverse mutational backgrounds. Pharmacological ascorbate depleted cellular NAD+ preferentially in cancer cells versus normal cells, leading to depletion of ATP and robustly increased α-tubulin acetylation in cancer cells. While ATP depletion led to cell death, over-acetylated tubulin led to inhibition of motility and mitosis. Collagen was increased, and cancer cell epithelial-mesenchymal transition (EMT) was inhibited, accompanied with inhibition in metastasis. IVC was safe in patients and showed the possibility to prolong patient survival. There was no interference to gemcitabine pharmacokinetics by IVC administration. Taken together, these data revealed a multi-targeting mechanism of pharmacological ascorbate’s anti-cancer action, with minimal toxicity, and provided guidance to design larger definitive trials testing efficacy of IVC in treating advanced pancreatic cancer.

Vitamin C IV reduced pain amongst post-operative patients

Effect of Intravenous Vitamin C on Postoperative Pain in Uvulopalatopharyngoplasty with Tonsillectomy

Ayatollahi, V., Dehghanpour Farashah, S., Behdad, S., Vaziribozorg, S., & Rabbani Anari, M. (2017). Effect of intravenous vitamin C on postoperative pain in uvulopalatopharyngoplasty with tonsillectomy. Clin Otolaryngol, 42(1), 139-143. doi:10.1111/coa.12684

Postoperative pain is a common problem in hospitals. Adults undergoing uvulopalatopharyngoplasty (UPPP) with tonsillectomy experience an unacceptable level of intense postoperative pain, especially during the first 24 h after surgery. This study investigated the analgesic effects of vitamin C in patients undergoing UPPP and tonsillectomy. This study was done on forty patients that were evaluated in a randomised double-blinded clinical trial. According to this study, administration of vitamin C 3 g IV intraoperative reduced postoperative pain without increased side-effects in patients undergoing UPPP and tonsillectomy.

Patients with pancreatic cancer benefited from vitamin C IV treatments

Pharmacological Ascorbate Inhibits Pancreatic Cancer Metastases via a Peroxide-Mediated Mechanism

O’Leary, B. R., Alexander, M. S., Du, J., Moose, D. L., Henry, M. D., & Cullen, J. J. (2020). Pharmacological ascorbate inhibits pancreatic cancer metastases via a peroxide-mediated mechanism. Sci Rep, 10(1), 17649. doi:10.1038/s41598-020-74806-2

Pharmacological ascorbate (P-AscH^–, high-dose, intravenous vitamin C) is cytotoxic to tumor cells in doses achievable in humans. Phase I studies in pancreatic cancer (PDAC) utilizing P-AscH^– have demonstrated increases in progression free survival, suggesting a reduction in metastatic disease burden. The purpose of this study was to determine the effects of P-AscH^– on metastatic PDAC. Several in vitro and in vivo mechanisms involved in PDAC metastases were investigated following treatment with P-AscH^–. Serum from PDAC patients in clinical trials with P-AscH^– were tested for the presence and quantity of circulating tumor cell-derived nucleases. P-AscH^– inhibited invasion, basement membrane degradation, decreased matrix metalloproteinase expression, as well as clonogenic survival and viability during exposure to fluid shear stress. In vivo, P-AscH^– significantly decreased formation of ascites, tumor burden over time, circulating tumor cells, and hepatic metastases. We conclude that P-AscH^– attenuates the metastatic potential of PDAC and may prove to be effective for treating advanced disease.

IV vitamin C is a safe and effective treatment for fatigue

Intravenous Vitamin C Administration Reduces Fatigue in Office Workers: A Double-Blind Randomized Controlled Trial

Suh, S. Y., Bae, W. K., Ahn, H. Y., Choi, S. E., Jung, G. C., & Yeom, C. H. (2012). Intravenous vitamin C administration reduces fatigue in office workers: a double-blind randomized controlled trial. Nutr J, 11, 7. doi:10.1186/1475-2891-11-7

Studies of the efficacy of vitamin C treatment for fatigue have yielded inconsistent results. One of the reasons for this inconsistency could be the difference in delivery routes. Therefore, we planned a clinical trial with intravenous vitamin C administration. We evaluated the effect of intravenous vitamin C on fatigue in office workers in group of 141 healthy volunteers, the trial group received 10 grams of vitamin C with normal saline intravenously, while the placebo group received normal saline only. Since vitamin C is a well-known antioxidant, oxidative stress was measured. Fatigue score, oxidative stress, and plasma vitamin C levels were measured before intervention, and again two hours and one day after intervention. Adverse events were monitored. Intravenous vitamin C reduced fatigue at two hours, and the effect persisted for one day. There were no significant differences in adverse events between two groups. High dose intravenous vitamin C proved to be safe and effective against fatigue in this study.

Vitamin C IV appears to improve markers for mental stress

Ascorbic Acid Inhibits Vascular Remodeling Induced by Mental Stress in Overweight/Obese Men

Batista, G. M. S., Rocha, H. N. M., Storch, A. S., Garcia, V. P., Teixeira, G. F., Mentzinger, J., . . . Rocha, N. G. (2020). Ascorbic acid inhibits vascular remodeling induced by mental stress in overweight/obese men. Life Sci, 250, 117554. doi:10.1016/j.lfs.2020.117554

Mental stress (MS) is related to endothelial dysfunction in overweight/obese men. It is believed that the pro-oxidant profile, associated with an imbalance in the vascular remodeling process, may contribute to deleterious effects of MS on endothelial function. However, it is unknown whether administration of ascorbic acid (AA), a potent antioxidant, can prevent oxidative and remodeling dysfunction during MS in these subjects. AA appears to minimize the oxidative imbalance and vascular remodeling induced by MS.

Patients with coronary heart disease benefited from vitamin C IV prior to surgery

The Effect of Intravenous Vitamin C Infusion on Periprocedural Myocardial Injury for Patients Undergoing Elective Percutaneous Coronary Intervention

Wang, Z. J., Hu, W. K., Liu, Y. Y., Shi, D. M., Cheng, W. J., Guo, Y. H., . . . Zhou, Y. J. (2014). The effect of intravenous vitamin C infusion on periprocedural myocardial injury for patients undergoing elective percutaneous coronary intervention. Can J Cardiol, 30(1), 96-101. doi:10.1016/j.cjca.2013.08.018

This small study has determined the effect of vitamin C on myocardial reperfusion in patients undergoing elective percutaneous coronary intervention (PCI). This study was to explore whether antioxidant vitamin C infusion before the procedure is able to affect the incidence of periprocedural myocardial injury (PMI) in patients undergoing PCI. In this prospective single-centre randomized study, 532 patients were randomized into 2 groups: the vitamin C group, which received a 3-g vitamin C infusion within 6 hours before PCI, and a control group, which received normal saline. The primary end point was the troponin I-defined PMI, and the second end point was the creatine kinase (CK)-MB-defined PMI. After PCI, the incidence of PMI was reduced, whether defined by troponin or by CK-MB, compared with the control group. Logistic multivariate analysis showed that preprocedure use of vitamin C is an independent predictor of PMI either defined by troponin I or by CK-MB. In patients undergoing elective PCI, preprocedure intravenous treatment with vitamin C is associated with less myocardial injury.

Patients with sciatic nerve pain due to piriformis syndrome benefited from IV mannitol in conjunction with oral B vitamins

Effect of Mannitol plus Vitamin B in the Management of Patients with Piriformis Syndrome

Huang, Z. F., Lin, B. Q., Torsha, T. T., Dilshad, S., Yang, D. S., & Xiao, J. (2019). Effect of Mannitol plus Vitamins B in the management of patients with piriformis syndrome. J Back Musculoskelet Rehabil, 32(2), 329-337. doi:10.3233/bmr-170983

Piriformis syndrome (PS) is an entrapment of the sciatic nerve by the piriformis muscle, or myofascial pain from the piriformis muscle. The aim of this study was to investigate the effectiveness of Mannitol plus Vitamins B regime in the management of PS. Twenty-two patients were included in this study and received 250 ml of mannitol 20% intravenous infusion for 5 days + Vitamins B (vitamin B1 10 mg + vitamin B2 10 mg + vitamin B12 50 μg PO) for 6 weeks. The clinical evaluations showed a significant reduction (p< 0.05) of tenderness, FAIR test, Beatty's maneuver, Freiberg's maneuver and Pace's maneuver when compared with baseline evaluation during the 3rd and 6th month follow-ups. A statistically significant improvement of pain was measured by NRS at resting (p< 0.001), at night (p< 0.001) and during activities (p< 0.001) and LAS with prolonged sitting (p< 0.001), standing (p< 0.001) and lying (p< 0.001). Concomitantly, swelling of SN revealed a significant reduction (p= 0.003) from 86.4% to 18.2%. Mannitol plus Vitamins B is effective in the management of piriformis syndrome, and it could be an alternative regime in treating PS.

High dose vitamin B12 therapy has been beneficial for patients with peripheral nerve injuries

Safety and efficacy of intravenous ultra-high dose methylcobalamin treatment for peripheral neuropathy: a phase I/II open label clinical trial

Shibuya, K., Misawa, S., Nasu, S., Sekiguchi, Y., Beppu, M., Iwai, Y., . . . Kuwabara, S. (2014). Safety and efficacy of intravenous ultra-high dose methylcobalamin treatment for peripheral neuropathy: a phase I/II open label clinical trial. Intern Med, 53(17), 1927-1931. doi:10.2169/internalmedicine.53.1951

No clinically effective treatment for promoting peripheral axonal regeneration has yet been established. Several experimental studies in vitro and in vivo have shown that a high dose of methylcobalamin (MeCbl), an analogue of vitamin B12, promotes axonal growth in peripheral nerve injury. We herein assessed the safety and efficacy of an ultra-high dose MeCbl treatment for patients with peripheral neuropathy and chronic axonal degeneration. Fourteen patients with immune-mediated or hereditary neuropathy in the chronic progressive or stable phase were enrolled. The primary endpoints were safety and improvement in the Medical Research Council (MRC) sum score in at least two muscles of the 20 muscles. Intravenous ultra-high dose MeCbl treatment is a safe and potentially efficacious therapy for patients with peripheral neuropathy and chronic axonal degeneration.

Patients with restlessness (akathisia) benefitted from high dose vitamin B

Vitamin B6 treatment in acute neuroleptic-induced akathisia: a randomized, double-blind, placebo-controlled study

Lerner, V., Bergman, J., Statsenko, N., & Miodownik, C. (2004). Vitamin B6 treatment in acute neuroleptic-induced akathisia: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry, 65(11), 1550-1554. doi:10.4088/jcp.v65n1118

Treatment strategies for acute neuroleptic-induced akathisia (NIA) contain anticholinergic (antimuscarinic) agents, dopamine agonists, gamma-aminobutyric acid (GABA)-ergic agents, beta-blockers, benzodiazepines, and serotonin antagonists. Nevertheless, many patients who suffer from acute akathisia fail to respond to treatment. In earlier studies, vitamin B6 was found to be effective in the treatment of neuroleptic-induced movement disorders. The purpose of this study was to evaluate the efficacy of vitamin B6 in the treatment of acute NIA. This is the first report of B6 as a treatment for NIA. Our preliminary results indicate that high doses of vitamin B6 may be useful additions to the available treatments for NIA, perhaps due to its combined effects on various neurotransmitter systems.

IV vitamin B12 showed comparable results to oral B9 for lowering homocysteine levels in hemodialysis patients

Pharmacological dose of vitamin B12 is as effective as low-dose folinic acid in correcting hyperhomocysteinemia of hemodialysis patients

Chiu, Y. W., Chang, J. M., Hwang, S. J., Tsai, J. C., & Chen, H. C. (2009). Pharmacological dose of vitamin B12 is as effective as low-dose folinic acid in correcting hyperhomocysteinemia of hemodialysis patients. Ren Fail, 31(4), 278-283. doi:10.1080/08860220902780010

Various regimens of folic acid-based and vitamin B12 (Vit B12) supplementations have been tried for lowering plasma homocysteine (Hcy) levels in uremic patients. However, the therapeutic potency of low-dose folic acid and Vit B12 alone is not properly understood. In this study, seventy-five patients on chronic hemodialysis (HD) therapy were randomized into three groups. After three months of treatment, plasma levels of Hcy decreased significantly in all three groups when compared with their baselines (all p < 0.05). Our study showed that IV pharmacologic dose of Vit B12 alone is as effective as low-dose folic acid in correcting hyperhomocysteinemia in chronic HD patients, and combining both drugs in low doses may have added effects.

Use of IV vitamin B, specifically B12, proved beneficial for end-stage kidney disease

Intravenous administration of vitamin B12 in the treatment of hyperhomocysteinemia associated with end-stage renal disease

Vrentzos, G. E., Papadakis, J. A., Vardakis, K. E., Maliaraki, N., Stilianou, K., Arvanitis, A., . . . Ganotakis, E. S. (2003). Intravenous administration of vitamin B12 in the treatment of hyperhomocysteinemia associated with end-stage renal disease. J Nephrol, 16(4), 535-539.

High serum levels of total homocysteine (tHcy) are common in dialysis patients with end-stage renal disease (ESRD). We assumed that these patients may have decreased response to conventional folic acid (FOL) and vitamin B12 (B12) administered orally. This study aimed to evaluate the efficacy of an intravenous (i.v.) B12 regimen in ESRD patients and compare it with the conventional regimen. Our results suggest that ESRD patients on dialysis have ‘B12 resistance’, and that they should have, in addition to their FOL therapeutic regimen, i.v. B12 treatment to reduce their elevated tHcy levels.

Therapeutic use of vitamin B1 may slow the development and progression of heart disease

Thiamine (vitamin B1) improves endothelium-dependent vasodilatation in the presence of hyperglycemia

Arora, S., Lidor, A., Abularrage, C. J., Weiswasser, J. M., Nylen, E., Kellicut, D., & Sidawy, A. N. (2006). Thiamine (vitamin B1) improves endothelium-dependent vasodilatation in the presence of hyperglycemia. Ann Vasc Surg, 20(5), 653-658. doi:10.1007/s10016-006-9055-6

Brachial artery vasoactivity (BAVA) is a reliable, noninvasive method of assessing endothelium-dependent vasodilatation (EDV) in vivo. Acute hyperglycemia, impaired glucose tolerance (IGT), and diabetes mellitus impair EDV, a precursor to atherosclerosis. Thiamine is a coenzyme important in intracellular glucose metabolism. The purpose of this study was to evaluate the effect of thiamine on BAVA in the presence of hyperglycemia. EDV was improved by thiamine in the presence of hyperglycemia in healthy subjects and in patients with IGT and NIDDM. The mechanism by which thiamine improves EDV is not due to a glucose-lowering effect as thiamine had no effect on EDV under normoglycemic conditions. Routine administration of thiamine might improve endothelial function and therefore slow the development and progression of atherosclerosis, especially in patients with IGT and NIDDM who are prone to develop accelerated atherosclerosis.

Use of oral (B9) and intramuscular B12 increased tolerance of the chemotherapeutic Pemetrexed (than those not taking B vitamins)

A phase I study of pemetrexed (LY231514) supplemented with folate and vitamin B12 in Japanese patients with solid tumours

Nakagawa, K., Kudoh, S., Matsui, K., Negoro, S., Yamamoto, N., Latz, J. E., . . . Fukuoka, M. (2006). A phase I study of pemetrexed (LY231514) supplemented with folate and vitamin B12 in Japanese patients with solid tumours. British journal of cancer, 95(6), 677-682. doi:10.1038/sj.bjc.6603321

The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of pemetrexed with folate and vitamin B12 supplementation (FA/VB(12)) in Japanese patients with solid tumours and to investigate the safety, efficacy, and pharmacokinetics of pemetrexed. Partial response was achieved for 5/23 evaluable patients (four with non-small cell lung cancer (NSCLC) and one with thymoma). The MTD/RD of pemetrexed were determined to be 1,200/1,000 mg m(-2), respectively, that is, a higher RD than without FA/VB(12) (500 mg m(-2)). Pemetrexed with FA/VB(12) showed a tolerable toxicity profile and potent antitumour activity against NSCLC in this study.

Vitamin B supports the treatment of diabetic neuropathy

Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial

Didangelos, T., Karlafti, E., Kotzakioulafi, E., Margariti, E., Giannoulaki, P., Batanis, G., . . . Kantartzis, K. (2021). Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients, 13(2). doi:10.3390/nu13020395

The aim of this study is to investigate the effect of normalizing vitamin B12 (B12) levels with oral B12 (methylcobalamin) 1000 μg/day for one year in patients with diabetic neuropathy (DN). Patients and methods: In this prospective, double-blind, placebo-controlled trial, 90 patients with type 2 diabetes on metformin for at least four years and both peripheral and autonomic DN were randomized to an active treatment group (n = 44) receiving B12 and a control group (n = 46) receiving a placebo. All patients had B12 levels less than 400 pmol/L. The treatment of patients with DN with 1 mg of oral methylcobalamin for twelve months increased plasma B12 levels and improved all neurophysiological parameters, sudomotor function, pain score, and QoL, but it did not improve CARTS and MNSIE.

IV Vitamin B benefited critically ill patients with heart disease

Intravenous thiamine is associated with increased oxygen consumption in critically ill patients with preserved cardiac index

Berg, K. M., Gautam, S., Salciccioli, J. D., Giberson, T., Saindon, B., & Donnino, M. W. (2014). Intravenous thiamine is associated with increased oxygen consumption in critically ill patients with preserved cardiac index. Ann Am Thorac Soc, 11(10), 1597-1601. doi:10.1513/AnnalsATS.201406-259BC

The aim of this study was to evaluate the effect of intravenous thiamine on oxygen consumption (o2) in critically ill patients. This was a small, exploratory open-label pilot study conducted in the intensive care units at a tertiary care medical center. Critically ill adults requiring mechanical ventilation were screened for enrolment. After 3 hours of baseline data collection, 200 mg of intravenous thiamine was administered. The administration of a single dose of thiamine was associated with a trend toward increase in o2 in critically ill patients. There was a significant increase in o2 in those patients with preserved or elevated CI. Further study is needed to better characterize the role of thiamine in oxygen extraction.

Patients with a thiamine deficiency who were administered IV vitamin B1 showed a reduction of lactate levels after septic shock and possibly decreased mortality

Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study

Donnino, M. W., Andersen, L. W., Chase, M., Berg, K. M., Tidswell, M., Giberson, T., . . . Cocchi, M. N. (2016). Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med, 44(2), 360-367. doi:10.1097/ccm.0000000000001572

The primary goal of this study was to determine if intravenous thiamine would reduce lactate in patients with septic shock. The primary outcome was lactate levels 24 hours after the first study dose. Of 715 patients meeting the inclusion criteria, 88 patients were enrolled and received study drug. There was no difference in the primary outcome of lactate levels at 24 hours after study start between the thiamine and placebo groups (median: 2.5 mmol/L [1.5, 3.4] vs. 2.6 mmol/L [1.6, 5.1], p = 0.40). There was no difference in secondary outcomes including time to shock reversal, severity of illness and mortality. 35% of the patients were thiamine deficient at baseline. In this predefined subgroup, those in the thiamine treatment group had statistically significantly lower lactate levels at 24 hours (median 2.1 mmol/L [1.4, 2.5] vs. 3.1 [1.9, 8.3], p = 0.03). There was a statistically significant decrease in mortality over time in those receiving thiamine in this subgroup (p = 0.047). Administration of thiamine did not improve lactate levels or other outcomes in the overall group of patients with septic shock and elevated lactate. In those with baseline thiamine deficiency, patients in the thiamine group had significantly lower lactate levels at 24 hours and a possible decrease in mortality over time.

Diabetics with peripheral neuropathy may benefit from IV alpha-lipoic acid

Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy

Ziegler, D., & Gries, F. A. (1997). Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes, 46 Suppl 2, S62-66. doi:10.2337/diab.46.2.s62

Antioxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes, providing a rationale for a potential therapeutic value in diabetic patients. The effects of the antioxidant alpha-lipoic acid (thioctic acid) were studied in two multicenter, randomized, double-blind placebo-controlled trials. In the Alpha-Lipoic Acid in Diabetic Neuropathy Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. In conclusion, intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is safe and effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in NIDDM.

IV alpha-lipoic acid has myriad health benefits for patients undergoing liver surgery/transplant

A-lipoic acid reduces postreperfusion syndrome in human liver transplantation – a pilot study

Casciato, P., Ambrosi, N., Caro, F., Vazquez, M., Müllen, E., Gadano, A., . . . Chuluyan, E. (2018). α-lipoic acid reduces postreperfusion syndrome in human liver transplantation – a pilot study. Transpl Int, 31(12), 1357-1368. doi:10.1111/tri.13314

A double-blind randomized controlled trial was performed to compare the safety and efficacy of α-lipoic acid (ALA) in liver transplantation (LT). The grafts were randomized to receive ALA or placebo before the cold ischemia time. Furthermore, patients transplanted with the ALA-perfused graft received 600 mg of intravenous ALA, while patients with the nonperfused graft received the placebo just before graft reperfusion. Hepatic biopsy was performed 2 h postreperfusion. Blood samples were collected before, during and 1 and 2 days after reperfusion. There was a decrease in PHD2 and an increase in alpha subunit of hypoxia-inducible factor-1 (HIF-1α) and baculoviral IAP repeat containing 2 (Birc2) transcript levels in the biopsies from the ALA-treated versus the control group of patients. Additionally, plasma levels of alarmins were lower in ALA-treated patients than control patients, which suggests that ALA-treated grafts are less inflammatory than untreated grafts. These results showed that ALA is safe for use in LT, induces gene changes that protect against hypoxia and oxidative stress and reduces the appearance of PRS.

Use of IV alpha-lipoic acid can improve the health of patients with circulatory dysfunction

A-lipoic acid can improve endothelial dysfunction in subjects with impaired fasting glucose

Xiang, G., Pu, J., Yue, L., Hou, J., & Sun, H. (2011). α-lipoic acid can improve endothelial dysfunction in subjects with impaired fasting glucose. Metabolism, 60(4), 480-485. doi:10.1016/j.metabol.2010.04.011

Several studies showed that impairment of endothelium-dependent arterial dilation (EDAD) exists in subjects with impaired fasting glucose (IFG). The crucial mechanism of this endothelial dysfunction remains unclear. We hypothesized that oxidative stress may be partially responsible for the impairment in EDAD in subjects with IFG. Thus, the present study was designed to assess whether the antioxidant α-lipoic acid can improve endothelial dysfunction in subjects with IFG. Sixty subjects with newly diagnosed IFG and 32 healthy individuals with normal glucose tolerance were enrolled. Subjects were randomized into 2 groups: untreated experimental group (n = 30) and α-lipoic acid treatment group (n = 30, α-lipoic acid 600 mg via intravenous infusion once a day for 3 weeks). We measured EDAD at baseline and after 3 weeks of intervention. At baseline, EDADs in α-lipoic acid and untreated experimental groups were 4.03% and 4.14%, respectively, which were significantly lower than that in controls (5.72%) (P < .001). After 3 weeks of intervention, there was a remarkable increase in EDAD (reaching 5.10%; ΔEDAD, 26.5%) (P < .01) and a significant decrease in plasma thiobarbituric acid reactive substances (TBARS) (29.1%) (P < .05) in IFG subjects treated with α-lipoic acid. Our data showed that IFG subjects have impaired endothelial function and that antioxidant α-lipoic acid can improve endothelial function through a decrease of oxygen-derived free radicals.

Patients with diabetic neuropathy had better outcomes and lower oxidative stress with IV alpha-lipoic acid

The efficacy of the intravenous administration of the trometamol salt of thioctic (alpha-lipoic) acid in diabetic neuropathy

Strokov, I. A., Kozlova, N. A., Mozolevskiĭ Iu, V., Miasoedov, S. P., & Iakhno, N. N. (1999). [The efficacy of the intravenous administration of the trometamol salt of thioctic (alpha-lipoic) acid in diabetic neuropathy]. Zh Nevrol Psikhiatr Im S S Korsakova, 99(6), 18-22.

A two-central randomised single-blind placebo-controlled study was conducted to assess efficacy of intravenous administration of trometamol salt of thioctic (alpha-lipoic) acid in 200 ml of physiological solution in 40 non-insulin dependent diabetic patients with symptomatic diabetic neuropathy. 10 patients of the control group received a physiological solution stained with 1% solution of riboflavin mononucleate (B2 vitamin) as placebo. Intravenous infusion was administered once daily during a period of 3 weeks. Diabetic neuropathy score was assessed at the entry as well as on days 7, 14 and 21 of therapy. Indicators of lipid peroxidation (oxidative stress)–malonic dialdehyde levels in plasma and membranes of erythrocytes. Electroneuromyography were performed. Most of the patients (29) noted symptomatic improvement after 7-10 infusions and on day 14 a significant reduction of the diabetic neuropathy score was noted in comparison to a baseline (p < 0.05). The further improvement of clinical picture had been pronounced by day 21 (p < 0.001). Improvement of symptom score was obtained in 39 patients (97.5%). The response rate in the control group was 40%. Parameters of oxidative stress and electroneuromyography improved significantly in the main group of patients, while these in placebo group remained without changes.

IV alpha-lipoic acid proved safe and effective for use with type-2 diabetes patients

Curative effect of alpha-lipoic acid on peripheral neuropathy in type 2 diabetes: a clinical study

Liu, F., Zhang, Y., Yang, M., Liu, B., Shen, Y. D., Jia, W. P., & Xiang, K. S. (2007). [Curative effect of alpha-lipoic acid on peripheral neuropathy in type 2 diabetes: a clinical study]. Zhonghua Yi Xue Za Zhi, 87(38), 2706-2709.

The goal of this study was to evaluate the effect of alpha-lipoic acid (ALA) on diabetic peripheral neuropathy (DPN). 95 type 2 diabetic patients complicated with DPN were randomly divided into 2 groups: treatment group (n = 52), receiving ALA 600 mg/d in normal saline 250 ml given by intravenous drip infusion once a day for 14 days; and control group (n = 43), administered with radix salviae 20 ml by intravenous drip infusion once a day for 14 days. Before and 7 and 14 days after the management fasting glucose (FPG), fasting insulin (FINS), supersensitive C reactive protein (sCRP), and HbA1c were measured, and total symptom score (TSS) and Michigan neuropathy screening instrument (MNSI) were used to evaluate the nervous symptoms. The findings suggest that ALA effectively improves the sensitive symptoms of DPN patients and is safe for most of the patients.

Use of IV alpha-lipoic acid with diabetics improved heart function

Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial

Heinisch, B. B., Francesconi, M., Mittermayer, F., Schaller, G., Gouya, G., Wolzt, M., & Pleiner, J. (2010). Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial. Eur J Clin Invest, 40(2), 148-154. doi:10.1111/j.1365-2362.2009.02236.x

The aim of this study was to investigate the effect of alpha-lipoic acid (ALA) treatment on endothelium-dependent and -independent vasodilatation, assessed by forearm blood flow (FBF), in patients with type 2 diabetes mellitus. A total of 30 subjects with type 2 diabetes were included in this randomized, controlled, double-blinded, parallel group study. FBF responses to intra-arterial acetylcholine (ACh) and glycerol trinitrate (GTN) were measured before and after 21 days of intravenous treatment with 600 mg alpha-lipoic acid or placebo. FBF responses were comparable at baseline. After treatment, FBF reactivity to ACh and GTN was unchanged in subjects receiving placebo. By contrast, ALA treatment increased endothelium-dependent vasodilatation to ACh (P < 0.05) but not to GTN compared with baseline. Intravenous ALA treatment improves endothelium-dependent vasodilatation in patients with type 2 diabetes, in the absence of effects on forearm vasomotor function. If this salutary action translates into vascular risk reduction remains to be established.

Patients with diabetes and erectile dysfunction benefited from IV alpha-lipoic acid treatments

Study on the clinical value of alprostadil combined with α-lipoic acid in treatment of type 2 diabetes mellitus patients with erectile dysfunction

Zhang, L., Zhang, H. Y., Huang, F. C., Huang, Q., Liu, C., & Li, J. R. (2016). Study on the clinical value of alprostadil combined with α-lipoic acid in treatment of type 2 diabetes mellitus patients with erectile dysfunction. Eur Rev Med Pharmacol Sci, 20(18), 3930-3933.

This study investigated the clinical value of alprostadil combined with the α-lipoic acid in treating type 2 diabetes mellitus with erectile dysfunction (DMED). We selected a total of 76 cases of patients who were admitted to endocrinology department of our hospital from June 2014 to June 2015 and diagnosed as DMED, and the average age was (46.7 ± 7.2) years old, average course of diabetes mellitus was (6.2 ± 2.8) years and average body mass index was (25.4 ± 1.3) kg/m2. 40 cases were randomly divided in the observation group while 36 cases were divided in the control group. They received blood glucose control therapy. The patients in the observation group received 60 mg alprostadil hydrochloride and 600 mg α-lipoic acid added into 250 mL normal saline, intravenous drip once per day for 2 weeks. The patients in the control group took tadalafil 5 mg orally, once per night for 2 weeks as a course of treatment. The effective rate of treatment in observation group is significantly higher than that in the control group (95.0% vs. 80.5%, p < 0.05). The score of IIEF-5, EHGS and the FMD value of brachial artery of the observation group after the operation were significantly higher than that of the control group (p < 0.05). The adverse reaction rate in the observation group was lower than that in the control group (7.5% vs. 13.9%, p < 0.05). Alprostadil combined with α-lipoic acid can improve DMED patients' vascular endothelial function and erection hardness to treat erectile dysfunction with less adverse effects and better safety.

IV alpha-lipoic acid shown as useful treatment for diabetic neuropathy

The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial

Ametov, A. S., Barinov, A., Dyck, P. J., Hermann, R., Kozlova, N., Litchy, W. J., . . . Ziegler, D. (2003). The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care, 26(3), 770-776. doi:10.2337/diacare.26.3.770

Since alpha-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(+) K(+) ATPase activity in experimental diabetes and in humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms. Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n = 60) or placebo (n = 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Intravenous racemic ALA, a potent antioxidant, rapidly and to a significant and meaningful degree, improved such positive neuropathic sensory symptoms as pain and several other neuropathic end points. This improvement of symptoms was attributed to improved nerve pathophysiology, not to increased nerve fiber degeneration. Because of its safety profile and its effect on positive neuropathic sensory symptoms and other neuropathic end points, this drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy.

Alpha-lipoic acid in the treatment of autonomic diabetic neuropathy (controlled, randomized, open-label study)

Tankova, T., Koev, D., & Dakovska, L. (2004). Alpha-lipoic acid in the treatment of autonomic diabetic neuropathy (controlled, randomized, open-label study). Rom J Intern Med, 42(2), 457-464.

The aim of this study was to evaluate the effect of alpha-lipoic acid in autonomic diabetic neuropathy in a controlled, randomized, open-label study. There was a significant improvement after treatment in the score for severity of cardiovascular autonomic neuropathy–from 6.43 +/- 0.9 to 4.24 +/- 1.8 (p<0.001), while in the control group it worsened from 6.18 +/- 1.3 to 6.52 +/- 0.9 (p>0.1). We found improvement in the Valsalva manoeuvre after treatment – from 1.05 +/- 0.04 to 1.13 +/- 0.08 (p<0.001); in the deep-breathing test -from 3.4 +/- 2.8 to 10.4 +/- 5.7 (p<0.001); and in the lying-to-standing test--from 0.99 +/- 0.01 to 1.01 +/- 0.02 (p>0.1), while in the control group there was no improvement. There was a beneficial effect of treatment on the change of systolic blood pressure at the lying-to-standing test–from 22.7 +/- 11.5 to 9.8 +/- 7.9 (p<0.001), while in the control group the change was 20.5 +/- 11.1 mmHg and 19.7 +/- 12.9 mmHg (p>0.1), respectively. We found improvement in diabetic enteropathy in six patients; in the complaints of dizziness, instability upon standing in six patients; in neuropathic edema of the lower extremities in four patients and in erectile dysfunction in four patients after treatment, while in the control group no change was reported in the symptoms and signs of autonomic neuropathy by the end of the follow-up period. Our results demonstrate that alpha-lipoic acid (Thiogamma) appears to be an effective drug in the treatment of the different forms of autonomic diabetic neuropathy.

Type-2 diabetes patients benefited from IV alpha-lipoic acid, and results indicated it may reduce cardiovascular disease risk

Treatment with alpha-lipoic acid reduces asymmetric dimethylarginine in patients with type 2 diabetes mellitus

Mittermayer, F., Pleiner, J., Francesconi, M., & Wolzt, M. (2010). Treatment with alpha-lipoic acid reduces asymmetric dimethylarginine in patients with type 2 diabetes mellitus. Transl Res, 155(1), 6-9. doi:10.1016/j.trsl.2009.08.004

Elevated asymmetric dimethylarginine (ADMA) concentrations predict cardiovascular events in patients with type 2 diabetes mellitus (T2DM). It has been shown that alpha-lipoic acid (ALA) improves endothelial function and oxidative stress in these patients. The present study investigated if ALA reduces ADMA in patients with T2DM. Plasma concentrations of ADMA, L-arginine and symmetric dimethylarginine (SDMA) were determined in a double-blind, randomized, placebo-controlled study in patients with T2DM. Intravenous ALA (n = 16) or placebo (n = 14) was administered daily for 3 weeks. ALA reduced ADMA while no change was observed with placebo (mean change -0.05 micromol/1[95% CI: -0.01; -0.09] vs. 0.01 micromol/1 [95% CI: -0.05; -0.03]; ANOVA p = 0.031). SDMA and L-arginine were not affected by ALA. In conclusion ALA treatment reduces ADMA in patients with T2DM. Long-term studies need to demonstrate if ALA may cause cardiovascular risk reduction.

Use of both IV alpha-lipoic acid and IV vitamin C improved outcomes for a patient with renal cell carcinoma

The Long-Term Survival of a Patient With Stage IV Renal Cell Carcinoma Following an Integrative Treatment Approach Including the Intravenous α-Lipoic Acid/Low-Dose Naltrexone Protocol

Berkson, B. M., & Calvo Riera, F. (2018). The Long-Term Survival of a Patient With Stage IV Renal Cell Carcinoma Following an Integrative Treatment Approach Including the Intravenous α-Lipoic Acid/Low-Dose Naltrexone Protocol. Integr Cancer Ther, 17(3), 986-993. doi:10.1177/1534735417747984

In this case report, we describe the treatment of a 64-year-old male patient diagnosed with metastatic renal cell carcinoma (RCC) in June of 2008. In spite of a left nephrectomy and the standard oncological protocols, the patient developed a solitary left lung metastasis that continued to grow. He was informed that given his diagnosis and poor response to conventional therapy, any further treatment would, at best, be palliative. The patient arrived at the Integrative Medical Center of New Mexico in August of 2010. He was in very poor health, weak, and cachectic. An integrative program-developed by one of the authors using intravenous (IV) α-lipoic acid, IV vitamin C, low-dose naltrexone, and hydroxycitrate, and a healthy life style program-was initiated. From August 2010 to August 2015, the patient’s RCC with left lung metastasis was followed closely using computed tomography and positron emission tomography/computed tomography imaging. His most recent positron emission tomography scan demonstrated no residual increased glucose uptake in his left lung. After only a few treatments of IV α-lipoic acid and IV vitamin C, his symptoms began to improve, and the patient regained his baseline weight. His energy and outlook improved, and he returned to work. The patient had stable disease with disappearance of the signs and symptoms of stage IV RCC, a full 9 years following diagnosis, with a gentle integrative program, which is essentially free of side effects. As of November 2017 the patient feels well and is working at his full-time job.

Use of PRP proved more successful long term than cortisone injections for plantar fasciitis refractory to conservative treatment.

Monto RR. Platelet-rich plasma efficacy versus corticosteroid injection treatment for chronic severe plantar fasciitis. Foot Ankle Int. 2014 Apr;35(4):313-8. http://www.ncbi.nlm.nih.gov/pubmed/24419823 DOI: 10.1177/1071100713519778

Abstract

Background: Chronic plantar fasciitis is a common orthopedic condition that can prove difficult to successfully treat. In this study, autologous platelet-rich plasma (PRP), a concentrated bioactive blood component rich in cytokines and growth factors, was compared to traditional cortisone injection in the treatment of chronic cases of plantar fasciitis resistant to traditional nonoperative management.

Methods: Forty patients (23 females and 17 males) with unilateral chronic plantar fasciitis that did not respond to a minimum of 4 months of standardized traditional nonoperative treatment modalities were prospectively randomized and treated with either a single ultrasound guided injection of 3 cc PRP or 40 mg DepoMedrol cortisone. American Orthopedic Foot and Ankle Society (AOFAS) hindfoot scoring was completed for all patients immediately prior to PRP or cortisone injection (pretreatment = time 0) and at 3, 6, 12, and 24 months following injection treatment. Baseline pretreatment radiographs and MRI studies were obtained in all cases to confirm the diagnosis of plantar fasciitis.

Results: The cortisone group had a pretreatment average AOFAS score of 52, which initially improved to 81 at 3 months posttreatment but decreased to 74 at 6 months, then dropped to near baseline levels of 58 at 12 months, and continued to decline to a final score of 56 at 24 months. In contrast, the PRP group started with an average pretreatment AOFAS score of 37, which increased to 95 at 3 months, remained elevated at 94 at 6 and 12 months, and had a final score of 92 at 24 months.

Conclusions: PRP was more effective and durable than cortisone injection for the treatment of chronic recalcitrant cases of plantar fasciitis.

Level of evidence: Level I, prospective randomized comparative series.

Patients with mild knee osteoarthritis benefited from a reduction of pain and an improvement in function with PRP injections.

Gobbi A, Lad D, Karnatzikos G. The effects of repeated intra-articular PRP injections on clinical outcomes of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. 2014 Apr 20. http://www.ncbi.nlm.nih.gov/pubmed/24748286 DOI: 10.1007/s00167-014-2987-4

Abstract

Purpose: To assess the outcome of intra-articular platelet-rich plasma (PRP) injections into the knee in patients with early stages of osteoarthritis (OA) and to determine whether cyclical dosing would affect the end result.

Methods: This is a prospective, randomized study in which 93 patients (119 knees) were followed up for a minimum of 2 years. Fifty knees were randomly selected prior to the first injection, to receive a second cycle at the completion of 1 year. A cycle consisted of three injections, each given at a monthly interval. The outcome was assessed using Knee Injury and Osteoarthritis Outcome Score (KOOS), Visual Analogue Scale (VAS), Tegner and Marx scoring systems, recorded prior to the first injection and then at 12, 18 and 24 months.

Results: There was a significant improvement in all scores over time compared to the pre-treatment value (p < 0.001). At 12 months, both groups showed similar and significant improvement. At 18 months, except for KOOS (Symptoms) and Tegner score, all other parameters showed a significant difference between the two groups in favour of the patients who had received the second cycle (p < 0.001). At 2 years, the scores declined in both groups but remained above the pre-treatment value with no significant difference between the groups despite the patients with two cycles showing higher mean values for all the scores. Conclusion: Intra-articular PRP injections into the knee for symptomatic early stages of OA are a valid treatment option. There is a significant reduction in pain and improvement in function after 12 months, which can be further improved at 18 months by annual repetition of the treatment. Although the beneficial effects are ill sustained at 2 years, the results are encouraging when compared to the pre-treatment function.

Level of evidence: II.

Athletes with patellar tendonitis treated with PRP benefited from improvement in function and decrease in pain compared to treatment with Extracorporeal Shockwave Therapy (ESWT)

Vetrano M, Castorina A, Vulpiani MC, Baldini R, Pavan A, Ferretti A. Platelet-Rich Plasma Versus Focused Shock Waves in the Treatment of Jumper’s Knee in Athletes. Am J Sports Med. 2013 Feb 13. http://ajs.sagepub.com/content/early/2013/02/13/0363546513475345.abstract DOI: https://doi.org/10.1177/0363546513475345

Abstract

Background:

Tendinopathies represent a serious challenge for orthopaedic surgeons involved in treatment of athletes.

Purpose:

To compare the effectiveness and safety of platelet-rich plasma (PRP) injections and focused extracorporeal shock wave therapy (ESWT) in athletes with jumper’s knee.

Study Design:

Randomized controlled trial; Level of evidence, 1.

Methods:

Forty-six consecutive athletes with jumper’s knee were selected for this study and randomized into 2 treatment groups: 2 autologous PRP injections over 2 weeks under ultrasound guidance (PRP group; n = 23), and 3 sessions of focused extracorporeal shock wave therapy (2.400 impulses at 0.17-0.25 mJ/mm2 per session) (ESWT group; n = 23). The outcome measures were Victorian Institute of Sports Assessment–Patella (VISA-P) questionnaire, pain visual analog scale (VAS), and modified Blazina scale. A reviewer who was blinded as to the group allocation of participants performed outcome assessments before treatment and at 2, 6, and 12 months after treatment. Nonparametric tests were used for within-group (Friedman/Wilcoxon test) and between-group (Kruskal-Wallis/Fisher test) testing, and the significance level was set at .05.

Results:

The 2 groups were homogeneous in terms of age, sex, level of sports participation, and pretreatment clinical status. Patients in both groups showed statistically significant improvement of symptoms at all follow-up assessments. The VISA-P, VAS, and modified Blazina scale scores showed no significant differences between groups at 2-month follow-up (P = .635, .360, and .339, respectively). The PRP group showed significantly better improvement than the ESWT group in VISA-P, VAS scores at 6- and 12-month follow-up, and modified Blazina scale score at 12-month follow-up (P < .05 for all). Conclusion:

Therapeutic injections of PRP lead to better midterm clinical results compared with focused ESWT in the treatment of jumper’s knee in athletes.

Patients with knee osteoarthritis, who received PRP injections, showed diminished pain and increased quality of life.

Gobbi A, Karnatzikos G, Mahajan V and Malchira S. Platelet-Rich Plasma Treatment in Symptomatic Patients With Knee Osteoarthritis Preliminary Results in a Group of Active Patients. Sports Health: A Multidisciplinary Approach 2012 4: 162 http://sph.sagepub.com/content/4/2/162 DOI: https://doi.org/10.1177/1941738111431801

Abstract

Background: With increasing frequency, platelet-rich plasma (PRP) preparations have been used to treat cartilage lesions to regenerate tissue homeostasis and retard the progression of knee osteoarthritis (OA).

Purpose: To determine the effectiveness of intra-articular PRP injections in active patients with knee OA and to evaluate clinical outcomes in patients with and without previous surgical treatment for cartilage lesions.

Study Design: Case series.

Materials and Methods: Fifty patients with knee OA were followed for a minimum of 12 months. All were treated with 2 intra-articular injections of autologous PRP. Twenty-five patients had undergone a previous operative intervention for cartilage lesions, whereas 25 had not. Operated patients had undergone either cartilage shaving or microfracture. Multiple evaluative scores were collected at pretreatment and at 6 and 12 months posttreatment. The required sample of patients was determined beforehand by using statistical power analysis; International Knee Documentation Committee (subjective) score was defined as the primary parameter. A P value of less than 0.05 was considered statistically significant. General linear model–repeated measure test evaluated within-time improvement for each variable for all patients. Post hoc test with Bonferroni adjustment for multiple comparisons was performed to investigate the significance in improvement within time evaluations for each variable for the total sample. The differences in improvement between operated and nonoperated patients were also investigated, as were those between sexes.

Results: All patients showed significant improvement in all scores at 6 and 12 months (P < 0.01) and returned to previous activities. No significant difference in improvement was found between the evaluated subgroups (P < 0.01). Conclusions: The PRP treatment showed positive effects in patients with knee OA. Operated and nonoperated patients showed significant improvement by means of diminishing pain and improved symptoms and quality of life.

Clinical Relevance: There are only a few studies of PRP treatment for cartilage on osteoarthritic knees. Different PRP products might be more or less appropriate to treat different types of tissues and pathologies. The clinical efficacy of PRP remains under debate, and a standardized protocol has not yet been established.

PRP injections proved more effective and durable than cortisone for the treatment of severe chronic plantar fasciiti

Monto RR. Platelet-Rich Rich Plasma is More Effective than Cortisone for Chronic Severe Plantar Fasciitis. Paper presented at: The American Academy of Orthopaedic Surgeons; 2012 February 7-11; San Francisco, USA. http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=2841&sKey=09423cd2-c979-4c54-8fca-20e735438c71&cKey=3eb910a6-9b58-4d7b-a05a-65342f51a42d&mKey=BA8AA154-A9B9-41F9-91A7-F4A4CB050945

Abstract:

INTRODUCTION Chronic plantar fasciitis is a common but sometimes difficult condition to successfully treat. Platelet rich plasma (PRP), a concentrated bioactive component of autologous blood that is rich in cytokines and other growth factors, was compared with cortisone injection in the treatment of severe cases of plantar fasciitis resistant to traditional non-operative paradigms.

METHODS Thirty-six patients (16 males, 20 females) with severe chronic plantar fasciitis who had failed traditional non-operative treatment (rest, heel lifts, PT, NSAIDS, cam walker immobilization, night splinting, local modalities) were randomized into two study groups and evaluated prospectively. All patients had pre-treatment MRI and ultrasound studies consistent with plantar fasciitis. Group 1 was treated with a single ultrasound-guided injection of 40 mg methylprednisolone at the injury site and Group 2 was treated with a single ultrasound-guided injection of un-buffered autologous PRP at the injury site. All patients were then immobilized fully weight bearing in a cam walker for two weeks, started on eccentric home exercises and then allowed to return to normal activities as tolerated and without support.

RESULTS Group 1 had an average age of 59 (24-74) and had failed 5.4 months (4-24) of standard non-operative management and had pre-treatment AOFAS scores of 52 (24-60). The PRP group had an average age of 51 (21-67) and had failed 5.7 months (4-26) of standard non-operative management and had pre-treatment AOFAS scores of 37 (30-56). Post-treatment AOFAS scores in Group 1 initially improved to 81 (60-90) at three months but decreased to 74 (56-85) at six months and dropped further to 58 (45-77) at 12 months follow up. Post-treatment AOFAS scores in Group 2 improved to 95 (84-90) at three months and remained excellent at 94 (87-100) at six months and stayed at 94 (86-100) at 12 months follow up (CI 95% P=0.001). No patients were lost to follow up.

DISCUSSION AND CONCLUSION This study suggests that platelet rich plasma injection is significantly more effective and durable than cortisone injection for the treatment of severe chronic plantar fasciitis refractory to traditional non-operative management.

Patients with knee degeneration experienced reduced pain and increased knee function following PRP injection therapy

Filardo G, Kon E, Buda R, Timoncini A, Di Martino A, Cenacchi A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2011 Apr;19(4):528-35. Epub 2010 Aug 26. http://www.ncbi.nlm.nih.gov/pubmed/20740273 DOI: 10.1007/s00167-010-1238-6

Abstract

Purpose: Platelet-rich plasma (PRP) therapy is a simple, low-cost and minimally invasive method that provides a natural concentrate of autologous blood growth factors (GFs) that can be used to enhance tissue regeneration. In a previous analysis of a 12-month follow-up study, promising results were obtained when treating patients affected by knee degeneration with PRP intra-articular injections. The main purpose of this study was to investigate the persistence of the beneficial effects observed.

Methods: Of the 91 patients evaluated in the previous 12-month follow-up study, 90 were available for the 2-year follow-up (24 patients presented a bilateral lesion, in a total of 114 knees treated). All of the patients presented a chronic knee degenerative condition and were treated with three intra-articular PRP injections. IKDC and EQ-VAS scores were used for clinical evaluation. Complications, adverse events and patient satisfaction were also recorded.

Results: All of the evaluated parameters worsened at the 24-month follow-up: these parameters were at significantly lower levels with respect to the 12-month evaluation (the IKDC objective evaluation fell from 67 to 59% of normal and nearly normal knees; the IKDC subjective score fell from 60 to 51), even if they remained higher than the basal level. Further analysis showed better results in younger patients (P = 0.0001) and lower degrees of cartilage degeneration (P < 0.0005). The median duration of the clinical improvement was 9 months. Conclusions: These findings indicate that treatment with PRP injections can reduce pain and improve knee function and quality of life with short-term efficacy. Further studies are needed to confirm these results and understand the mechanism of action, and to find other application modalities, with different platelet and GF concentrations and injection timing, which provide better and more durable results.

Patients with tennis elbow experienced reduced pain and significantly more mobility with PRP injections (compared to corticosteroid injections).

Gosens T, Peerbooms JC, van Laar W, den Oudsten BL. Ongoing Positive Effect of Platelet-Rich Plasma Versus Corticosteroid Injection in Lateral Epicondylitis: A Double-Blind Randomized Controlled Trial With 2-year Follow-up. Am J Sports Med. 2011 Jun;39(6):1200-8. http://www.ncbi.nlm.nih.gov/pubmed/21422467 DOI: 10.1177/0363546510397173

Abstract

Background: Platelet-rich plasma (PRP) has been shown to be a general stimulation for repair and 1-year results showed promising success percentages.

Purpose: This trial was undertaken to determine the effectiveness of PRP compared with corticosteroid injections in patients with chronic lateral epicondylitis with a 2-year follow-up.

Study design: Randomized controlled trial; Level of evidence, 1.

Methods: The trial was conducted in 2 Dutch teaching hospitals. One hundred patients with chronic lateral epicondylitis were randomly assigned to a leukocyte-enriched PRP group (n = 51) or the corticosteroid group (n = 49). Randomization and allocation to the trial group were carried out by a central computer system. Patients received either a corticosteroid injection or an autologous platelet concentrate injection through a peppering needling technique. The primary analysis included visual analog scale (VAS) pain scores and Disabilities of the Arm, Shoulder and Hand (DASH) outcome scores.

Results: The PRP group was more often successfully treated than the corticosteroid group (P < .0001). Success was defined as a reduction of 25% on VAS or DASH scores without a reintervention after 2 years. When baseline VAS and DASH scores were compared with the scores at 2-year follow-up, both groups significantly improved across time (intention-to-treat principle). However, the DASH scores of the corticosteroid group returned to baseline levels, while those of the PRP group significantly improved (as-treated principle). There were no complications related to the use of PRP. Conclusion: Treatment of patients with chronic lateral epicondylitis with PRP reduces pain and increases function significantly, exceeding the effect of corticosteroid injection even after a follow-up of 2 years. Future decisions for application of PRP for lateral epicondylitis should be confirmed by further follow-up from this trial and should take into account possible costs and harms as well as benefits.

Use of PRP with osteoarthritic patients showed improvements in function and quality of life.

Wang-Saegusa A, Cugat R, Ares O, Seijas R, Cuscó X, Garcia-Balletbó M. Infiltration of plasma rich in growth factors for osteoarthritis of the knee short-term effects on function and quality of life. Arch Orthop Trauma Surg. 2011 Mar;131(3):311-7. Epub 2010 Aug 17. http://www.ncbi.nlm.nih.gov/pubmed/20714903 DOI: 10.1007/s00402-010-1167-3

Abstract

Purpose: Osteoarthritis (OA) is a highly prevalent, chronic, degenerative condition that generates a high expense. Alternative and co-adjuvant therapies to improve the quality of life and physical function of affected patients are currently being sought.

Methods: A total of 808 patients with knee pathology were treated with PRGF (plasma rich in growth factors), 312 of them with OA of the knee (Outerbridge grades I-IV) and symptoms of >3 months duration met the inclusion criteria and were evaluated to obtain a sample of 261 patients, 109 women and 152 men, with an average age of 48.39. Three intra-articular injections of autologous PRGF were administered at 2-week intervals in outpatient surgery. The process of obtaining PRGF was carried out following the Anitua Technique. Participants were asked to fill out a questionnaire with personal data and the following assessment instruments: VAS, SF-36, WOMAC Index and Lequesne Index before the first infiltration of PRGF and 6 months after the last infiltration.

Results: Statistically significant differences (P < 0.0001) between pre-treatment and follow-up values were found for pain, stiffness and functional capacity in the WOMAC Index; pain and total score, distance and daily life activities in the Lequesne Index; the VAS pain score; and the SF-36 physical health domain. There were no adverse effects related to PRGF infiltration. Conclusion: At 6 months following intra-articular infiltration of PRGF in patients with OA of the knee, improvements in function and quality of life were documented by OA-specific and general clinical assessment instruments. These favourable findings point to consider PRGF as a therapy for OA.

Patients with elbow pain showed significant benefit from PRP injections, suggesting PRP be used prior to surgical interventions.

Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006 Nov;34(11):1774-8. http://ajs.sagepub.com/content/34/11/1774.abstract DOI: https://doi.org/10.1177/0363546506288850

Abstract

Background

Elbow epicondylar tendinosis is a common problem that usually resolves with nonoperative treatments. When these measures fail, however, patients are interested in an alternative to surgical intervention.

Hypothesis

Treatment of chronic severe elbow tendinosis with buffered platelet-rich plasma will reduce pain and increase function in patients considering surgery for their problem.

Study Design

Cohort study; Level of evidence, 2.

Methods

One hundred forty patients with elbow epicondylar pain were evaluated in this study. All these patients were initially given a standardized physical therapy protocol and a variety of other nonoperative treatments. Twenty of these patients had significant persistent pain for a mean of 15 months (mean, 82 of 100; range, 60-100 of 100 on a visual analog pain scale), despite these interventions. All patients were considering surgery. This cohort of patients who had failed nonoperative treatment was then given either a single percutaneous injection of platelet-rich plasma (active group, n = 15) or bupivacaine (control group, n = 5).

Results

Eight weeks after the treatment, the platelet-rich plasma patients noted 60% improvement in their visual analog pain scores versus 16% improvement in control patients (P =. 001). Sixty percent (3 of 5) of the control subjects withdrew or sought other treatments after the 8-week period, preventing further direct analysis. Therefore, only the patients treated with platelet-rich plasma were available for continued evaluation. At 6 months, the patients treated with platelet-rich plasma noted 81% improvement in their visual analog pain scores (P =. 0001). At final follow-up (mean, 25.6 months; range, 12-38 months), the platelet-rich plasma patients reported 93% reduction in pain compared with before the treatment (P <. 0001). Conclusion

Treatment of patients with chronic elbow tendinosis with buffered platelet-rich plasma reduced pain significantly in this pilot investigation. Further evaluation of this novel treatment is warranted. Finally, platelet-rich plasma should be considered before surgical intervention.

This study shows platelet-rich fibrin treatments showed positive impacts for regenerating soft tissue defects.

Platelet-Rich Fibrin and Soft Tissue Wound Healing: A Systematic Review

Miron, R. J., Fujioka-Kobayashi, M., Bishara, M., Zhang, Y., Hernandez, M., &

Choukroun, J. (2017). Platelet-Rich Fibrin and Soft Tissue Wound Healing: A

Systematic Review. Tissue Eng Part B Rev, 23(1), 83-99.

https://doi.org/10.1089/ten.TEB.2016.0233

One area of research that has gained tremendous awareness in recent years is that of

platelet-rich fibrin (PRF), which has been utilized across a wide variety of medical

fields for the regeneration of soft tissues. This systematic review gathered all the

currently available in vitro, in vivo, and clinical literature utilizing PRF for soft tissue

regeneration, augmentation, and/or wound healing. In those clinical studies, 9 out of

the 13 studies (69.2%) demonstrated a statistically relevant positive outcome for the

primary endpoints measured. In total, 18 studies (58% of clinical studies) reported

positive wound-healing events associated with the use of PRF, despite using controls.

Furthermore, 27 of the 31 clinical studies (87%) supported the use of PRF for soft

tissue regeneration and wound healing for a variety of procedures in medicine and

dentistry. In conclusion, the results from the present systematic review highlight the

positive effects of PRF on wound healing after regenerative therapy for the

management of various soft tissue defects found in medicine and dentistry.

This analysis shows that PRP had significant positive benefits on knee injuries.

The Clinical Use of Platelet-Rich Plasma in Knee Disorders and Surgery-A

Systematic Review and Meta-Analysis

Trams, E., Kulinski, K., Kozar-Kaminska, K., Pomianowski, S., & Kaminski, R. (2020).

The Clinical Use of Platelet-Rich Plasma in Knee Disorders and Surgery-A Systematic

Review and Meta-Analysis. Life (Basel), 10(6). https://doi.org/10.3390/life10060094

The number of articles evaluating platelet-rich plasma (PRP) efficacy in the recovery

of knee disorders and during knee surgery has exponentially increased over the last

decade. A systematic review with meta-analyses was performed by assessing selected

studies of local PRP injections to the knee joint. The study was completed in

accordance with 2009 Preferred Reporting Items for Systematic Reviews and Meta-

Analyses (PRISMA) statement. A multistep search of PubMed, Embase, Cochrane

Database of Systematic Reviews, and Clinicaltrials.gov was performed to identify

studies on knee surgery and knee lesion treatment with PRP. Of the 4004 articles

initially identified, 357 articles focusing on knee lesions were selected and,

consequently, only 83 clinical trials were analyzed using the revised Cochrane risk-ofbias

tool to evaluate risk. In total, seven areas of meta-analysis reported a positive

effect of PRP. Among them, 10 sub-analyses demonstrated significant differences in

favor of PRP when compared to the control groups (p < 0.05). This study showed the

positive effects of PRP, both on the recovery of knee disorders and during knee

surgery; however further prospective and randomized studies with a higher number

of subjects and with lower biases are needed.

This research considers whether platelet-rich plasma therapy can reduce neuropathic pain.

Platelet-rich plasma and the elimination of neuropathic pain

Kuffler, D. P. (2013). Platelet-rich plasma and the elimination of neuropathic pain.

Mol Neurobiol, 48(2), 315-332. https://doi.org/10.1007/s12035-013-8494-7

This paper discusses the normal physiological cascade of trauma-induced events that

lead to chronic neuropathic pain and its eventual elimination, techniques being

studied to reduce or eliminate neuropathic pain, and how the application of plateletrich

plasma may lead to the permanent elimination of neuropathic pain. It concludes

that platelet-rich plasma eliminates neuropathic pain primarily by platelet- and stem

cell-released factors initiating the complex cascade of wound healing events, starting

with the induction of enhanced inflammation and its complete resolution, followed by

all the subsequent steps of tissue remodeling, wound repair and axon regeneration

that result in the elimination of neuropathic pain, and also by some of these same

factors acting directly on neurons to promote axon regeneration thereby eliminating

neuropathic pain.

An animal study shows that platelet-rich plasma improved skin and wound healing.

Platelet-rich plasma accelerates skin wound healing by promoting reepithelialization

Xu, P., Wu, Y., Zhou, L., Yang, Z., Zhang, X., Hu, X., . . . Cheng, B. (2020). Platelet-rich

plasma accelerates skin wound healing by promoting re-epithelialization. Burns

Trauma, 8, tkaa028. https://doi.org/10.1093/burnst/tkaa028

Autologous platelet-rich plasma (PRP) has been suggested to be effective for wound

healing. However, evidence for its use in patients with acute and chronic wounds

remains insufficient. The aims of this study were to comprehensively examine the

effectiveness, synergy and possible mechanism of PRP-mediated improvement of

acute skin wound repair. PRP treatment significantly reduced the production of

inflammatory cytokines interleukin-17A and interleukin-1β. An increase in the local

vessel intensity and enhancement of re-epithelialization were also observed in

animals with PRP administration and were associated with enhanced secretion of

growth factors such as vascular endothelial growth factor and insulin-like growth

factor-1. Moreover, PRP treatment ameliorated the survival and activated the

migration and proliferation of primary cultured ESCs, and these effects were

accompanied by the differentiation of ESCs into adult cells following the changes of

CD49f and keratin 10 and keratin 14. PRP improved skin wound healing by

modulating inflammation and increasing angiogenesis and re-epithelialization.

However, the underlying regulatory mechanism needs to be investigated in the

future. Our data provide a preliminary theoretical foundation for the clinical

administration of PRP in wound healing and skin regeneration.

A study which shows platelet-rich plasma as beneficial for treatment of and recovery from sciatica nerve pain.

Ultrasound-guided platelet-rich plasma injection and multimodality ultrasound

examination of peripheral nerve crush injury

Zhu, Y., Jin, Z., Wang, J., Chen, S., Hu, Y., Ren, L., . . . Wang, Y. (2020). Ultrasoundguided

platelet-rich plasma injection and multimodality ultrasound examination of

peripheral nerve crush injury. NPJ Regen Med, 5(1), 21.

https://doi.org/10.1038/s41536-020-00101-3

The goal of this study was to investigate the effects of serial ultrasound-guided PRP

injections of the appropriate concentration on the treatment of sciatic nerve crush

injury, and explore the value of multimodality ultrasound techniques in evaluating the

prognosis of crushed peripheral nerve. he neurological function and

electrophysiological recovery evaluation, and the comparison of the multimodality

ultrasound evaluation with the histological results of sciatic nerve crush injury were

performed to investigate the regenerative effects of PRP at different concentrations on

the sciatic nerve crush injury. Our results showed that the PRP with a 4.5-fold

concentration of whole blood platelets could significantly stimulate the proliferation

and secretion of SCs and nerve repair. The changes in stiffness and blood perfusion

were positively correlated with the collagen area percentage and VEGF expression in

the injured nerve, respectively. Thus, serial ultrasound-guided PRP injections at an

appropriate concentration accelerates the recovery of axonal function. Multimodality

ultrasound techniques provide a clinical reference for prognosis by allowing the

stiffness and microcirculation perfusion of crush-injured peripheral nerves to be

quantitatively evaluated.

A randomized, controlled study showing platelet-rich plasma reduced pain amongst patients with lumbar pain.

Lumbar Intradiskal Platelet-Rich Plasma (PRP) Injections: A Prospective, Double-

Blind, Randomized Controlled Study

Tuakli-Wosornu, Y. A., Terry, A., Boachie-Adjei, K., Harrison, J. R., Gribbin, C. K.,

LaSalle, E. E., . . . Lutz, G. E. (2016). Lumbar Intradiskal Platelet-Rich Plasma (PRP)

Injections: A Prospective, Double-Blind, Randomized Controlled Study. Pm r, 8(1), 1-

10; quiz 10. https://doi.org/10.1016/j.pmrj.2015.08.010

The aim of this study was to determine whether single injections of autologous

platelet-rich plasma (PRP) into symptomatic degenerative intervertebral disks will

improve participant-reported pain and function. Participants were randomized to

receive intradiskal PRP or contrast agent after provocative diskography. Data on pain,

physical function, and participant satisfaction were collected at 1 week, 4 weeks, 8

weeks, 6 months, and 1 year. Participants in the control group who did not improve at

8 weeks were offered the option to receive PRP and subsequently followed.

Participants who received intradiskal PRP showed significant improvements in FRI,

NRS Best Pain, and NASS patient satisfaction scores over 8 weeks compared with

controls. Those who received PRP maintained significant improvements in FRI scores

through at least 1 year of follow-up. Although these results are promising, further

studies are needed to define the subset of participants most likely to respond to

biologic intradiskal treatment and the ideal cellular characteristics of the intradiskal

PRP injectate.

A meta-analysis showing that platelet-rich plasma reduced pain, had no adverse side effects, and increased patient satisfaction amongst those with low back pain.

Efficacy of Platelet-rich Plasma for Low Back Pain: A Systematic Review and Metaanalysis

Xuan, Z., Yu, W., Dou, Y., & Wang, T. (2020). Efficacy of Platelet-rich Plasma for Low

Back Pain: A Systematic Review and Meta-analysis. J Neurol Surg A Cent Eur

Neurosurg, 81(6), 529-534. https://doi.org/10.1055/s-0040-1709170

Platelet-rich plasma (PRP) may be beneficial for patients with low back pain.

However, the results remain controversial. We conducted a systematic review and

meta-analysis to explore the efficacy of PRP for low back pain. Three RCTs involving

131 patients were included in the meta-analysis. Overall, compared with control

intervention for low back pain, PRP injection was found to reduce pain scores

significantly (mean difference: – 1.47; 95% confidence interval [CI], – 2.12 to – 0.81; p <

0.0001), improve the number of patients with > 50% pain relief at 3 months (risk

ratio [RR]: 4.14; 95% CI, 2.22-7.74; p < 0.00001), and offer relatively good patient

satisfaction (RR: 1.91; 95% CI, 1.04-3.53; p = 0.04). No increase in adverse events was

reported after PRP injection (RR: 1.92; 95% CI, 0.94-3.91; p = 0.07). Compared with

control intervention for low back pain, PRP injection was found to improve pain relief

and patient satisfaction significantly with no increase in adverse events.

A review which indicates platelet-rich plasma injections are safe and effective for low back pain.

Intradiscal platelet-rich plasma (PRP) injections for discogenic low back pain:

an update

Monfett, M., Harrison, J., Boachie-Adjei, K., & Lutz, G. (2016). Intradiscal platelet-rich

plasma (PRP) injections for discogenic low back pain: an update. Int Orthop, 40(6),

1321-1328. https://doi.org/10.1007/s00264-016-3178-3

The aim of this article is to provide an overview of clinical and translational research

on intradiscal platelet-rich plasma (PRP) as a minimally invasive treatment for

discogenic low back pain. Results: There is strong in vitro evidence that supports the

use of intradiscal PRP for discogenic low back pain. There are also promising findings

in select preclinical animal studies. A clinical study of 29 participants who underwent

intradiscal PRP injections for discogenic low back pain found statistically and

clinically significant improvements in pain and function through two years of followup.

Intradiscal PRP is a safe and a possibly effective treatment for discogenic low back

pain. Future studies are warranted to determine the best candidates for this

treatment, what the optimal injectate is and what relationships exist between patientreported

outcomes and radiological findings.

A study which shows that platelet-rich plasma is a promising regenerative therapy for lower back pain.

Intradiscal Platelet-Rich Plasma Injection for Discogenic Low Back Pain and

Correlation with Platelet Concentration: A Prospective Clinical Trial

Jain, D., Goyal, T., Verma, N., Paswan, A. K., & Dubey, R. K. (2020). Intradiscal

Platelet-Rich Plasma Injection for Discogenic Low Back Pain and Correlation with

Platelet Concentration: A Prospective Clinical Trial. Pain Med, 21(11), 2719-2725.

https://doi.org/10.1093/pm/pnaa254

Discogenic pain is common cause of low back ache and may result in significant

morbidity. Platelet-rich plasma (PRP) is an upcoming regenerative therapy that has

treatment potential for this condition. The objective of this study was to correlate

platelet concentration in intradiscal PRP injection with improvement in low back pain

and functional status at three and six months. Twenty patients completed the study.

The improvement in NRS and ODI scores positively correlated with platelet

concentrations in the PRP sample. We determined the correlation coefficient (r) of

platelet concentrations with a reduction in NRS at three months (r = 0.65) and six

months (r = 0.73) and in ODI score at three months (r = 0.72) and six months (r =

0.7). This study supports the use of intradiscal PRP for treatment of discogenic pain

with preferably higher platelet counts to elicit a favorable response.

A meta-analysis showing the effectiveness of platelet-rich plasma injection for lower back and extremity pain.

Do Regenerative Medicine Therapies Provide Long-Term Relief in Chronic Low

Back Pain: A Systematic Review and Meta-analysis

Sanapati, J., Manchikanti, L., Atluri, S., Jordan, S., Albers, S. L., Pappolla, M. A., . . .

Hirsch, J. A. (2018). Do Regenerative Medicine Therapies Provide Long-Term Relief

in Chronic Low Back Pain: A Systematic Review and Meta-analysis. Pain Physician,

21(6), 515-540.

This study aimed to assess the effectiveness of MSCs or PRP injections in the

treatment of low back and lower extremity pain. Twenty-one injection studies met

inclusion criteria. There were 12 lumbar disc injections, 5 epidural, 3 lumbar facet

joint, and 3 sacroiliac joint studies RESULTS: Evidence synthesis based on a singlearm

meta-analysis, randomized controlled trials (RCTs), and observational studies,

disc injections of PRP and MSCs showed Level 3 evidence (on a scale of Level I

through V). Evidence for epidural injections based on single-arm meta-analysis, a

single randomized controlled trial and other available studies demonstrated Level 4

(on a scale of Level I through V) evidence. Similarly, evidence for lumbar facet joint

injections and sacroiliac joint injections without meta-analysis demonstrated Level 4

evidence (on a scale of Level I through V). The findings of this systematic review and

single-arm meta-analysis shows that MSCs and PRP may be effective in managing

discogenic low back pain, radicular pain, facet joint pain, and sacroiliac joint pain,

with variable levels of evidence in favor of these techniques.

This blinded, controlled study compared the use of prolotherapy with placebo and showed significant reduction in pain on patients with rotator cuff injuries.

Dextrose Prolotherapy Versus Control Injections in Painful Rotator Cuff

Tendinopathy

Bertrand, H., Reeves, K. D., Bennett, C. J., Bicknell, S., & Cheng, A. L. (2016).

Dextrose Prolotherapy Versus Control Injections in Painful Rotator Cuff

Tendinopathy. Arch Phys Med Rehabil, 97(1), 17-25.

https://doi.org/10.1016/j.apmr.2015.08.412

The Use of Platelet Rich Plasma (PRP) for Individuals Following a Vehicular Accident

This study aimed to compare the effect of dextrose prolotherapy on pain levels and

degenerative changes in painful rotator cuff tendinopathy against 2 potentially active

control injection procedures. Persons (N=73) with chronic shoulder pain,

examination findings of rotator cuff tendinopathy, and ultrasound-confirmed

supraspinatus tendinosis/tear. Three monthly injections either (1) onto painful

entheses with dextrose (Enthesis-Dextrose), (2) onto entheses with saline (Enthesis-

Saline), or (3) above entheses with saline (Superficial-Saline). All solutions included

0.1% lidocaine. All participants received concurrent programmed physical therapy.

The 73 participants had moderate to severe shoulder pain (7.0±2.0) for 7.6±9.6 years.

There were no baseline differences between groups. Blinding was effective. At 9-

month follow-up, 59% of Enthesis-Dextrose participants maintained ≥2.8

improvement in pain compared with Enthesis-Saline (37%; P=.088) and Superficial-

Saline (27%; P=.017). Enthesis-Dextrose participants’ satisfaction was 6.7±3.2

compared with Enthesis-Saline (4.7±4.1; P=.079) and Superficial-Saline (3.9±3.1;

P=.003). USPRS findings were not different between groups (P=.734). In participants

with painful rotator cuff tendinopathy who receive physical therapy, injection of

hypertonic dextrose on painful entheses resulted in superior long-term pain

improvement and patient satisfaction compared with blinded saline injection over

painful entheses, with intermediate results for entheses injection with saline.

Dextrose prolotherapy may improve on the standard care of painful rotator cuff

tendinopathy for certain patients.

This review shows prolotherapy as beneficial for spinal stability and low back pain.

Lumbar instability as an etiology of low back pain and its treatment by

prolotherapy: A review

Hauser, R. A., Matias, D., Woznica, D., Rawlings, B., & Woldin, B. A. (2021). Lumbar

instability as an etiology of low back pain and its treatment by prolotherapy: A review.

J Back Musculoskelet Rehabil. https://doi.org/10.3233/bmr-210097

While proper diagnosis is key, diagnosing the underlying cause of low back pain may

often be unclear. In this review article, we discuss lumbar instability as an etiology of

low back pain and its treatment by prolotherapy. Our findings suggest that spinal

ligaments may be an underlying culprit in the development of lumbar instability with

resultant low back pain and associated disorders. In these cases, adequate treatment

consisting of non-biologic prolotherapy or cellular prolotherapy, including platelet

rich plasma (PRP), can be beneficial in restoring spinal stability and resolving chronic

low back pain.

This review confirmed prolotherapy as a cost-effective treatment for shoulder pain and an alternative to surgery.

Dextrose Prolotherapy for Chronic Shoulder Pain: A Case Report

Seenauth, C., Inouye, V., & Langland, J. O. (2018). Dextrose Prolotherapy for Chronic

Shoulder Pain: A Case Report. Altern Ther Health Med, 24(1), 56-60.

Shoulder pain is one of the most common pain complaints reported by patients.

Consensus is lacking on its ideal treatment, and many different treatments are

available and used. Prolotherapy is an injection-based therapy that has shown

significant results in treating many common musculoskeletal pain conditions,

including osteoarthritis, lateral epicondylosis, and low-back pain. The study intended

to evaluate the use of dextrose prolotherapy in the treatment of shoulder pain. The

research team performed a case study. The participant was a middle-aged male with a

long-term history of untreated shoulder pain. Injections were placed in the patient’s

glenohumeral joint space, the acromioclavicular joint, the subacromial space, and the

insertion of the supraspinatus. Each location was injected with a solution of 50%

dextrose diluted with 1% lidocaine, 0.25% bupivacaine, and 1 mg methylcobalamin.

The final concentration of dextrose in the solution was approximately 22.8%.

Following 3 sessions of prolotherapy, the patient reported a 90% reduction in pain

and full restoration of normal activity. The findings suggest that dextrose prolotherapy

may be an effective treatment for chronic shoulder pain and may be an alternative to

surgery or other more costly and invasive interventions.

This review shows prolotherapy is indicated for treatment in tendinopathies, knee and finger joint OA, and spinal/pelvic pain due to ligament dysfunction.

A Systematic Review of Dextrose Prolotherapy for Chronic Musculoskeletal Pain

Hauser, R. A., Lackner, J. B., Steilen-Matias, D., & Harris, D. K. (2016). A Systematic

Review of Dextrose Prolotherapy for Chronic Musculoskeletal Pain. Clin Med Insights

Arthritis Musculoskelet Disord, 9, 139-159. https://doi.org/10.4137/cmamd.S39160

The aim of this study was to systematically review dextrose (d-glucose) prolotherapy

efficacy in the treatment of chronic musculoskeletal pain. The RCTs were high-quality

Level 1 evidence (Physiotherapy Evidence Database ≥8) and found dextrose injection

superior to controls in Osgood-Schlatter disease, lateral epicondylitis of the elbow,

traumatic rotator cuff injury, knee OA, finger OA, and myofascial pain; in

biomechanical but not subjective measures in temporal mandibular joint; and

comparable in a short-term RCT but superior in a long-term RCT in low back pain.

Many observational studies were of high quality and reported consistent positive

evidence in multiple studies of tendinopathies, knee OA, sacroiliac pain, and iliac

crest pain that received RCT confirmation in separate studies. Eighteen studies

combined patient self-rating (subjective) with psychometric, imaging, and/or

biomechanical (objective) outcome measurement and found both positive subjective

and objective outcomes in 16 studies and positive objective but not subjective

outcomes in two studies. All 15 studies solely using subjective or psychometric

measures reported positive findings. Use of dextrose prolotherapy is, therefore,

supported for treatment of tendinopathies, knee and finger joint OA, and

spinal/pelvic pain due to ligament dysfunction. Efficacy in acute pain, as first-line

therapy, and in myofascial pain cannot be determined from the literature.

This review examines the pathophysiology of ligament laxity and indicates prolotherapy as a curative treatment option.

Chronic neck pain: making the connection between capsular ligament laxity and

cervical instability

Steilen, D., Hauser, R., Woldin, B., & Sawyer, S. (2014). Chronic neck pain: making the

connection between capsular ligament laxity and cervical instability. Open Orthop J,

8, 326-345. https://doi.org/10.2174/1874325001408010326

The objectives of this narrative review are to provide an overview of chronic neck

pain as it relates to cervical instability, to describe the anatomical features of the

cervical spine and the impact of capsular ligament laxity, to discuss the disorders

causing chronic neck pain and their current treatments, and lastly, to present

prolotherapy as a viable treatment option that heals injured ligaments, restores

stability to the spine, and resolves chronic neck pain. Therefore, we propose that in

many cases of chronic neck pain, the cause may be underlying joint instability due to

capsular ligament laxity. Currently, curative treatment options for this type of cervical

instability are inconclusive and inadequate. Based on clinical studies and experience

with patients who have visited our chronic pain clinic with complaints of chronic

neck pain, we contend that prolotherapy offers a potentially curative treatment option

for chronic neck pain related to capsular ligament laxity and underlying cervical

instability.

This review shows prolotherapy as a positive for tendinopathies.

Prolotherapy in primary care practice

Rabago, D., Slattengren, A., & Zgierska, A. (2010). Prolotherapy in primary care

practice. Prim Care, 37(1), 65-80. https://doi.org/10.1016/j.pop.2009.09.013

Prolotherapy is an injection-based complementary and alternative medical therapy for

chronic musculoskeletal pain. Prolotherapy techniques and injected solutions vary by

condition, clinical severity, and practitioner preferences; over several treatment

sessions, a fairly small volume of an irritant or sclerosing solution is injected at sites

on painful ligament and tendon insertions and in adjacent joint space during several

treatment sessions. Prolotherapy is becoming increasingly popular in the United

States and internationally and is actively used in clinical practice. Prolotherapy has

been assessed as a treatment for various painful chronic musculoskeletal conditions

that are refractory to “standard of care” therapies. Although anecdotal clinical success

guides the use of prolotherapy for many conditions, clinical trial literature supporting

evidence-based decision-making for the use of prolotherapy exists for low back pain,

several tendinopathies, and osteoarthritis.

This controlled research shows prolotherapy as a positive treatment option for rotator cuff injuries.

Effectiveness of prolotherapy in the treatment of chronic rotator cuff lesions

Seven, M. M., Ersen, O., Akpancar, S., Ozkan, H., Turkkan, S., Yıldız, Y., & Koca, K.

(2017). Effectiveness of prolotherapy in the treatment of chronic rotator cuff lesions.

Orthop Traumatol Surg Res, 103(3), 427-433.

https://doi.org/10.1016/j.otsr.2017.01.003

Rotator cuff lesions are one of the major causes of shoulder pain and dysfunction.

Numerous non-surgical treatment modalities have been described for chronic rotator

cuff lesions, but the debate continues over the optimal procedure. The aim of this

report is to present the results of prolotherapy in the treatment of chronic refractory

rotator cuff lesions. We recruited 120 patients with chronic rotator cuff lesions and

symptoms that persisted for longer than 6 months. Patients were divided into two

groups: one treated with exercise (control group; n=60) and the other treated with

prolotherapy injection (prolotherapy group; n=60). In the latter, ultrasound-guided

prolotherapy injections were applied under aseptic conditions. In the former, patients

received a physiotherapy protocol three sessions weekly for 12 weeks. Both groups

were instructed to carry out a home exercise program. Using a within-group

comparison, both groups achieved significant improvements over baseline, as

measured by the VAS, SPADI, WORC index, and shoulder range of motion (P<0.001).

Using a between-group comparison, a significant difference was found in the VAS

scores at baseline, weeks 3, 6, and 12, and last follow-up. In addition, significant

differences were found in the SPADIs and WORC indices at weeks 6 and 12 and the

last follow-up. Significant differences were found in shoulder abduction and flexion at

week 12 and last follow-up, and in internal rotation at last follow-up. In the

prolotherapy group, 53 patients (92.9%) reported excellent or good outcomes; in the

control group, 25 patients (56.8%) reported excellent or good outcomes.

This study shows prolotherapy is a safe and effective therapeutic option for tendons and bones.

Ultrasound-Guided Prolotherapy for Acromial Enthesopathy and

Acromioclavicular Joint Arthropathy: A Single-Arm Prospective Study

Hsieh, P. C., Chiou, H. J., Wang, H. K., Lai, Y. C., & Lin, Y. H. (2019). Ultrasound-

Guided Prolotherapy for Acromial Enthesopathy and Acromioclavicular Joint

Arthropathy: A Single-Arm Prospective Study. J Ultrasound Med, 38(3), 605-612.

https://doi.org/10.1002/jum.14727

Prolotherapy is an injection-based complementary treatment for various

musculoskeletal diseases. The aim of this study was to evaluate the therapeutic

efficacy of ultrasound-guided prolotherapy in the treatment of acromial enthesopathy

and acromioclavicular joint arthropathy. Thirty-one patients with chronic moderateto-

severe shoulder pain were recruited from September 2015 to September 2017.

Ultrasound-guided prolotherapy was performed by injecting 10 mL of a 15% dextrose

solution into the acromial enthesis of the deltoid or acromioclavicular joint capsule

aseptically. Prolotherapy was given in 2 sessions separated by a 1-month interval.

Twenty of the 31 patients reported substantial pain reduction without adverse effects

after the intervention. The mean VAS score reduction ± SD was 4.3 ± 2.6

(pretreatment, 6.8 ± 1.5; posttreatment, 2.5 ± 2.1; P < .01). Ultrasound-guided

prolotherapy with a 15% dextrose solution is an effective and safe therapeutic option

for moderate-to-severe acromial enthesopathy and acromioclavicular joint

arthropathy.

This controlled study shows that prolotherapy is not only a useful treatment short and long term for shoulder and rotator cuff injuries but is preferable over steroid treatments.

Comparison of the Effectiveness of Ultrasound-Guided Prolotherapy in

Supraspinatus Tendon with Ultrasound-Guided Corticosteroid Injection of

Subacromial Subdeltoid Bursa in Rotator Cuff-Related Shoulder Pain: A Clinical

Trial Study

Nasiri, A., Mohamadi Jahromi, L. S., Vafaei, M. A., Parvin, R., Fakheri, M. S., &

Sadeghi, S. (2021). Comparison of the Effectiveness of Ultrasound-Guided

Prolotherapy in Supraspinatus Tendon with Ultrasound-Guided Corticosteroid

Injection of Subacromial Subdeltoid Bursa in Rotator Cuff-Related Shoulder Pain: A

Clinical Trial Study. Adv Biomed Res, 10, 12. https://doi.org/10.4103/abr.abr_181_20

Shoulder pain is the third most common type of musculoskeletal disorder and rotator

cuff (RC) tendinopathy is the most frequent diagnosis. Ultrasound is the most

preferable guidance tool for diagnostic and interventional purposes. The aim of this

study is to compare the effectiveness of the prolotherapy injection with corticosteroid

injection in patients with RC dysfunction. Thirty to sixty-five-year-old patients with

chronic RC disease were divided into two groups. Ultrasound-guided dextrose

prolotherapy of supraspinatus tendon was done for one group and ultrasound-guided

corticosteroid injection in the subacromial bursa was done for the other groups. Visual

analog scale (VAS) and Shoulder Pain and Disability Index (SPADI) were evaluated for

both groups at baseline, 3 and 12 weeks after injections. Thirty-three patients were

included in the result. Both the groups showed significant improvement in VAS and

SPADI scores in 3 and 12 weeks after injections compared with preinjection times

with no difference between two groups neither in 3 weeks nor in 12 weeks after

injections. Both ultrasound-guided dextrose prolotherapy and CS injections are

effective in the management of RC-related shoulder pain in both short-term and longterm

with neither being superior to the other. Therefore, prolotherapy may be a safe

alternative therapy instead of corticosteroid injection due to lack of its side effects.

This study shows that prolotherapy reduced pain and provided disability relief for shoulder pain.

Effect of Hypertonic Dextrose Injection on Pain and Shoulder Disability in

Patients with Chronic Supraspinatus Tendinosis: A Randomized Double-Blind

Controlled Study

Lin, C. L., Chen, Y. W., Wu, C. W., Liou, T. H., & Huang, S. W. (2021). Effect of

Hypertonic Dextrose Injection on Pain and Shoulder Disability in Patients with

Chronic Supraspinatus Tendinosis: A Randomized Double-Blind Controlled Study.

Arch Phys Med Rehabil. https://doi.org/10.1016/j.apmr.2021.07.812

This study aimed to investigate the effect of hypertonic dextrose injection on pain and

disability in patients with chronic supraspinatus tendinosis. The secondary aim was to

evaluate its effect on the tendon range of motion (ROM) and morphology. The study

group exhibited significant improvements in the VAS (mean difference [MD], -2.1;

95% confidence interval [CI], -2.7 to -1.4; P<.001) and SPADI (MD, -11.6; 95% CI, -16.5

to -6.7; P<.001) scores compared with baseline scores at week 2. However, the effect

was not sustained to week 6. Flexion ROM increased at weeks 2 (MD, 14.1; 95% CI,

5.7-22.5; P<.001) and 6 (MD, 8.9; 95% CI, 2.4-15.4; P=.003) compared with baseline.

The thickness of the supraspinatus tendon improved at weeks 6 (MD, .50; 95% CI, .26-

.74; P<.001) and 12 (MD, .61; 95% CI, .37-.84; P<.001) compared with baseline. The

ratio of histograms also improved at weeks 6 (MD, .19; 95% CI, .06-.32; P=.002) and 12

(MD, .26; 95% CI, .10-.41; P<.001) compared with baseline. Hypertonic dextrose

injection could provide short-term pain and disability relief in patients with chronic

supraspinatus tendinosis. Ultrasound imaging at week 6 revealed changed tendon

morphology.

This study shows significant benefits from prolotherapy for the treatment of shoulder pain/rotator cuff injuries.

The effectiveness of prolotherapy on failed rotator cuff repair surgery

Akpancar, S., Örsçelik, A., Seven, M. M., & Koca, K. (2019). The effectiveness of

prolotherapy on failed rotator cuff repair surgery. Turk J Phys Med Rehabil, 65(4),

394-401. https://doi.org/10.5606/tftrd.2019.3222

The aim of the present study was to investigate the effectiveness of prolotherapy

injections in the treatment of failed rotator cuff repair surgery. Between May 2014 and

March 2016, a total of 15 patients (5 males, 10 females; mean age 49.4±10.7 years;

range, 33 to 71 years) with failed rotator cuff repair surgery who had at least six

months of complaints and were refractory to at least of three months of conservative

methods were included. Ultrasound-guided prolotherapy injections were performed

under aseptic conditions, and the patients were instructed to carry out a home-based

exercise program. Clinical assessment of shoulder function was performed using a

visual analog scale (VAS) for pain, Shoulder Pain and Disability Index (SPADI),

Western Ontario Rotator Cuff (WORC) Index, patient satisfaction and shoulder range

of motion. All patients were examined at baseline, at Week 3, 6, and 12 and at the

final follow-up visit. The intra-group comparison showed that the patients achieved

significant improvements at all time points, compared to baseline as measured by

VAS, SPADI, WORC index, and shoulder range of motion (p<0.001). Twelve patients

(80%) reported excellent or good outcomes. The results show that prolotherapy is

effective in the treatment of patients with failed rotator cuff repair surgery with

significant improvements in the shoulder functions and pain relief.

This study shows prolotherapy can be more effective than physiotherapy for chronic rotator cuff injuries. (2021)

Periarticular Neurofascial Dextrose Prolotherapy Versus Physiotherapy for the

Treatment of Chronic Rotator Cuff Tendinopathy: Randomized Clinical Trial

Kazempour Mofrad, M., Rezasoltani, Z., Dadarkhah, A., Kazempour Mofrad, R.,

Abdorrazaghi, F., & Azizi, S. (2021). Periarticular Neurofascial Dextrose Prolotherapy

Versus Physiotherapy for the Treatment of Chronic Rotator Cuff Tendinopathy:

Randomized Clinical Trial. J Clin Rheumatol, 27(4), 136-142.

https://doi.org/10.1097/rhu.0000000000001218

Rotator cuff tendinopathy is a common cause of shoulder pain. We aimed to compare

periarticular (neurofascial) dextrose prolotherapy versus physiotherapy for treatment

of chronic rotator cuff tendinopathy in the short term. We carried out a randomized

clinical trial with 2 arms at a university hospital. In total, 66 patients with chronic

rotator cuff tendinopathy, proven by magnetic resonance imaging, were randomly

allocated to 2 groups. The outcomes were change in shoulder pain intensity (primary)

and disability (secondary) index using a questionnaire for Shoulder Pain and

Disability Index. For physiotherapy, participants received superficial heat,

transcutaneous electrical nerve stimulation, and pulsed ultrasound. Also, they carried

out an exercise program, 10 sessions of 30 minutes for 3 weeks. For prolotherapy, we

used 8 mL of 12.5% dextrose and 40 mg of 2% lidocaine. The mixture was injected 2

times with 1-week interval superficially around the shoulder joint and to tender points

along the suprascapular nerve. Neurofascial dextrose was more effective than

physiotherapy for alleviating pain in 2 weeks (p < 0.001), and they were similar 3

months after the interventions (p = 0.055). For disability, dextrose was more effective

than physiotherapy 2 weeks and 3 months (both p < 0.001) after the interventions.

However, the changes in the physiotherapy group seemed to be more sustained. Both

interventions are effective for the short-term management of rotator cuff

tendinopathy. However, prolotherapy is more successful as the initial treatment.

Besides, the treatment time is much shorter for dextrose prolotherapy compared with

physiotherapy.

This study shows prolotherapy can be more effective than physiotherapy for chronic rotator cuff injuries. (2018)

Comparative Effectiveness of Ultrasound-Guided Intratendinous Prolotherapy

Injection with Conventional Treatment to Treat Focal Supraspinatus Tendinosis

George, J., Li, S. C., Jaafar, Z., & Hamid, M. S. A. (2018). Comparative Effectiveness of

Ultrasound-Guided Intratendinous Prolotherapy Injection with Conventional

Treatment to Treat Focal Supraspinatus Tendinosis. Scientifica (Cairo), 2018, 4384159.

https://doi.org/10.1155/2018/4384159

This study aimed to evaluate the efficacy of dextrose prolotherapy injection for focal

supraspinatus rotator cuff tendinosis via outcomes such as functional score, range of

movement, and real-time ultrasound parameters. 12 adult patients with focal

supraspinatus tendinosis recruited after they had less than 30% improvement in

functional (DASH) scores after one month of physiotherapy following initial

presentation. Seven patients had 0.5-1.0 ml of prolotherapy injection (12.5% dextrose,

0.5% lignocaine) injected into the area of focal tendinosis under ultrasound guidance.

Meanwhile, five patients continued standard physiotherapy with no intervention

performed. Regional area of echogenicity in decibels, DASH, range of movements of

the shoulder, pain, and sleep scores were measured at baseline and at 12 weeks. The

prolotherapy group showed significant improvement in shoulder abduction (p=0.030)

and an improvement in sleep score (p=0.027). The echogenicity of area of tendinosis

significantly increases at the end of treatment (p=0.009). However, there was a

nonsignificant reduction in pain score in the injection group (43.5%) and in the

control group (25%) at 12 weeks (p > 0.005). Ultrasound-guided intratendinous

prolotherapy injection significantly improves patient’s range of abduction and

improves sleep within 12 weeks of treatment compared to conventional

physiotherapy management.

Research Supports the Use of Naturopathic Medicine

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