Topical Naltrexone Is a Safe and Effective Alternative to Standard Treatment of Diabetic Wounds

Abstract

Objective: Diabetes affects more than 29 million individuals in the United States, resulting in healthcare costs approaching $245 billion. Approximately 15% of these individuals will develop a chronic, non-healing foot ulcer (diabetic foot ulcer [DFU]) that, if untreated, may lead to amputation. The current treatments for DFU are expensive, have significant side-effects, and often result in non-compliance. A new topical treatment is described that accelerates cutaneous wound repair and is disease modifying by targeting underlying aberrant diabetic pathways. Approach: The efficacy of naltrexone (NTX), an opioid receptor antagonist, and Regranex Ò was compared in preclinical studies using type 1 diabetic rats. Dorsal cutaneous wounds were treated topically with 0.03% NTX, Regranex, or moisturizing cream alone. Wound closure, DNA synthesis, and cytokine production were monitored. Results: Wound closure rates with topical NTX in type 1 diabetic rats were comparable to Regranex. Topical NTX accelerated DNA synthesis, as measured by BrdU incorporation, increased mast cells, and enhanced expression of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), a marker for angiogenesis. Regranex had little effect on DNA synthesis, mast cells, and VEGF expression relative to vehicle-treated wounds, and it only temporarily increased PDGF expression. Fibroblast growth factor expression was not altered by either treatment. Innovation: Topical application of 0.03% NTX cream accelerates diabetic wound closure. Conclusion: Blockade of the opioid growth factor (OGF)-OGF receptor (OGFr) axis utilizing 0.03% NTX cream is comparable to standard care in preclinical studies, and it provides a safe, inexpensive, and effective alternative for treatment of diabetic wounds.

Mast Cells in Diabetes and Diabetic Wound Healing

“…Omega-3 fatty acids significantly decreased the diabetic wound area by affecting the concentration of MCs [97]. Topical administration of 0.03% naltrexone, an opioid receptor antagonist, could accelerate diabetic wound closure by promoting deoxyribonucleic acid synthesis, increasing MCs, and enhancing the expression of PDGF and VEGF [98]. DSCG in subcutaneously mesh-implanted C57BL/6J mice decreased early inflammation and fibrotic responses [99].…”

Wearable Technology for Chronic Wound Monitoring: Current Dressings, Advancements, and Future Prospects

“…In numerous clinical trials, rhPDGF-BB has been shown to help in the treatment of chronic lower extremity diabetic ulcers by increasing the incidence of complete healing as well as functioning as a safe therapy that is well tolerated (Steed and Study Group, 1995 ; Smiell et al, 1999 ). Naltrexone (NTX) is an alternative therapy that is FDA approved for systemic application and is currently being evaluated for topical treatment (McLaughlin et al, 2017 ). Internationally, Trafermin (AdisInsight, 2016 ) and Nepidermin (AdisInsight, 2015 ) are also used for the treatment of decubitus wounds but are not FDA approved for clinical use in the US.…”

Harnessing the Power of Mast Cells in Unconventional Immunotherapy Strategies and Vaccine Adjuvants

“…Whether this was due to activation of mast cells or due to depletion of mast cell granules is unknown, as pre-operative injection resulted in quicker closure of perforations than post-operative injection. In a diabetic rat model, treatment with naltrexone, an opioid receptor antagonist, was as effective as the standard of care for improving wound healing [152]. Notably, naltrexone increased both the amounts of mast cells at the healing site and the amount of angiogenesis [152,153].…”

“…In a diabetic rat model, treatment with naltrexone, an opioid receptor antagonist, was as effective as the standard of care for improving wound healing [152]. Notably, naltrexone increased both the amounts of mast cells at the healing site and the amount of angiogenesis [152,153]. While it is not known whether naltrexone effects mast cells directly, it is likely that an increase in their numbers would improve healing in diabetic wounds which typically display lower amount of mast cells than non-diabetic models [152].…”

“…Notably, naltrexone increased both the amounts of mast cells at the healing site and the amount of angiogenesis [152,153]. While it is not known whether naltrexone effects mast cells directly, it is likely that an increase in their numbers would improve healing in diabetic wounds which typically display lower amount of mast cells than non-diabetic models [152]. Mast cells can also be used more directly to promote healing.…”