Can Phenytoin Help Heal Diabetic And Venous Ulcers?

Allen Jacobs DPM FACFAS

Extemporaneous compounding offers the ability to individualize treatment for the specific needs of each patient. Frequently, compounding allows the creation of topical preparations that are otherwise not commercially available. Topical preparations can provide increased concentration within the wound as they have the ability to alter local wound dynamics and chronic wound physiology without systemic modification of the selected agents.1

Utilizing topical compounded medications, one can attain a variety of wound care objectives such as stimulation of epithelialization, stimulation of granulation tissue, upregulation of growth factors, reduction of bacterial or fungal bioburden, increased vascular perfusion, and local debridement. When utilizing topical compounds, clinician may achieve multiple objectives simultaneously.

Topical compounds include the following:

• phenytoin (Dilantin, Pfizer) to promote granulation tissue;
• misoprostol (Cytotec, Pfizer) to accelerate wound healing;
• metronidazole (Flagyl, Pfizer) to provide antimicrobial effects and reduce wound odor by limitation of anaerobic bacteria; or
• nifedipine (Procardia, Pfizer), which one can utilize to increase vascular perfusion to the wound.2

Additional examples of medications that one could add to a compounded wound formulation might include: lidocaine; tetracaine or bupivacaine for the reduction of pain; pentoxifylline (Trental, Sanofi-Aventis) to improve blood viscosity as well as synergistic action with calcium channel blockers; or the use of topical estrogen to increase rates of wound healing and stimulate collagen synthesis.

When indicated, one may include a variety of antibiotics such as metronidazole, vancomycin, gentamicin or ciprofloxacin (Cipro, Bayer) together with antifungal agents such as fluconazole (Diflucan, Pfizer) or terbinafine (Lamisil, Novartis).

When considering compound wound care therapy, the central question is what the treating healthcare provider wishes to accomplish for each wound at each stage of wound healing. In other words, it is possible to consider manipulation of the wound healing process rather than determining which pre-made product one will utilize. Compounding therefore allows for individualization of care for each patient. It is adjunctive to standard wound care therapies.

What The Research Says About Phenytoin For Wound Healing

A systematic review of phenytoin looking at Pubmed, Medline, Cinhal and the Cochrane database examined 14 randomized controlled trials on the use of phenytoin for wound healing.3 The conclusion was that phenytoin had moderate evidence to support its use for the treatment of diabetic ulcers, venous leg ulcers and necrotic wounds.

The stimulatory effects of the phenytoin were initially a side effect in the treatment of seizure disorders with gingival hyperplasia resulting from the utilization of oral phenytoin. Investigation has demonstrated that phenytoin stimulates collagen and total protein synthesis, stimulates hydroxyproline synthesis, increases fibroblastic activity, increases monocyte and macrophage production of platelet derived growth factors, increases interleukin 1 beta and increases myofibroblast production.4-6

Authors have shown that the incorporation of phenytoin into polyvinyl alcohol dressings stimulates fibroblast and myofibroblast production, resulting in more rapid achievement of both wound healing and the remodeling phase.7 Utilizing phenytoin impregnated dressings, researchers have noted crater formation of the epidermis, decreased necrosis and greater dermal accumulation of collagen.7

Physicians have utilized the stimulatory effects of phenytoin to increase the efficacy of skin grafting. In a study of 16 patients with large diabetic foot ulcerations, researchers applied phenytoin between two and eight weeks to the wounds, and subsequently applied skin grafts.8 Graft survival was 100 percent in 12 patients with a 90 percent take in three patients and a 60 percent take in the remaining patient. The authors concluded that phenytoin was safe and efficacious, and appeared to enhance the survival of split-thickness skin grafts in diabetic foot ulcerations. Personally, I have utilized phenytoin to increase the effectiveness of skin graft substitutes such as Dermagraft (Shire Regenerative Medicine), Apligraf (Organogenesis) and PriMatrix (TEI Biosciences).

In another study, 32 patients with a chronic diabetic ulceration received 2% topical phenytoin aerosol powder daily together with weekly debridement.9 Researchers also utilized offloading and a standard wound gauze dressing. Twenty-five percent of the patients achieved greater than a 50 percent reduction in wound size over eight weeks.

Another study compared phenytoin versus standard therapy utilizing either DuoDerm (ConvaTec) or a triple antibiotic.10 The time to healing with topical phenytoin was 35.3 days +/-14.3 days in comparison to 51.8 days +/-19.6 days with DuoDerm and 53.8 days +/-8.5 days with the triple antibiotic. The time to presentation of healthy granulation tissue with phenytoin averaged two to seven days and the time to healthy granulation tissue of the comparators averaged six to 21 days.

Phenytoin can treat venous leg ulcerations. In a study of 104 patients, researchers compared phenytoin impregnated dressings to saline dressings.11 At eight weeks, phenytoin treated patients had achieved 64.8 percent healing whereas the control group demonstrated 52 percent healing. Researchers noted that a more rapid reduction in surface area generally occurred in the phenytoin treated group of patients with venous leg ulcers.

In another study of ulcerations including diabetic, venous and arterial ulcers, researchers compared phenytoin to standard wound care absent phenytoin.12 Twenty-nine of 40 phenytoin treated ulcers achieved healing whereas only 10 of 35 ulcers treated with standard wound care achieved healing.

What You Should Know About Other Uses Of Phenytoin

Studies have demonstrated the effectiveness of phenytoin in providing more rapid therapeutic healing in better cosmetic results following the excision of melanocytic nevi on the face and back of the patients.13 In a rat model, researchers compared phenytoin with silver sulfadiazine, dexamethasone injection, and a combination of phenytoin and dexamethasone for the treatment of burns.14 Phenytoin demonstrated more rapid wound contracture, more rapid epithelialization and faster healing. The authors noted that the combination of phenytoin and dexamethasone was superior to dexamethasone alone.

Another study reported a successful use of 2% topical phenytoin for the treatment of recalcitrant chronic pyoderma gangrenosum.15 The authors noted that 66 percent healed at four weeks and 33 percent partially healed at four weeks. Researchers have also demonstrated that the use of 1% phenytoin in the rat model reduces post-mastectomy lymph node dissection seroma formation in comparison to saline.16

The wound healing stimulatory benefit of phenytoin also extends to medications similar in structure to phenytoin. With full-thickness excisional and incisional wounds in an experimental rat model, study authors noted that the use of phenobarbital and ethosuximide increased hydroxyproline and promoted collagen synthesis.17 The authors note that these medications are similar in structure to phenytoin.17

In Summary

Phenytoin appears to be effective in producing more rapid wound healing in diabetic foot ulcerations and venous leg ulcerations. In addition, it may be of benefit in the treatment of burns as well as ulcerations associated with pyoderma gangrenosum. It is possible that phenytoin may assist in successful skin grafting as well as the utilization of skin graft substitutes.

Phenytoin appears to be an inexpensive topical agent, which one may utilize to assist standard wound care therapy. Clinicians may also combine phenytoin topically with other agents such as antibiotics, antifungal agents, local anesthetics or medications to increase wound healing.

References

1. Chiu HY, Tsai TF. Topical use of systemic drugs in dermatology: a comprehensive review. J Am Acad Dermatol. 2011; 65(5):1048.

2. Wynn T, Thompson C. Case report: Wound care of a diabetic foot ulcer. Int J Pharma Compounding. 2004; 8(4):265-267

3. Shaw J, Hughes CM, Lagan KM, Bell PM. The clinical effect of topical phenytoin on wound healing: a systematic review. Br J Dermatol. 2007; 157(5):997-1004.

4. Akalin FA, Bozkurt FY, Sengun D, et al. Hydroxyproline and total protein levels in gingiva from patients treated with phenytoin and cyclosporine-A. J Nihon Univ Sch Dent. 1996; 38(1):21-30.

5. Iacopino AM, Doxey D, Cutler CW, et al. Phenytoin and cyclosporine A specifically regulate macrophage phenotype and expression of platelet-derived growth factor and interleukin-1 in vitro and in vivo: possible molecular mechanism of drug-induced gingival hyperplasia. J Periodontal. 1997; 68(1):78-83.

6. Dill RE, Iacopino AM. Myofibroblasts in phenytoin-induced hyperplastic connective tissue in the rat and in human gingival overgrowth. J Periodontal. 1997; 68(4):375-80.

7. Zahedi P, Rezaeian I, Jafari SH. In vitro and in vivo evaluations of phenytoin sodium-loaded electrospun PVA, PCL, and their hybrid nanofibrous mats for use as active wound dressings. J Materials Sci. 2013;48(8):3147-3159.

8. Younes N, Albsoul A, Badran D, Obedi S. Wound bed preparation with 10 percent phenytoin ointment increases the take of split thickness skin graft in large diabetic ulcers. Dermatol Online J. 2006; 12(6):5.

9. El-Nahas M, Gawish H, Tarshoby M, State O. The impact of topical phenytoin on recalcitrant neuropathic diabetic foot ulceration. J Wound Care. 2009; 18(1):33-37.

10. Rhodes RS, Heyneman CA, Culbertson VL, et al. Topical phenytoin treatment of stage II decubitus ulcers in the elderly. Ann Pharmacother. 2001; 35(6):675-81.

11. Hokkam E, El-Labban G, Shams M, et al. The use of topical phenytoin for healing chronic venous ulcerations. Int J Surg. 2011; 9(4):335-8.

12. Pendse AK, Sharma A, Sodani A, Hada S. Topical phenytoin in wound healing. Int J Dermatol.1993; 32(3):214-7.

13. Pereira CA, Alchorne Ade O. Assessment of the effect of phenytoin on cutaneous healing from excision of melanocytic nevi on the face and on the back. BMC Dermatol.2010; 10:7.

14. Meena K, Mohan AV, Sharath B, et al. Effect of topical phenytoin on burn wound healing in rats. Indian J Exp Biol. 2011; 49(1):56-59.

15. Fonseka HF, Ekanayake SM, Dissanayake M. Two percent topical phenytoin sodium solution in treating pyoderma gangrenosum: a cohort study. Int Wound J. 2010; 7(6):519-23.

16. Eser M, Tutal F, Kement M, et al. Effects of local phenytoin on seroma formation after mastectomy and axillary lymph node dissection: an experimental study on mice. BMC Surg. 2012; 12:25.

17. Ajwee DM, Disi AM, Qunaibi EA, Taha MO. Ethosuximide and phenobarbital promote wound healing via enhancing collagenization. Chem Biol Drug Des. 2012; 79(1):137-42.

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