Topical phenytoin for wound healing1. Department of Pharmacology, Maulana Azad Medical College, New Delhi.2. Skin & VD Specialist, TNC Hospital, MCD, Delhi.
Ashima Bhatia MD1, Surya Prakash DVD2
Dermatology Online Journal 10 (1): 5
Oral phenytoin is used widely for the treatment of convulsive disorders and about half the patients treated develop gingival overgrowth as a side effect. The apparent stimulatory effect has prompted its assessment in wound healing. Studies have shown topical phenytoin to promote healing of decubitus ulcers, venous stasis ulcers, diabetic ulcers, traumatic wounds, burns, and leprosy trophic ulcers. The mechanism of action has been postulated to be multifactorial. The present literature indicates that topical phenytoin deserves further investigation as a wound-healing agent in controlled dose-finding clinical trials.
Non-healing or chronic wounds are a significant healthcare problem today; the quest for better wound-healing agents is perhaps one of the oldest challenges for medical practice. One such agent that has been tried in wound healing is phenytoin. Phenytoin (diphenylhydantoin) was introduced into therapy in 1937 for the effective control of convulsive disorders. A common side effect with phenytoin treatment for epilepsy is the development of fibrous overgrowth of gingiva, although mild skin and skull thickening may also occur. This apparent stimulatory effect of phenytoin on connective tissue suggested an exciting possibility for its use in wound healing.
In 1939 Kimball first observed that gingival hyperplasia occurred in some patients treated with phenytoin; this stimulated the study regarding the potential use of phenytoin in wound healing . Shapiro carried out the first controlled clinical trial in 1958, finding that periodontal patients with surgical wounds who were pretreated with oral phenytoin had less inflammation, less pain, and accelerated healing compared with controls . Subsequently, phenytoin was found to promote the healing of dental extraction sockets and to increase the tensile strength of experimental skin and corneal wounds [4, 5]. Accelerated fracture and periosteal healing with systematically administrated phenytoin was observed in several animal studies [6, 7, 8, 9].
The earliest clinical study of phenytoin in cutaneous wound healing used oral phenytoin sodium to treat venous stasis ulcers in 28 patients in a double-blind, placebo-controlled trial . At the end of 13 weeks, the mean-wound area in the treatment group decreased by 0.65 cm², whereas in the control group, the lesion area increased by 7.7 cm².
Subsequently, there have been studies and case reports of the use of topical phenytoin for a wide variety of soft tissue infections and ulcers. Bansal and Mukul compared topical phenytoin with sodium chloride (0.9 %) dressing in the treatment of leprosy trophic ulcers . In the phenytoin group, granulation tissue was well established and wound discharge was eliminated within 1 week whereas in the control group discharge persisted through the second and third weeks and comparable degree of granulation required 2 weeks. Comparable efficacy has been shown by Malhotra and Amin , Menezes et al.  and Bogert et al.  in trophic leprosy ulcers.
El Zayat examined the effects of topical phenytoin in comparison with chlorhexidine and hydrogen peroxide in fifteen patients with intractable decubitus ulcers and missile wounds . In the phenytoin group, time to healing ranged from 1 to 3 weeks, with only one of fifteen patients requiring skin grafting. In the control group, healing time was 6-8 weeks and five of fifteen patients required skin grafts. Positive wound cultures became negative in nine of eleven patients after 10 days of phenytoin treatment.
Phenytoin was tried in the treatment of gluteal abscesses secondary to intramuscular injection by Lodha et al. . The control patients were treated with eusol (15 %) and urea solution (4 %). The same degree of reduction in wound area was achieved in the phenytoin group at 10 days and in the control group at day 20.
Phenytoin has also been examined in the treatment of diabetic foot ulcers . Mean healing time was 21 days in the phenytoin group verses 45 days in the control group in which sterile occlusive dressings were used.
Pendse et al. compared phenytoin with sodium chloride (0.9 %) dressings in 75 patients with chronic wounds of various etiologies (burns, cellulitis, trauma, amputation stump, postoperative) . Negative cultures were achieved in 50 percent of phenytoin treated wounds (compared to 17 % of controls) by day 7. Oluwatosin et al. compared topical phenytoin with honey dressings for the treatment of chronic leg ulcers and found that phenytoin was superior to honey as a topical agent .
Second- and third-degree burn wounds were also treated with phenytoin and compared to silver sulfadiazine cream . In the second degree burns, the percent reduction in mean-burn area was 89.6 percent for the phenytoin sites versus 56.9 percent for the silver sulfadiazine treated wounds (p < 0.001).
Phenytoin may also be useful in enhancing the healing of clean surgical wounds . Phenytoin was compared with an occlusive dressing (Opsite™) and topical soframycin in the healing of split thickness skin autograft donor sites in 60 patients. Mean time to complete healing was 6.2 days in the phenytoin group compared with 8.6 days in the Opsite™ group and 12.6 days in the soframycin group.
Phenytoin has also been tried in healing of decubitus ulcers and compared with Duoderm™ dressings or triple antibiotic ointment applications . The mean + S.D time to healing in the phenytoin group was 35.3 + 14.3 days compared with 51.8 + 19.6 and 53.8 + 8.5 days for the Duoderm™ and triple antibiotic ointment groups, respectively.
Favorable therapeutic responses have been reported in open trials with oral phenytoin in patients with epidermolysis bullosa [23, 24, 25], however oral administration of this drug is not widely accepted as effective . An open trial with topical phenytoin in epidermolysis bullosa simplex patients suggested a quicker healing of the ulcers .
Mechanism of action
The mechanism by which phenytoin accelerates wound healing is unknown. Clinical, animal, and in vitro studies suggest that phenytoin may be involved in the healing process at several levels including stimulating fibroblast proliferation, enhancing the formation of granulation tissue, decreasing collagenase activity (by reducing its production or secretion or both), promoting deposition of collagen and other connective tissue components, decreasing bacterial contamination, and decreasing wound exudate [28, 29, 30]. Biopsies of phenytoin treated open wounds show neovascularization, collagenization, and decreased polymorphonuclear and eosinophil cell infiltration [16, 17, 20].
Shafer investigated the stimulatory effect of phenytoin sodium on cell lines from normal and neoplastic tissues . Phenytoin increased proliferation 50-90 percent in two fibroblast cell lines, but had no effect on cells derived from heart, kidney, lung, intestine, squamous epithelium, or four of five tumor cell lines. Vijayasingham et al. found no stimulation of proliferation of human dermal fibroblasts or epidermal keratinocytes in culture . They proposed that phenytoin may act indirectly in vivo on keratinocytes by affecting membrane transport of cations, which in turn alters cytokine and growth-factor activities that affect inflammatory cells. Alternatively, it is possible that only certain subgroups of functionally-distinct fibroblasts respond to phenytoin.
Moy et al. determined that the effect of phenytoin on human skin fibroblasts is both concentration and time dependent . At low phenytoin concentration (5mg/l) and short incubation times (3 hr), phenytoin markedly enhanced cell proliferation. However, at higher concentrations (> 25 mg/l) and longer incubation times (> 25 hr), a decrease in fibroblast proliferation occurred. Phenytoin also reduced collagenase activity, not by direct enzyme inhibition, but by decreasing the synthesis centrally via the pituitary-adrenal axis or by competitive antagonism of the glucocorticoid receptor .
A number of clinical studies indicate that phenytoin decreases the bacterial load of wounds [15, 16, 17, 18, 34]. Topical phenytoin was reported to eliminate Staphylococcus aureus, E. coli, Klebsiella spp. and Pseudomonas spp. from wounds within 7-9 days [15, 34]. In a guinea pig model of wound healing, it was found that phenytoin more readily cleared gram negative organisms than gram positive bacteria from wounds . It is unknown if phenytoin has intrinsic antibacterial activity, or if the effect of phenytoin on the bacterial load of wounds is mediated indirectly by effects on inflammatory cells and neovascularization [15, 34].
Local pain relief has also been observed with topical phenytoin therapy, which can be explained by its membrane-stabilizing action; the reduced inflammatory response may also contribute [22, 29]. Facilitation of nerve regeneration has also been reported with phenytoin .
Preparation and administration
The best method of delivery of topical phenytoin is not known. Phenytoin powder has been applied directly to wounds in a thin, uniform layer and then covered with gauze. Some authors have used pure phenytoin or phenytoin sodium powder, and other authors have used powder from phenytoin capsules. However, the powder from the capsules is reported to cause a white eschar-like coating. This can be prevented by mixing phenytoin with NaCl (0.9 %) and applying this with gauze . One report suggests that the use of phenytoin suspension can be convenient, but it contains several added ingredients. Injectable phenytoin has a high pH (about 12) and should not be used topically because it can damage skin . Modaghegh et al. compared four topical phenytoin formulations (gel, cream, phenytoin sodium powder, and phenytoin powder) in a rat model of wound healing and concluded that the phenytoin powder showed the most favorable results .
Bulk research-grade powder can be used, and is available in many countries. Phenytoin in a vehicle for topical application is also available in France. One suggested formula is the use of phenytoin powder (90 % to 100 %) with Polyox™. Polyox™ is a polymer that can bind water and help the powder maintain contact with the skin .
Side effects from topical phenytoin are rare. Some patients have a transient burning sensation when the powder is initially applied, but this can be prevented by using pure phenytoin powder instead of phenytoin sodium. A generalized rash that resolved when treatment was stopped has also been reported [22, 28, 30]. Hypertrophic granulation tissue was noted in 10-36 percent of patients in two studies [17, 18]. This is reversed by stopping treatment, and it is suggested that stopping treatment when the wound area is covered with a granulation base can prevent this effect.
Systemic absorption of topical phenytoin is not significant. Most studies that have monitored serum phenytoin levels during topical application have shown the levels to be undetectable. Only one case report showed any significant levels of serum phenytoin after topical phenytoin . This involved a massive pressure ulcer that required 12.5 grams per day of phenytoin to cover the wound. Despite this large topical dose, which exceeded by several fold the estimated lethal oral dose of phenytoin in adults (2-5 g), the serum concentration was only 4.3 mg/L 1 month after initiation of the topical treatment.
Topical phenytoin has proven useful for a wide variety of soft tissue wounds. Some of these include leprosy trophic ulcers, decubitus ulcers, diabetic foot ulcers, burns, traumatic wounds, war-related missile wounds, venous stasis ulcers, and abscesses. Topical phenytoin also appears to be potentially useful in epidermolysis bullosa simplex. However, the use of topical phenytoin for wound healing is not approved by the Food and Drug Administration at present. In a 1984 paper by an investigator in the FDA office of Orphan Products Development, wound healing was listed as an "important application for which phenytoin appears to be potentially useful." The general guidelines for the off-label use of pharmaceuticals are that "it is entirely proper if the proposed use is based on rational scientific theory, expert medical opinion, or controlled clinical studies." Thus, both topical and oral uses of phenytoin for wound healing are within the guidelines set forth by the FDA .
Currently, much attention and faith are being placed on the development of expensive topical molecular factors for wound healing. The efficacy of such agents still needs to be proven in clinical trials and the cost factor should be kept in mind. Phenytoin is cheap, easy to use, and readily available. Clinical studies using topical phenytoin therapy suggest that it may be useful for the treatment of both acute and chronic wounds of various etiologies. Although these results are encouraging, the efficacy of topical phenytoin therapy has yet to be confirmed by double-blind placebo-controlled studies. Large, controlled studies are needed to confirm the benefits of topical phenytoin in wounds of varied etiologies, as well as to determine the optimal dose and method of delivery.
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