The application of phenytoin in the treatment of diabetic ulcers

Dear Editors,

Phenytoin, a well‐known medicine for seizures, has been reported to have a positive therapeutic impact on diabetic foot ulcers in recent years through external application because of the enhancement of fibroblast proliferation 1, 2, collagen production 1, 2 and granulation tissue formation 1.

The agent has gained increasing clinical attention because it is inexpensive and easy to apply and its advantage of shortening wound healing time 1 as compared with the conventional treatments. However, till date, no consensus has been reached regarding phenytoin's effectiveness in the treatment of diabetic foot ulcers despite the reported safety of its topical use.

This study attempts to explore the efficacy of topical phenytoin in the treatment of diabetic foot ulcers based on medical literature review. The PubMed database was searched for articles in English from January 1980 to May 2015 using the key words ‘phenytoin’, ‘diabetic foot’, ‘ulcer’, ‘wound’ and ‘healing’. The cited references from collected articles were also cross‐searched. Laboratory‐based studies were excluded from our investigation. Four investigators were involved in this study. While one investigator was responsible for literature search, the other three analysed the available data from published studies, including the study design, study period, patient characteristics and the treatment outcomes.

Related studies were assigned to the appropriate ‘level of evidence’ according to the Oxford Centre for Evidence‐Based Medicine 2011 (http://www.cebm.net/ocebm‐levels‐of‐evidence). Totally, seven studies met the inclusion criteria (Table 1), including three randomised controlled trials (RCTs) (Level I) 1, 2, 3, one cohort study (Level II) 4, two case series (Level IV) 5, 6 and one case report (Level V) 7.

Table 1.

Studies investigating the therapeutic effects of topical phenytoin on wound healing

Authors	Year	Number of patients and grouping	Form or dosage of topical phenytoin	Treatment duration	Significance of treatment outcome	Level of evidence
Patil et al. 1	2013	Total 100: 50 (phenytoin); 50 (normal saline dressing)	Phenytoin powder mixed with normal saline: (0–5 cm2:100 mg; 5·1–9 cm2: 150 mg; 9·1–15 cm2: 200 mg; >15 cm2: 300 mg)	6 weeks or until complete healing	Discharge reduced in day 14 (< day 21) Average hospital stay: 20·04 days (<26·10 days). P < 0·005	I
Shaw et al. 2	2011	Total 65: 31 (phenytoin); 34 (conventional dressing)	Phenytoin‐containing (6 mg/cm2) alginate‐based, hydrogel dressing	16 weeks	No difference in ulcer closure rate or in ulcer area. P > 0·05	I
Pai et al. 3	2001	Total 70: 36 (phenytoin); 34 (talc and colloidal silicon dioxide)	Phenytoin powder mixed with normal saline: (0–5 cm2: 100 mg; 5·1–9 cm2: 150 mg; 9·1–15 cm2: 200 mg; >15 cm2: 300 mg)	6 weeks or until complete healing	No difference in reduction of ulcer area or in ulcer area. P > 0·05	I
Muthukumarasamy et al. 4	1991	Total 100: 50 (phenytoin); 50 (sterile occlusive dressing)	Phenytoin powder applied in a thin uniform layer to the ulcer surface	5 weeks	Mean time to complete healing: 21 days with phenytoin and 45 days with control. P <0·05 Negative wound cultures achieved earlier with phenytoin. P < 0·005	II
El‐Nahas et al. 5	2009	32	Phenytoin in the form of 2% aerosol powder	8 weeks	Eight patients achieving more than 50% reduction in ulcer size	IV
Younes et al. 6	2006	16	10% w/w phenytoin ointment	2–8 weeks prior to auto‐grafting	Graft survival rate: 100% in 12 patients; 80–90% in 3 patients; 60% in 1 patient	IV
Spaia et al. 7	2004	1	1–2 ampoules of phenytoin (used for intravenous anti‐convulsion) on ulcer open for 60 minutes before dressing	2 months	Healing accelerated and complete Eradication of bacterial colonies	V

Of the three RCTs, one has demonstrated significant improvement in wound healing by decreasing discharge, slough and microbial colonies through topical phenytoin application 1. Hospitalisation period was also shown to be significantly shorter in the phenytoin group than in the conventional normal saline wound‐dressing group (P < 0·005) 1. However, the other two RCTs did not suggest statistically significant differences in wound healing between the topical phenytoin group and the control group (P > 0·05) 2, 3. In the cohort study, the ulcer healing rate was faster in the phenytoin group than in the usual occlusive dressing group (P < 0·05) 4. In concert with this finding, the two case series and the case report all demonstrated positive therapeutic effects of phenytoin on accelerating wound healing 5, 6, 7. Moreover, the case report also highlighted the eradication of bacterial colonies from the wounds 7. No side effects, such as toxicity, were noted in the included studies.

Although a positive result of the literature review with evidence ranging from levels I to V in the current studies was found without increased morbidity, it was still difficult to draw a definite conclusion regarding the therapeutic effect of phenytoin on diabetic foot ulcers because of a wide variation in drug concentrations, the forms of application and the treatment duration. Besides, the included study did not compare the effect of phenytoin with that of other topical agents. Therefore, further studies are needed not only to evaluate phenytoin's effectiveness in a clinical setting but also to experimentally reveal its latent mechanism in order to get a clear picture of its role in the treatment of diabetic foot ulcers.

Yi‐Shan Liu, MD1, Tzong‐Shiun Li, MD, PhD2, Cheuk‐Kwan Sun, MD, PhD3, Kai‐Che Wei, MD, MS4, Chia‐Ju Liu, PhD5
1Department of Dermatology
E‐Da Hospital & I‐Shou University
Graduate Institute of Science Education and Environmental Education
National Kaohsiung Normal University
Kaohsiung, Taiwan
2Department of Plastic Surgery
China Medical University Hospital
Taichung, Taiwan
3Department of Emergency Medicine
E‐Da Hospital
Kaohsiung, Taiwan
4Department of Dermatology
Kaohsiung Veterans General Hospital
Kaohsiung, Taiwan
5Graduate Institute of Science Education and Environmental Education
National Kaohsiung Normal University
Kaohsiung, Taiwan
draliceliu@yahoo.com.tw