International Wound Journal ISSN 1742-4801

LETTER TO THE EDITOR

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 pro-
duction (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 phenytoins 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 pheny-
toin in the treatment of diabetic foot ulcers based on medical
literature review. The PubMed database was searched for arti-
cles in English from January 1980 to May 2015 using the key
words phenytoin, diabetic foot, ulcer, wound and heal-
ing. The cited references from collected articles were also

Table 1 Studies investigating the therapeutic effects of topical phenytoin on wound healing

Number of Form or dosage Signicance of Level of

Authors Year patients and grouping of topical phenytoin Treatment duration treatment outcome evidence

Patil et al. (1) 2013 Total 100: 50 Phenytoin powder mixed 6 weeks or until 1. Discharge reduced in day I
(phenytoin); 50 with normal saline: complete healing 14 (< day 21)
(normal saline (05 cm2 :100 mg; 2. Average hospital stay:
dressing) 519 cm2 : 150 mg; 2004 days (<2610 days).
9115 cm2 : 200 mg; P < 0005
>15 cm2 : 300 mg)
Shaw et al. (2) 2011 Total 65: 31 Phenytoin-containing 16 weeks No difference in ulcer closure I
(phenytoin); 34 (6 mg/cm2 ) rate or in ulcer area. P > 005
(conventional alginate-based,
dressing) hydrogel dressing
Pai et al. (3) 2001 Total 70: 36 Phenytoin powder mixed 6 weeks or until No difference in reduction of I
(phenytoin); 34 with normal saline: complete healing ulcer area or in ulcer area.
(talc and colloidal (05 cm2 : 100 mg; P > 005
silicon dioxide) 519 cm2 : 150 mg;
9115 cm2 : 200 mg;
>15 cm2 : 300 mg)
Muthukumarasamy 1991 Total 100: 50 Phenytoin powder 5 weeks 1. Mean time to complete II
et al. (4) (phenytoin); 50 applied in a thin healing: 21 days with
(sterile occlusive uniform layer to the phenytoin and 45 days
dressing) ulcer surface with control. P <005
2. Negative wound cultures
achieved earlier with
phenytoin. P < 0005

El-Nahas 2009 32 Phenytoin in the form of 8 weeks Eight patients achieving more IV
et al. (5) 2% aerosol powder than 50% reduction in ulcer
size
Younes 2006 16 10% w/w phenytoin 28 weeks prior to Graft survival rate: 100% in 12 IV
et al. (6) ointment auto-grafting patients; 8090% in 3
patients; 60% in 1 patient
Spaia et al. (7) 2004 1 12 ampoules of 2 months 1. Healing accelerated and V
phenytoin (used for complete
intravenous 2. Eradication of bacterial
anti-convulsion) on colonies
ulcer open for
60 minutes before
dressing

2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd doi: 10.1111/iwj.12531 1
Letter to the Editor
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) (13), one cohort study (Level II) (4), two case series
(Level IV) (5,6) and one case report (Level V) (7).
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 < 0005)
(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 > 005) (2,3). In the
cohort study, the ulcer healing rate was faster in the phenytoin
group than in the usual occlusive dressing group (P < 005)
(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 (57). 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 evi-
dence ranging from levels I to V in the current studies was found
without increased morbidity, it was still difficult to draw a def-
inite conclusion regarding the therapeutic effect of phenytoin
on diabetic foot ulcers because of a wide variation in drug con-
centrations, the forms of application and the treatment duration.
Besides, the included study did not compare the effect of pheny-
toin with that of other topical agents. Therefore, further studies
are needed not only to evaluate phenytoins effectiveness in a
clinical setting but also to experimentally reveal its latent mech-
anism in order to get a clear picture of its role in the treatment
of diabetic foot ulcers.
Acknowledgements
We herein declare no conflicts of interest and funding received
for this work from any organizations.
2 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd
Y.-S. Liu et al.
Yi-Shan Liu, MD1 , Tzong-Shiun Li, MD, PhD2 , Cheuk-Kwan
Sun, MD, PhD3 , Kai-Che Wei, MD, MS4 , Chia-Ju Liu, PhD5
1 Department of Dermatology
E-Da Hospital & I-Shou University
Graduate Institute of Science Education and Environmental
Education
National Kaohsiung Normal University
Kaohsiung, Taiwan
2 Department of Plastic Surgery
China Medical University Hospital
Taichung, Taiwan
3 Department of Emergency Medicine
E-Da Hospital
Kaohsiung, Taiwan
4 Department of Dermatology
Kaohsiung Veterans General Hospital
Kaohsiung, Taiwan
5 Graduate Institute of Science Education and Environmental
Education
National Kaohsiung Normal University
Kaohsiung, Taiwan
draliceliu@yahoo.com.tw
References
1. Patil V, Patil R, Kariholu PL, Patil LS, Shahapur P. Topical phenytoin
application in Grade I and II diabetic foot ulcers: a prospective study. J
Clin Diagn Res 2013;7:223840.
2. Shaw J, Hughes CM, Lagan KM, Stevenson MR, Irwin CR, Bell PM.
The effect of topical phenytoin on healing in diabetic foot ulcers: a
randomized controlled trial. Diabet Med 2011;28:11547.
3. Pai MR, Sitaraman N, Kotian MS. Topical phenytoin in diabetic ulcers:
a double blind controlled trial. Indian J Med Sci 2001;55:5939.
4. Muthukumarasamy MG, Sivakumar G, Manoharan G. Topical pheny-
toin in diabetic foot ulcers. Diabetes Care 1991;14:90911.
5. El-Nahas M, Gawish H, Tarshoby M, State O. The impact of topical
phenytoin on recalcitrant neuropathic diabetic foot ulceration. J Wound
Care 2009;18:337.
6. 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;12:5.
7. Spaia S, Eleftheriadis T, Pazarloglou M, Askepidis N, Ioannidis I,
Touboura A, Vayonas G. Phenytoin efficacy in treating the diabetic foot
ulcer of a haemodialysis patient. Nephrol Dial Transplant 2004;19:753.