Original Articles THE EFFECT OF PHENYTOIN ON HEALING OF WAR AND NON-WAR INTRACTABLE WOUNDS
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Volume 2, Number 2
Medical Journal of the Tabestan 1367
Islamic Republic of Iran Zelghadeh 1408
Summer 1988
Original Articles
THE EFFECT OF PHENYTOIN ON HEALING
OF
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WAR AND NON-WAR INTRACTABLE WOUNDS
S. MODAGHEGH, M.D., M.A. GHORAIAN, M.D., M. MOSHKGOU,
M.D., AND A. REZAIZADEH, M.D.
From the Departlllenl oj Medicine. Shahid Rahnamun Hospital; Iran Unil'enity or Medical Science'S. and Sina
Hospital. Tehran University of Medical Sciences. Tehran. Islalllic Repllblic of Iran.
ABSTRACT
Phenytoin (PHT), a drug in clinical use for over fifty years as an
anticonvulsant, has heen reported to promote the healing of skin and soft
tissue wounds, ulcers and second degree hurns.
We treated 19 patients with war-related missile wounds and 6 with
chronic, non-healing (previously treated at least for.') months with antihiotics
and hetadine or acetic acid dressing) civilian ulcers with topical phenytoin
sodium powder daily without antihiotic therapy for up to 4 weeks. Missile
wounds had a mean healing time of2 weeks and civilian intractahle ulcers, a
maximum healing time of4 weeks, compared to historical controlS requiring
6-� weeks for missile wounds and at least 5 months of non-effective previous
treatment for intractahle wounds.
Twenty two patients showed complete healing within four weeks. Three
required skin grafts for fim�1 closure. PHT provided rapid pain relief.
Although seventeen wounds had positive hacterial cultures prior to treat
ment, none were positive after one week of PHT treatment. No antihiotics
were required. We helieve wider use of this safe, inexpensive, readily
availahle, and easy-to-use wound healing agent is indicated.
MllRI, Vol.2, No.2, 81-86, 1988
were less painful. Histological examination revealed
INTRODUCTION
accelerated clot organization and neovascularization,
Phenytoin (PHT), used topically or orally, has been decreased inflammatory infiltrate, increased numbers
reported to enhance the healing of various types of of young fibroblasts, increased numbers of collagen
cutaneous ulcers, including venous stasis, decubitus, fibrils, and prominent epithelial proliferation.2
diabetic and trophic ulcers in leprosy, as well as second Subsequent work substantiated Shapiro's findings
degree burns. and extended the use of phenytoin to topical applica
Bodkin, in 1945, reported that phenytoin promoted toin in periodontal disease. :l.(, Much of this work was
healing in pruritus ani. I In 1958, Shapiro studied the done in East Germany and France in the 1970's. A
effects of oral phenytoin pretreatment on the healing of topical'preparation of phenytoin for use in periodontal
surgically-created gingival wounds in patients with disease is currently marketed in France.
periodontal disease. Wounds in the phenytoin-treated The benefits of topical PHT in the treatment of
patients not only showed accelerated healing, but also chronic skin ulcers and second-degree burns were
81
Phenytoin on wound healing
reported by Rodriguez-Norieg.a, Table I. Types of wounds.
Gonzalez, et all{ in 1983. Currently there are topical
phenytoin clinical trials being conducted for ulcers Type of wounds No. of Patients
'md/or burns in the Dominican RepublIc, Ghana,
,
. . '1-12
India, Mexico,and Snlanka,among other countnes. War wounds 19
Some work has also been done in the United States, Bed sores 3
Diabetic neuropa thy I
and further trials are being organized there.
Iatrogenic I
Because of these encouraging results, and because Machine injury I
of our need for easily applicable, efficacious, inexpen
sive and readily available topical agents for the treat
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Total 25
ment of wounds, we have conducted a clinical trial of
topical phenytoin in war and other wounds at the
Shahid Rahnamun Hospital in Tehran. It was our hope trois requiring 6-8 weeks. The non-warlesions that had
that the use of topical phenytoin would alleviate the been unresponsive to various treatments over a five
suffering of patients afflicted with such wounds. month period, r equired longer treatment periods; and
maximum healing time was 4 weeks.
PATIENTS AND METHODS The patient requiring the longest treatment (4
weeks) was a65 year old man with diabeticneuropathy.
Twenty-five patients were treated with topical
He had a deep w ound in the third interphalangeal space
sodium phenytoin in an open trial. Nineteen of these
of his left foot with an E.coji-positive culture. His
patients had war-related missile i?juries. The oth� r six
wound had progressively worsened despite six months
had the following wounds: decubitus ulcers (3), diabe
of antibiotic therapy and betadine dressing twice daily.
tic ulcer (I), iatrogenic (I) and industrial (machine)
He had been r eferred to us for amputation. With
injury (I) (see Table I). All the patients were male, and
phenytoin treatment and without antibiotic therapy,
age ranged from 18 to 65.
. his lesion was completely healed after four weeks and
Most of the war-injured patients were treated with
the culture became negative after one week. Amputa
topical phenytoin within ten days of the injury The six
: tion was not required.
patients with non-war wounds had previously been
In all wounds, healthy granulation tissue formed
treated for at least five months with various other
and wound exudate ceased by the end of the first week
therapies including antibiotic therapy and betadine
of PHT treatment. With regard to wound bacteriology,
and/or acetic acid dressing. Their lesions had not only
all 17 initially positive wound cultures (see Table II)
failed to improve, but they actually worsened.
were negative after one week of phenytoin treatment.
At the onset of phenytoin treatment, all antibiotics
As noted above, no antibiotics were used.
and antiseptic dressings were discontinued. Wound
Another important benefit of the topical applica
swabs were taken for bacterial cultures initially and
tion of phenytoin powder was the relief of pain.
repeated weekly during phenytoin treatment. W�und
Although the use of phenytoin sodium powder can
area was measured by planimetry in some patients
produce an initial burning sensation, this resolves
when possible, and initial wound size ranged from
within 5 minutes. Non-sodium containing phenytoin
12-700 cm2.
apparently does not produce burning, but was not
All wounds were debrided as necessary. Necrotic
avaliable to us for these patients.
tissue was removed until a clean tissue base and healthy
bleeding were observed. At this point, the wound was Two case reports serve to illustrate the effectiveness
. of the phenytoin powder:
cleansed with normal saline, dried, and covered with a
uniform, thin layer of phenytoin sodium powder.
Dressing change and phenytoin application was p�r
Case 1
A 25-year old man with muscle herniation secon
formed daily during the course of treatment, which
dary to a war injury had undergone surgical closure of
ranged from 2 to 4 weeks, depending on the wound.
the fascia of the anterior compartment of his left lower
RESULTS Table II. Wound culture results.
With phenytoin treatment, 22 of the 25 patients had Type of Bacteria
. No. of Cultures
�
complete wound healing within 2-4 wee s. The rema111-
ing 3 patients had a satisfactory granulatIOn �esponse to
. E.coli 6
topical phenytoin, but did require skin graft111g for f111al Staph coagUlase-positive 5
wound closure. In the missile wounds, where treatment Klebsiella 3
was usually begun within ten days of injur�, mean Pseudomonas 3
.
healing time was 2 weeks compared to hlstoncal con-
82
S. Mouaghegh. M.D. et al
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Fig. I,A. Contammated wound before treatment with PHT. Fig. I,B. One week after treatment with topical phenytoin.
. Clean
wound with granulation tissue.
leg. Subsequently he developed an anterior compart
ment syndrome requiring fasciotomy. Postoperative
ly, the wound became infected and did not heal. He
und�rwent eight surgical debridements and treatment
with various antibIOtics including gentamicin and
cephalosporins over a five-month period with no im
provement.
Because of his failure to improve, he Was referred to
our department. On admission, he had a 60 cm2 grossly
contaminated wound of the left anterior lower leg (Fig.
I,A). Tibia was exposed. The patient had a left
peroneal nerve palsy and could not extend the left great
,toe and foot. He was in severe pain, and had
hyperesthesia in the wound area.
After debridement, phenytoin powder was applied.
No antibiotics were used. Following a week of PHT
,treatment, the wound culture was negative, exudate
disappeared, and healthy granulation tissue appeared
in the floor and egges of the wound (Fig.l, B). The
,patient was free of pain.
,
After three weeks of PHT treatment, granulation
tissue filled the wound and it could be dosed with
sutures (Fig.I,C). Subseque�tly, there was functional
recovery of the left peroneal nerve, which had pre
viously shown no signs of regeneration. The patient
was now able to extend his left great toe and foot
(Fig. 1,C). Fig. I,C. After closure and complete healing.
83
Phenytion on wound healing
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Fig. 2,A. Contaminated wound before treatment with PHT. Fig. 2,B. Clean wound with granulation tissue,
ease 2
A 19-year old man was transferred to our depart
ment one week after several missile fragments had
created an extensive wound of the posterior left thigh.
There were two smaller wounds on the posterior left
calf. On examination the major wourid covered the
whole length and two thirds the circumference of the
left thigh posteriorly (Fig.2,A). By planiinetry it mea
sured 70 cm. 2 It was full of necrotic tissue and grossly
infected, as were the two smaller wounds. Cultures
revealed Pseudomonas. There was no sciatic nerve
fuction.
After extensive surgical debridement, phenytoin
sodium powder was applied. One week later healthy
granulation tissue had appeared and wound cultures
were negative (Fig. 2,B). Within two weeks, healthy
granulation tissue had covered the entire wound
(Fig. 2,C) and the patient underwent skin grafting for
wound closure (Fig. 2, O). Thereafter the wound
healed completely (Fig.2,E). When the patient was
ambulated, it was noted that there had been return of
sciatic nerve function.
Other than the initial burning sensation, there were
no adverse effects with the exception of one general
ized skin rash after the first application of the powder to
extensive bed sores in a paraplegic patient. The powder Fig. 2,C. Two weeks after phenyoin treatment-healthy granulation
application was discontinued and the rash resolved. tissue of thigh and leg.
84
S. Modaghegh, M.D. et al
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Fig. 2,D. The same wound following closure and skin grafting. Fig. 2,E. Site of the healed wound on the posterior aspect of the right
thigh.
DISCUSSION iology studies and wound biopsies would have been
'
valuable. However, our clinical observations were very
Phenytoin has a dramatic effect on the healing of c1e-ar: phenytoin is a. very effective wound healing
wounds. Applied topically, it stimulates the formation agent.
of granulation tissue; provides local pain relief, reduc In future clinical trials and applications, important
ing the need for pain medications; decreases wound questions to be answered include optimal topical dose
exudation and results in elimination of bacterial con (amount and frequency); the possible use of a delivery
tamination and infection; and leads to complete heal vehicle or ointment base; combination with other
ing or provides a healthy granulation tissue base for agents or modes of therapy; amount, if any, of systemic
skin grafting and surgical wound closure. Our findings absorption; and mechanisms by which phenytoin acts.
are consistent with reports of other t�ials in various Definition of the latter may provide improved or new
types of wounds and ulcers and emphasizes the particu approaches to its use.
lar usefulness of topical phenytoin powder in war For example, as part of our own studies of optimal
wounds, under conditions of treatment that are espe delivery modes for topical phenytoin, we have evalu
cially difficult. ated the effects of topical phenytoin on the healing o f
An optimal wound healing treatment regimen is one standardized full-thickness skin wounds i n 24 rats.
that is effective, inexpensive, safe, readily available, (Although this data is to be the subjeat of a separate
and easy to apply. Based on our experience, topical report, a summary is relevant here). The rats were
phenytoin meets these criteria and is more effective divided into six groups: four treated with different
than other therapeutic measures currently available to formulations of phenytoin (gel, cream, phenytoin
us. Because of the rapid healing it induces, hospital sodiuin powder, and sodium-free phenyton powder),
stays are shortened. The need for antibiotics and one with a topical excipient only, and the sixth, a
analgesics is reduced, thereby yielding further cost nO-treatment control.
savings and minimizing the possibility of toxicity or Until the fifth or sixth day of treatment, there was no
dependence resulting from use of these agents. With clear difference between the groups. From this point on
the exception of one case of skin rash, which appeared however, granulation tissue formation and healing was
on the first application of the powder and resolved with clearly much faster in the four PHT groups, with the
ceasation of therapy, the method has proved very safe sodium-free phenytoin providing the best overall re
in our hands. The cost of phenytoin itself is minimal and sults.
it is both readily available and easy to use, even under Phenytoin has been reported to have various effects
the most difficult war-time conditions. on the wound healing process. Clinical studies indicate
Because of the difficult conditions under which we several major features: decreased inflammatory re
had to work, there were many measurements we were sponse, increased fibroblast proliferation, increased
not able to make and many questions we were not able collagen content, and increased new blood vessel
to answer. Even consistent planimetry and photogra formation. 2.7.H In the laboratory, PHT has been shown
1:1 .14
phy were met with difficulty. More quantitative bacter- to increase tensile wound strength, promote cor-
85
Phenytion on wound healing
neal wound healing, 15 accelerate healing of mandibu 1-8, 1972.
lar fractures in rabbits,16 stimulate fibroblast 6- Otto R, Ludewig, R, Kotzschke HJ: Specific action of local
phenytoin application on periodontal disease. Stomato DDR
proliferation, 17 inhibit collagenase and collagen pepti
27: 262-8, 1977.
dase activity, 18 increase collagen content and matura 7- Rodriguez-Noriega E, Esparza-Ahumada S, Andrade-Perez IS,
tion in granulation tissue,19 reduce the degradation of Espejo-Plascencia I, Chapa-Alvarez lR: Treatment of soft
older collagen in tissue culture,20 inhibit the release of tissue ulcerations with topical diphenylhydantoinate. Invest
lysosomal and cytoplasmic enzymes,21-23 decrease the Medica Int 10: 184-6, 1983.
8- Mendiola-Gonzalez IF, Espejo-Plascencia I, Chapa-Alvarez
catabolic effects of cortisol,24 and inhibit prostaglandir1
lR, Rodriguez-Noriega E: Sodium diphenylhydantoin in
and thromboxane formation.25 burns: effects on pain and healing. Invest Medica Int 10: 443-7.
We would like to suggest that epidermal growth
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1983.
factor (EGF) may be involved in phenytoin's effects on 9- Barba-Rubio 1: Diphenylhydantoin in leprosy, Presented to the
XII Congress of Dermatology, Oaxaca, Mexico, Oct. 9-12,
wound healing. Given the fact that epidermal growth
1985.
factor is released in the wound at about the fifth or sixth 10- Malhotra YX, Amin SS: Healing effect of diphenylhydantoin
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Dermatologists, Venereologists and Leprologists, Pune, India,
effect at about this time, it is reasonable to postulate
lanuary 9-11, 1987.
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Int 1 Dermatol, 1988.
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