Introduction

Phenytoin is an anticonvulsant drug available in the market since 1937. It acts by blocking neuronal excitation by binding to sodium channels at rest, preventing them from becoming functional and generating excitatory action potentials⁽¹⁾. The possibility of its use as a healing agent began to be investigated by primary experimental studies in the field of dentistry, when, in 1939, hypergranulation of gingival tissue was recognized as its adverse effect, which suggested possible use of this drug as a healing agent in wounds^(2-3).

The exact mechanism through whichphenytoininduces tissue healing is unclear, and the ways to apply it for this purpose are not standardized⁽⁴⁾. However, the dissemination of satisfactory results of empirical research about the performance ofphenytoinin healing chronic wounds such as pressure, vascular and diabetic ulcers, has caught the attention of nurses that deal with this theme, such as stomatherapy expert nurses.

Phenytoin is a low-cost drug, and the study of its healing capacity for clinical practice is important. However, there is a need for research that can elucidate the subject and encourage its discussion in our context. Therefore, this research chose as the subject of investigative interest the scientific production on the therapeutic potential ofphenytoinin the wound healing process in humans. The objectives were to describe how the scientific production presents the use ofphenytoinas a healing agent and to discuss its applicability in wounds.

Method

An integrative literature review from 2003 to 2011 was performed. The temporal limit is justified by the publication of the study The clinical effect of topicalphenytoinon wound healing: a systematic review by the British Journal of Dermatology⁽³⁾, which, although published in 2007, adopted temporal delimitation of 1963 to the middle of the year 2003.

Inclusion criteria were: a) articles that discussed the use ofphenytoinin healing any kind of tissue injury in humans, b) available in Portuguese, English or Spanish.

The integrative review was divided into six stages: the first stage was the selection of the review question, which characterizes the definition of the subject to be studied; second stage was the selection of the bibliography. The third stage was the categorization of studies considering the data collection form validated by Ursi⁽⁵⁾.

The fourth stage was the review of inclusion criteria, critical reading, and systematic data analysis. The fifth step was interpretation of the results, discussion, organization and tabulation of information. And the sixth step was the presentation of the review to enable the critical analysis of the findings by the reader, as recommended by the method adopted.

The guiding question of the review was: How is the healing potential ofphenytoinpresented in the scientific literature regarding its clinical applicability in human wounds. The selection of articles occurred in mid-April of 2012, in the following databases: Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed, Cochrane and Latin American and Caribbean Literature on Health Sciences (LILACS), accessed through the Virtual Health Library (VHL) portal. For the search of articles in the Latin American database, the descriptor phenytoin and the term wounds were used, and in the American databases, the descriptor phenytoin combined with the words wound; wound healing was used.

In MEDLINE, the descriptor phenytoin, when refined by combining it with the word wound using the boolean operator AND retrieved 92 studies. When the term wound was combined with wound healing using the Boolean operator AND, the research retrieved 82 studies. After duplicate exclusion, on a first analysis, considering titles and abstracts when available, 36 articles were selected. Repeating the same search model in PubMed and Cochrane, studies were duplicated, therefore no articles were included in this stage.

In the Latin American database, the descriptorphenytoinrefined with the term wounds retrieved two studies, and one article was selected. The combination of the descriptor with the term wound healing retrieved no indication. Therefore, the preliminary selection was composed of 37 articles, which were categorized by the form adopted in this review. The categorization pointed to the need for full reading of the selected material, the texts being downloaded online and/or requested from institutional libraries. After a complete reading, 18 articles were included in the research, advancing to the fifth stage of this integrative review.

Data analysis used the level of evidence hierarchy, adopting standardized classification of evidence from one to seven: one corresponds to systematic review that examined randomized controlled trials, considered to be the type of research with highest reliability and scientific validity; Two: randomized clinical trial (RCT): with comparable groups and randomly divided in order to test interventions; Three: cohort study: study with observation and follow-up of the development of situations and/or injuries to the groups exposed to risks; Four: case-control study: interventions are applied to a given group, and the results are compared with a group which did not receive the intervention and serves as a parameter for comparison; Five: case series: the intervention is performed in several people and the outcomes analyzed and discussed in a particularized observational manner; Six: expert opinion: people considered experts opine on the possible interventions and the possible outcomes expected using empirical work experience, without testing the mentally prepared hypotheses; Seven: Preclinical studies - studies conducted through experimentation on live animals or in controlled situations and laboratory test tubes.

From these criteria, force of evidence can be classified as strong, moderate and weak: research levels 1 and 2 have strong research evidence, levels 3 and 4 have moderate research evidence and levels 5 and 7 have weak research evidence. Beyond the force level, evidence has a degree of recommendation generated by the following rating: A - when the search result recommends the intervention, B - when the search result is not conclusive, and C - when the search result contraindicates the intervention⁽⁶⁾. This classification was adopted in this study.

Results

The analysis of 18 articles in this literature review shows evidence of topicalphenytoinas a healing agent applied to a range of chronic wounds and also acute wounds, in addition to its systemic use in the management of fistulas of the gastrointestinal tract. Beneficial effects published urged the creation of the hypothesis of its topical use in the treatment of vitiligo, expanding the options for clinical investigation in other diseases that affect the skin, other than wounds themselves.

The Middle Eastern countries stand out in the scientific literature regarding the healing potential ofphenytoinin humans, followed by: the United Kingdom, India, China and Brazil.

When considering the level of evidence and degree of recommendation, the United Kingdom is again highlighted, with two important strong-evidence studies published by the same author. Altogether the scientific production is typically published in English and performed in the academic medical area, especially the area of dermatological medicine, followed by endocrinology, surgery, neurology and dentistry. There was scientific production published in Portuguese, developed in the area of oncology nursing, as shown in Chart 1.

Chart 1 

In the period of time delimitation studied in this integrative review, every year there was scientific production at an average two to three articles/year, and the year 2011 had four articles. This facet indicates an increased investigative interest on the theme in question.

The scientific production analyzed is characterized by the investigation of the healing potential ofphenytoinby applying macerated pills directly on the wound, or the solution obtained from macerated pills or intravenous solution, both diluted in saline at a concentration of 5 or 10 mg/mL as shown in Table 1. Cream, ointment, alginate, lotion and aerosol were also other methods of application presented in the scientific production analyzed, although less frequently.

The clinical applicability ofphenytoinfor the purpose of healing wounds occurred primarily in diabetic foot and venous ulcers, followed by pressure and leprosy ulcers. The other lesions were: osteomyelitis in the oral cavity, pyoderma gangrenosum, radiodermitis grade III, and those resulting from excision of melanocytic nevi.

Overall, the studies were incomplete when describing how thephenytoinapplication was applied in the RCT, and the quality of methodological designs is still predominantly low, as was indicated in the pioneering work of Shaw and colleagues⁽³⁾.

Discussion

Benefits from the use ofphenytoinwere associated with increased granulation tissue, angiogenesis, and decreasing of wound size. In cases when the drug was used systemically for the management of fistulas, there was a significant decrease of the effluent flow - which suggests a likely decline in the size of the fistulas that can be justified by the anatomic healing process, probably induced byphenytoin⁽²⁰⁾.

Although the mechanisms by whichphenytoinheals human tissues are unclear, in vitro studies in laboratory animals and in human histopathology have contributed some information to the understanding of this phenomenon, by demonstrating stimulatory action of the drug on fibroblasts and collagen synthesis, cellular remodeling, inhibition of collagenase, and acceleration of autocrine and paracrine activity of growth factors through biochemical regulation of cell receptors involved^(3-4,8) and significant lymphocyte activation⁽²⁰⁾.

It is noteworthy that studies of moderate to strong evidence pointed to the analgesic effects of this drug for wounds⁽¹⁰⁾, and their authors mentioned the use ofphenytoinas a secure application^(10,12,15), important factors when one is concerned about systemic absorption that application of topicalphenytoinmay trigger.

In terms of comparisons, it is emphasized that topicalphenytoinshowed healing potential higher than saline, although lower than hydrocolloid⁽¹³⁾. This fact makes the use ofphenytoinas a healing agent attractive to health services devoid of greater resources for the acquisition of high-tech curative materials.

The scientific production on the healing potential ofphenytoinis characterized by research on wounds that are classic problems for generating costs to the public system of global health, exacerbated in developing countries. Again it is important to consider that this drug was considered safe, inexpensive and effective in wound healing by several researchers considered in this integrative review^{(4-8-12,16-17-17,19,21)}.

However, further research should be performed to fill in knowledge gaps on the topic. One example is that, notoriously, the same author who published a level-1 evidence study with inconclusive results regarding the application of the product on wounds, could not support the use ofphenytoinas a healing product in diabetic foot ulcers when doing an experiment with evidence level 2 using alginate formulation, unprecedented in the scientific literature on the subject. However, the author did not discuss this preference⁽¹⁴⁾.

Surprisingly,phenytoinhas been systemically used for the purpose of healing fistulas of the gastrointestinal tract, with encouraging results, although supported by weak research evidence and therefore with low strength of recommendation⁽²⁰⁾. However, it is a piece of information of interest to the field of oncology, including the use ofphenytoinin healing radiodermitis grade III⁽⁴⁾. Another study, not included in this review because it was not available at the time of the search in the indexed databases, investigated the use ofphenytoin0.5% for mouthwash in patients suffering from oral mucositis, resulting in improved quality of life of the group that received intervention⁽²³⁾.

The use of topicalphenytoinin the form of 100 mg macerated pills diluted with 5 mL of 0.9% saline solution, applied 12/12 hr on a stage-4 pressure ulcer in the sacral region on a 50-year-old patient confined to bed for multiple sclerosis sequelae, was performed by Brazilian physicians and medical students in the northern region of the country. They reported that in 72 days the ulcer was completely filled with granulation tissue⁽²⁴⁾. This was a study approved by the Research Ethics Committee with evidence level 5, with degree of recommendation 5A. But this study was also not included in this review because it was not available in the indexed databases.

In the Middle East, sprayphenytoinis available for wound healing, a product known as Healosol Spray: Wound Healing Promoter. Produced by the pharmacological company ACODIMA (Arab Company for Drug Industries Medical Appliances), it has as one of its indications the use in burn wounds⁽²⁵⁾, which again refers to the applicability ofphenytoinin radiodermatitis burns, like studies number 4 and 11 of this review.

In Jordan in 2012, a preclinical study conducted on laboratory animals was published investigating the potential for wound healing of ethosuximide, barbituric acid and phenobarbital due to their structural similarity withphenytoin. The authors concluded that ethosuximide has clinical potential for the treatment of chronic wounds likephenytoin⁽²⁶⁾, making new hypotheses emerge from clinical research in the field of healing of tissue injuries. It can be inferred that researchers have begun to investigate the healing potential of drugs similar tophenytoin.

The formulation ofphenytoinsolution from pills, capsules or intravenous use is inconvenient for topical use because of low solubility and high pH (around 12), which may have stinging and burning sensations as adverse effects^(4,21). Hence the importance of the use of more specific formulations. In this sense, the Pharmacy School of the Royal College of Surgeons in Ireland - RCSI - has researched formulations that may provide greater solubility ofphenytoinwith a pH around 7-8 to be administered to wounds⁽²⁷⁾.

The global organization of pharmacovigilance – the US Food and Drug Administration - known by the acronym FDA, has approved the use of originally systemic products for the topical treatment of wounds, including anesthetics, antibiotics, and growth factors. In order to describe such situations in which a product is used for other purposes than those indicated in the package insert, the term off-label prescription medication⁽²⁸⁾ was created.

Misoprostol, lidocaine, nifedipine, gentamicin and metronidazole are examples of drugs being prescribed to treat wounds in cream formulations, macerated pills, gel and spray, using the concept that can be called, in Brazil, off-label prescribing^(28-29). It is a controversial practice, although it exists in our environment, such as the use of substances based on essential fatty acids (EFA) widely used as healing wounds, but still lacking quality studies to support use regarding safety and efficacy issues⁽³⁰⁾. The FDA accepts clinical studies that support the safety and efficacy of the applicability of the drugs in off-label uses, as well as the National Health Surveillance Agency - ANVISA – the regulatory agency in Brazil, which opens promising fields for research.

Conclusion

The integrative literature review performed in this study concluded that topicalphenytoinhas strong evidence of beneficial effects on the healing process in venous, pressure, diabetic foot, leprosy, pyoderma gangrenosum ulcers and bed preparation for grafting. However, the studies conducted have moderate to low quality. More robust studies which support the use ofphenytoinprotocol as another option of healing agent in clinical practice are necessary.

Considering the way as scientific production presented the healing potential ofphenytoin, the importance of incentives to produce studies that show its potential indications in the healing process are needed, which will greatly contribute to the revision and updating of care measures developed by nursing and other areas of healthcare, technology and innovation.