Topical Phenytoin Improves Wound Healing With Analgesic and Antibacterial Properties and Minimal Side Effects: A Systematic Review

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Initially developed as an anticonvulsant in 1937,¹ phenytoin has shown promise in promoting wound healing according to Shapiro’s² observations in 1958. Gingival hyperplasia is a side effect of phenytoin use, and the effect of phenytoin on connective tissue proliferation may produce a similar result on granulation tissue during wound healing. While a systematic review by Shaw et al³ of literature published through 2005 suggested potential benefits of topical phenytoin on wound healing, 12 of the 14 included RCTs had methodological limitations, inadequately describing randomization, masking, and treatment allocation. Subsequent research has been published assessing the efficacy of topical phenytoin across different wound types, warranting further analysis with potentially higher levels of evidence.

Phenytoin is thought to accelerate the process of wound healing through various mechanisms (Figure 1). In vitro studies have demonstrated increased collagen deposition and neovascularization with phenytoin use.⁴ Fibroblast proliferation is increased,^5,6 likely due to upregulation of platelet-derived growth factor expression.⁷ Animal studies conducted in 1974 and 1957 attributed the analgesic effect of phenytoin to its membrane-stabilizing properties, including sodium channel blockade and inhibition of repetitive neuronal activity.^8,9 NRCTs in 1989 and 1991 suggested that the antibacterial properties of phenytoin could result from direct action¹⁰ or indirectly by affecting wound pH and improving circulation.¹¹ Studies published between 1988 and 1996 reported minimal systemic absorption when phenytoin was used topically on wounds,^12-15 a finding that was further supported by an RCT published in 2007.¹⁶

The authors of the present study conducted a systematic literature review to ascertain whether topical phenytoin use resulted in improved wound healing compared with controls, and to report any other beneficial or detrimental effects of topical phenytoin.

Study design
This systematic review was performed following the PRISMA guideline.¹⁷ The selected studies were screened and appraised for quality by 2 independent reviewers (K.O.S., Y.M.S.) who later extracted data from individual studies using a standardized table. When conflicts arose, the second author (Y.M.S.) decided the outcome.

Search strategy
A search of relevant studies published up to June 22, 2023, was conducted in the Cochrane Library, PubMed, PubMed Central, and MEDLINE databases. The Cochrane Library was searched using the keywords “topical,” “phenytoin,” and “wound.” PubMed, PubMed Central, and MEDLINE were searched using the following MeSH search strategy: (“Administration, Topical”[Mesh]) AND (“phenytoin/therapeutic use”[MeSH Terms]) AND (“Wounds and Injuries”[MeSH Terms] OR “Wound Healing”[MeSH Terms] OR “Granulation Tissue”[MeSH Terms]) NOT (“Seizures”[MeSH Terms]). The MeSH term for seizures was excluded because the screening search delivered many articles describing the use of prophylactic phenytoin to prevent seizures in persons who had experienced traumatic brain injury. Titles and abstracts were used to exclude irrelevant studies and those outside the scope of this review. Manual searches of reference lists from relevant articles also were conducted.

Studies were included if they described the study design as a controlled trial, that is, an RCT or an NRCT. Studies of other design types, such as in vitro studies, animal studies, and articles in languages other than English, were omitted. Only human studies in English were included, with no restrictions based on publication date.

Quality assessment
RCTs and NRCTs were appraised for quality using the RoB 2 tool¹⁸ and the ROBINS-I tool, respectively.¹⁹ Studies were included if the risk of bias in each domain was found to be low or if they were determined to have some concerns in, at most, a single domain. Trials with no information to evaluate the risk of bias for a single domain were included if the remaining domains were deemed low risk. Studies judged to have moderate, serious, or critical risk of bias in any given domain, those with some concerns in 2 or more domains, and those in which a lack of information prevented the assessment of 2 or more domains were excluded.

Extracted data and variables
The data extracted included wound type, mean patient age, mean wound size, duration of treatment, types of intervention, sample size, outcome measures, and reported adverse effects.

The search strategy resulted in 101 articles, 76 of which were excluded for various reasons (Figure 2). Twenty-eight articles^{10,11,16,20-44} were assessed for quality, and 3 of these were excluded^20,21,27 (Table 1). One article was excluded because a lack of information made it impossible to assess risk of bias, and there were concerns for bias in at least 2 domains in the other 2 articles. In total, 18 RCTs and 7 NRCTs were included for analysis. Fourteen of these had a low risk of bias in all domains (56%).^{11,16,23,25,26,28,31-33,35,37,41,42,44} The remaining had some risk of bias in a single domain (44%).^{10,22,24,29,30,34,36,38-40,43} The sample sizes of the included studies ranged between 20 and 130 (median, 60), with a total sample size of 1653 patients. The data collected from each study are shown in Table 2.

Comparators
Nine studies (36%) compared phenytoin with potentially pharmacologically active compounds, including but not limited to honey, EUSOL, and silver sulfadiazine.^{10,11,28,29,37-40,43} Sixteen studies (64%) only compared phenytoin with inert controls, the most common being normal saline.^{16,22-26,30-36,41,42,44}

Accelerated wound healing
Twenty-four studies assessed either reduction in wound size or time to complete wound healing, or both.^{10,11,16,22-26,28-32,34-44} Wound size was most commonly measured by tracing the wounds and calculating the area using graph paper. Other methods used to determine would size included photographs, 3-dimensional modeling software, and subjective evaluation. Of these 24 studies, 17 (71%) showed accelerated wound healing with phenytoin,^{10,11,22,24,26,30-32,34-36,38,40-44} whereas 5 (21%) showed no difference compared with controls.^{16,23,25,28,39} Two studies reported statistically significant improvement only early in the wound course, on day 2³² and day 7⁴⁰ but not during later stages.

Sutured episiotomy wound healing was evaluated using the REEDA scale. Lavaf et al²⁸ did not observe a statistically significant difference in wound edge approximation between topical phenytoin and honey cream. In a study published the following year, however, Pakniat et al²⁶ reported improved mean scores for all components of the REEDA scale with phenytoin. These were the only studies that investigated the effect of phenytoin on primary wound closure.

Increased granulation tissue
Nine (90%) of 10 studies that assessed the appearance and proportion of granulation tissue demonstrated an earlier appearance or a higher proportion of granulation tissue over the wound with the use of topical phenytoin.^{10,11,22,23,33,36,38,41,42,44} Increased granulation tissue may be partially responsible for accelerated wound healing, as suggested by Bansal and Mukul.⁴¹ Muthukumarasamy et al⁴⁴ and Pendse et al⁴² reported excessive granulation tissue production, which in the former study was reversible on cessation of phenytoin application.⁴⁴ Other investigators reported an absence of hypertrophic granulation tissue.^24,35,36

Reduction of bacterial contamination
Twelve studies^{10,11,26,28,29,33,35,36,38,39,41,44} evaluated the presence of discharge, slough, or exudates, and 8 studies^{11,22,36,38,39,42-44} used wound cultures for bacterial contamination. Nine of the 12 studies (75%) showed reduced discharge, slough, or exudate,^{10,11,26,28,33,36,38,40,44} and 6 of the 8 studies (75%) showed negative cultures following treatment with phenytoin.^{11,22,39,42-44} Interestingly, Pereira and de A Alchorne³⁵ reported an increase in exudates and attributed it to improved circulation from increased capillaries.

Pain reduction
Thirteen studies evaluated pain intensity using questionnaires, subjective pain scores, or visual analog scales.^{10,11,22,23,25,28-30,32,38-40,43} Seven (54%) of these studies demonstrated that phenytoin alleviated pain,^{10,11,22,30,38,39,43} while 4 (31%) showed no statistically significant difference between phenytoin and comparators,^25,28,32,40 and 1 study showed a benefit with phenytoin on the first day of administration.²³ In the remaining study, increased pain relief was achieved with aloe vera versus phenytoin.²⁹

Adverse effects
Subbanna et al¹⁶ reported minimal systemic absorption following topical application of phenytoin, corroborating the results of previous studies.^12-15 Fifteen studies in the current review (71%) reported no adverse effects resulting from topical phenytoin.^{11,16,23-26,29,32,35-38,40,41,43} Four studies did not mention adverse effects,^22,30,31,39 and only 6 studies (29%) reported mild local side effects that affected a minority of patients.^{10,28,33,34,42,44} A burning sensation was the most common side effect,^10,34,42 which was transient in 2 studies.^10,42 Patil et al³³ observed pruritus in 5 of 50 patients treated with phenytoin, and Lavaf et al²⁸ described short-lived irritation at the time of application. The only other side effect observed was a reversible production of excessive granulation tissue.^42,44 Pereira and de A Alchorne³⁵ suggested the burning sensation was a result of using phenytoin powder and advocated for the use of phenytoin dissolved in normal saline instead. However, the current literature review returned more instances in which the use of phenytoin powder produced no burning sensation.^11,38,44 Other alternatives suggested to mitigate the burning sensation include using acidic phenytoin^10,45 or using zinc oxide paste as a vehicle for the phenytoin.⁴⁶

Phenytoin is a relatively inexpensive drug that is readily available in most hospitals. Compared with control treatments, it has been shown to improve wound healing, increase granulation tissue, and reduce pain and bacterial contamination. Transient local irritation appears to be the only drawback of phenytoin. Due to minimal systemic absorption of phenytoin, there appears to be no risk for systemic toxicity. The pros and cons of phenytoin are noted in Table 3.

Topical phenytoin can produce dramatic results. For example, a 1996 case report discusses an adult male with morbid obesity, heart failure, and obesity-hypoventilation syndrome who was hospitalized for respiratory failure.¹² He developed recalcitrant pressure ulcers with sinus tracts that progressed to involve the entire lumbosacral area and buttocks in less than 80 days. Once topical phenytoin treatment was started, granulation tissue appeared within 2 days, nearly all sinus tracts healed after 54 days, and the wounds had significantly reduced in size after 4 months despite the patient’s unresolved comorbidities.¹²

Of the 25 studies included in the current review, 21 investigated the effects of phenytoin on wounds of a single etiology.^{10,11,16,22-26,28,30-37,39,41,43,44} Four studies investigated diabetic foot ulcers,^24,31,33,44 3 evaluated pressure ulcers,^11,16,37 2 assessed trophic ulcers secondary to leprosy,^36,41 and 1 study each evaluated traumatic wounds,²² burns,³⁹ chronic venous ulcers,²⁹ and abscess cavities.¹⁰ With the exception of superficial dermal burns and pressure ulcers, use of phenytoin resulted in improved wound healing. While phenytoin and silver sulfadiazine were not significantly different in terms of wound healing rate in patients with superficial dermal burns, phenytoin use did result in significantly more negative wound cultures (P < .01 on day 5 and P < .001 on day 10) and less wound pain (P < .01).³⁹

Eight of the 21 articles on wounds of a single etiology pertained to surgical wounds, with 3 on oral biopsy wounds,^23,30,32 2 on sutured episiotomies,^26,28 and 1 each on anal fistulotomies,²⁵ split-thickness skin graft donor sites,⁴³ and wounds resulting from the excision of melanocytic nevi.³⁵ Phenytoin improved wound healing in most of these settings, except anal fistulotomy wounds. As noted previously, for patients with sutured episiotomies, Pakniat et al²⁶ demonstrated that phenytoin resulted in a lower mean REEDA scale score compared with controls, in contrast to a prior study by Lavaf et al.²⁸ Further studies comparing phenytoin with standard of care for other types of sutured surgical and traumatic wounds may be warranted to investigate its potential benefits, as well as any effect on wound complications.

The remaining 5 studies included chronic ulcers of multiple etiologies. Phenytoin was superior to controls in 3 of these studies,^34,38,42 inferior to aloe vera in 1 study,²⁹ and not markedly different from honey in another study.⁴⁰

Phenytoin is reportedly superior to EUSOL,^10,38 framycetin, and occlusive polyurethane dressings.⁴³ As noted previously, compared with silver sulfadiazine, phenytoin use resulted in less pain and more culture-negative wounds, although wound healing was not significantly different.³⁹ Honey may produce effects similar to those observed with phenytoin.^28,40 Of the modalities evaluated, only 2 compounds appear to be more advantageous than phenytoin: aloe vera and hydrocolloid gel. Use of aloe vera resulted in increased reduction in pain and wound size compared with phenytoin.²⁹ Hydrocolloid gel may be more beneficial than phenytoin in managing certain pressure injuries.³⁷ Aloe vera likely has the greatest safety/effectiveness profile.

The current study incorporated more trials and a larger sample size than the 2007 systematic review by Shaw et al.³ Most included studies in the current review had a low risk of bias compared with the prior review. However, several RCTs did not describe the randomization process, and the majority were not double-masked. Several studies included multiple wounds in individual patients. Notably, Doshi et al²³ investigated 4 surgically created wounds per individual, with the subjects serving as their own controls, similar to the study by Pereira and de A Alchorne.³⁵ Bansal and Mukul⁴¹ performed a similar analysis on a subset of 10 patients with 2 ulcers each. This type of design potentially decreases the influence of confounding factors while simultaneously increasing the power. Most studies showed no significant difference in the mean age of patients or size of wounds.

The concentrations and dosages of phenytoin used varied in the included studies. To the knowledge of the authors of this review, only Bhatia et al³⁶ sought to compare the efficacy of different dosages, and they did not find a statistically significant difference. Phenytoin was applied as a powder, solution, suspension, lotion, cream, gel, and mucoadhesive paste. Motawea et al²⁴ found that phenytoin-loaded nanostructured lipid carrier hydrogel may produce results superior to those of phenytoin hydrogel. No other study compared delivery methods. Because the most appropriate dosage and formulation of phenytoin for topical use is unknown, the authors of the current study believe further studies are warranted. Additionally, studies differ in the frequency of phenytoin administration, and no study has investigated the effect of this variable on outcomes. Four RCTs have been registered in the International Clinical Trials Registry Platform as of 2023 with 3 intervention arms: phenytoin cream, an herbal cream, and control.^47-50 Three of these trials are investigating episiotomy wounds,^48-50 and the fourth is investigating postoperative pilonidal sinus wounds.⁴⁷ The authors of the current study recommend prospective, double-masked RCTs comparing various concentrations of phenytoin, frequencies of administration, and delivery vehicles to determine the optimal therapeutic regimen for the management of wounds.

This study has limitations. The study design of this systematic review included studies with some risk of bias in a single domain (44% of included studies). Using a MeSH strategy for searching online databases may have resulted in the omission of newer relevant studies. Non-English-language studies were excluded, and several studies that may have added to the collective evidence could not be retrieved despite the authors’ best efforts.

This review suggests that phenytoin improves wound healing and increases granulation tissue. It also has analgesic and antibacterial properties, which are desirable in treating wounds. Topical phenytoin is minimally absorbed, and adverse effects appear rare and transient. The authors of the current review believe further double-masked RCTs are warranted to investigate the optimal dose, frequency, and vehicle for application of phenytoin, as well as its effects on other types of postoperative wounds.

Authors: Kaiser O'Sahil Sadiq, MBBS; Yogamba Mysore Shivakumar, MBBS, MPH; Eshwar Kumar Burra, MBBS; Kamran Shahid, MBBS; Yonas Teferra Tamene, MD, MSN; Shefali Piyush Mody, MBBS; and Tuheen Sankar Nath, MBBS

Affiliation: California Institute of Behavioral Neurosciences & Psychology, Fairfield, CA 

Disclosure: The authors disclose no financial or other conflicts of interest.

Correspondence: Kaiser O'Sahil Sadiq, MBBS; California Institute of Behavioral Neurosciences & Psychology, Research Department, 4751 Mangels Blvd, Fairfield, CA 94534; kaiserosahil@gmail.com

Manuscript Accepted: December 20, 2023