The wound repair process begins soon after injury when the local immune response is activated; this process involves inflammation, fibroblast activation and migration, angiogenesis, reepithelialization, collagen bundle formation and collagen remodeling, granulation formation, and endothelial cell proliferation, which are maintained by EGF, transforming growth factor β (TGF- β), and bFGF.23-27
As shown in in vivo and in vitro histopathological studies, sucralfate has multiple beneficial effects on wound healing with few if any adverse effects. The primary benefit of sucralfate is to diminish inflammatory reaction and improve mucosal healing, potentially decreasing fibrosis, stricture formation, and EGF expression in tissue repair processes.24-37 Antepsin (which includes sucralfate) is available in pharmacies as a commercial product for the treatment of ulcers. Known as an anti-ulcer agent, sucralfate can produce polyethylene gycol fumarate (PEGF) and have a mucosal coating effect. A number of studies were published to support a localized form of protection using 14C-labeled sucralfate; specific binding to ulcerated mucosa was demonstrated in animal models and gastric ulcer in human gastrectomy specimens.28
It has been suggested in in vivo and animal studies4,21,29,30 that sucralfate increases EGF binding to ulcerated areas and stimulates epidermal cell proliferation and restoration. Konturek et al4 studied sucralfate gastroprotection and ulcer healing in a rat model in which sucralfate was shown to protect the gastric mucosa against damage caused by absolute ethanol and enhanced the healing rate of chronic gastric and duodenal ulcers, ulcer healing effects of sucralfate that may be mediated, in part, by EGF. The study4 also confirmed that sucralfate, like 16,16-dimethyl prostaglandin E2, protects the gastric mucosa against ethanol damage and increases mucosal generation of prostaglandins.
Burch et al21 examined the effects of sucralfate on the proliferation of cultured dermal fibroblasts and keratinocytes. Sucralfate induced proliferation of both cell types in quiescent cultures. Additionally, sucralfate enhanced prostaglandin E2 synthesis in basal keratinocytes and in interleukin (IL)-l-stimulated keratinocytes and dermal fibroblasts. Basal IL-1 and IL-6 release were not affected by sucralfate, but the agent-enhanced interleukin stimulated IL-6 release from fibroblasts. When applied daily to full-thickness wounds in rats, sucralfate increased the thickness of granulation tissue when assessed at day 12. The current study showed sucralfate induces proliferation of dermal fibroblasts and keratinocytes in culture and formation of granulation tissue in vivo. In addition, Sencan et al31 showed sucralfate treatment and prophylaxis with sucralfate ameliorates hypoxia/reoxygenation-induced intestinal injury in pup rats.
The current study showed that on day 4 in the sucralfate group, edema density (P = .034), epidermal detachment (P = .0220), epidermal-dermal cell infiltration (P = .007), and PNL infiltration scores (P = .021) were significantly higher than in the control group. Following wounding, neutrophil migration is essential for preventing infection and facilitating early debridement; lack of neutrophils during the early phase of wound healing can prolong the inflammatory phase.7 At the end of first week (day 7), most parameters were similar between the 2 groups. Only the epidermal-dermal PNL cell infiltration and elastic fibers scores were significantly different .
Following the inflammation phase, angiogenesis, collagen deposition, and reepithelialization increase, leading to the final stage of wound healing. In the current study, sucralfate was responsible for increased edema (vasodilation) and increased PNL infiltration (chemotaxis), owing to increased angiogenesis. Although overexpression of vascular endothelial growth factor (VEGF) was not measured in this study, it was speculated that because VEGF is noted for its effects on multiple components of the wound healing cascade, including angiogenesis and recently shown epithelialization and collagen deposition, it also increased.32 VEGF stimulates wound healing via multiple mechanisms including collagen deposition, angiogenesis, and epithelialization. In the clinical setting, the mitogenic, chemotactic, and permeability effects of VEGF may potentially help promote repair in nonhealing wounds in arterial occlusive disease and diabetes.33 In the current study, in the sucralfate group, angiogenesis, reepithelialization, and granulation tissue scores were significantly different, especially on days 14 and 21.
Collagen synthesis and restoration are step-by-step components of the healing phase. Type 1 collagen is responsible for wound contraction early in the healing process and then again as the wound draws closer to closure, where it is an essential part of reepithelialization. Unfortunately, type 1 collagen was not assessed in the study, but total collagen synthesis and density were significantly higher in the sucralfate group on days 14 and 21. In addition, on day 21, fibroblast density was significantly higher in the sucralfate group, and fibroblast upregulation is a known cofactor in the wound healing process.
Burch et al21 reported that sucralfate stimulates cell proliferation in the superficial skin layer. The ability of sucralfate to aid healing in the gastrointestinal tract led the current authors to evaluate its potential efficacy in the healing of skin wounds. The present study examined the effects of sucralfate on the healing of full-thickness skin wounds in rats. Burch et al21 showed sucralfate stimulates angiogenesis, PGE2 synthesis, and IL-6 release from cultured skin cell study, substances responsible for healing. Similarly, based on the histological results in the current study, sucralfate enhanced the proliferation of fibroblasts and collagen bundles, and vessel and granulation tissue formation were significantly more noticeable than in the control group. Similar to the current study, Behesti et al34 compared silver sulfadiazine, cold cream, and sucralfate in second-degree burn healing in rats. At days 7, 14, 21, and 28, pathological tissue samples showed topical sucralfate accelerated the burn wound healing process in comparison with both the control and silver sulfadiazine cream. The percentage of wound healing was calculated at 76%, 91%, and 100%, respectively, in the control, silver sulfadiazine, and sucralfate groups. At the end of the fourth week, granulation tissue was significantly thicker in the sucralfate group.
In a case report,35 sucralfate 10% cream was used successfully to obtain rapid improvement in the treatment of a newborn’s epidermolysis bullosa dystrophica wound. In their prospective trial, Guo et al36 used topical sucralfate to prevent radiodermatitis and pain control after CO2 laser therapy. Patients were randomized into the sucralfate group (n = 40) or the control group (n = 40). Postoperative pain scores, the frequency and duration of analgesic requirements, and postoperative wound bleeding episodes were compared between the 2 groups from the operative day to postoperative day 6. Patients in the sucralfate group experienced significantly less postoperative pain on postoperative days 1 and 2. Although no significant difference was noted in frequency and duration of analgesic use between the 2 groups, a trend toward lower frequency and fewer days of analgesic use in the sucralfate group was observed. In their randomized controlled trial, Zodpe et al37 demonstrated patients treated with sucralfate experienced less pain, rapid mucosal healing, and early return to daily activity after uvulopalatopharyngoplasty. The study involved 80 adult patients with obstructive sleep apnea syndrome, randomly allocated into either a sucralfate treatment group or a control group. Patients enrolled in the sucralfate group (n = 40) were instructed to gargle the sucralfate suspension and then swallow. Patients enrolled in the control group (n = 40) were instructed to gargle placebo suspension at the same doses and schedule. Throat pain and otalgia occurred significantly less often in sucralfate group, with less analgesic requirement and with rapid mucosal healing and early return to regular daily activities. No significant difference was noted in episodes of postoperative bleeding between the 2 groups (P = .37). Although sucralfate therapy may not provide complete analgesia after uvulopalatopharyngoplasty, it may reduce the amount of analgesic required, thus preventing dose-related adverse effects from the analgesic agent. It also can significantly reduce the total number of days needed to return to normal daily activities (P = .41).
In a double-blinded, randomized clinical trial, Miura et al38 studied topical sucralfate in post-adenotonsillectomy analgesia in children (N = 82). Participants were allocated to receive topical sucralfate or placebo in the intraoperative and postoperative periods 4 times a day for 5 days. Pain was measured through a faces pain scale. Oropharyngeal pain was significant reduced with use of sucralfate (mean, 95% confidence interval, and P value reported, respectively); day 1: 2.05, 1.53-2.58, P = .000; day 2: 2.1, 1.51-2.70, P = .001; day 3: 1.44, 0.88-1.99, P = .003; day 4: 1.13, 0.58-1.55, P = 0.027; and day 5: 0.67, 0.26-1.04, P = .021). In their randomized trials, Siupsinskiene et al39 also showed topical sucralfate significantly reduced pain in persons ages 6 to 58 years (N = 50) undergoing tonsillectomy or adenotonsillectomy from postoperative days 1 to 5. Participants were randomly included into either a sucralfate treatment group (n = 25) or into a control group (n = 25). Patients of the sucralfate group received topical sucralfate 4 times a day for 7 days. No topical treatment was applied to patients of the control group. A systemic analgesic was standardized. Post-tonsillectomy symptoms, including throat pain, odynophagia, and otalgia, were evaluated during over 7 postoperative days. Secondary outcomes were analgesic use, well being in general, return to regular daily activities, secondary hemorrhage, and side effects of sucralfate. This study39 revealed that between postoperative days 2 and 7, average throat pain scores of the patients using sucralfate were significantly lower than those of the control group patients (P < .05); the same results occurred with odynophagia scores over the entire 7-day postoperative period (P <.01) and with otalgia scores from postoperative day 4 (P <.05). Patients receiving sucralfate also had a significantly smaller need for analgesics, better scores of well being in general, and early return to regular daily activities, with no side effects of the treatment. In 1 of the few randomized, controlled, double-blind trials in the treatment of radiation proctitis, Kochhar et al40 treated patients with a 4-week course of oral sulfasalazine (3.0 g/d), and they were randomly assigned to receive prednisolone enemas (20 mg, twice daily) or sucralfate enemas (2.0 g, twice daily). Patients who were randomized to sucralfate enemas tolerated treatment better and had a superior response compared to prednisolone enemas.
McElvanna et al41 reported the endorectal topical preparation of sucralfate is a viable therapy for radiation proctitis, with minimal side effects using a protocol of twice-daily application, prepared using 2 1-g tablets mixed with 4.5 mL of water to produce a paste-like consistency. In this study, 23 patients (18 men postprostatic radiotherapy and 5 women postcervical radiotherapy; median age of 67 [range 32–75] years) with rectal bleeding occurring more than 6 months after radiotherapy were shown how to prepare and self-administer sucralfate paste enemas (SPEs) twice daily for 6 weeks. The clinical response was evaluated by comparing pre- and posttreatment clinical proctitis scores using the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer score (www.rtog.org). The median interval between pelvic irradiation and SPE treatment was 24 (range 7–69) months. Among the 22 patients with complete data, 16 (73%) demonstrated clinical improvement, 6 (27%) had neither clinical improvement nor deterioration, and 7 (32%) had resolution of all symptoms.
In their randomized, blinded, controlled trial comparing 10% sucralfate ointment to placebo among 41 patients with postanal fistulotomy, Alvandipour et al42 found sucralfate ointment reduced postoperative pain at rest and on defecation and improved wound healing compared to a placebo. Participants were randomly allocated to either sucralfate ointment (every 12 hours) or placebo. All patients were visited weekly for up to 5 weeks. Pain intensity and wound healing were assessed, and the sucralfate group had signiﬁcantly less pain at rest (1.92 ± 0.88 vs 2.96 ± 0.98; P = .002) and on defecation (1.68 ± 0.92 vs. 3.08 ± 1.12; P <.001) than the placebo group on the first through fifth postoperative visits. Complete wound healing was achieved after 8.15 ± 1 weeks in placebo group versus 5.9 ± 0.8 weeks in sucralfate group (P <.001), with no significant differences in the frequencies of postoperative complications between the 2 groups. A randomized placebo-controlled trial43 was conducted among 80 patients treated for anal fistulotomy wounds (29 women, 51 men; median age 23 [range 17–49] years); 76 participants completed the trial (sucralfate, 39; placebo, 37). Researchers43 observed complete wound healing in 37 patients (95%) at their 6-week follow-up in the sucralfate group and in 27 patients (73%) in the placebo group (P = .009). Mucosal coverage of the wound was significantly greater with sucralfate than with placebo at each measurement point (P = .01). No adverse events were observed. Postoperative pain scores were significantly lower for sucralfate than for placebo at 2 and 4 weeks after the start of treatment.
Some studies show topical sucralfate did not improve wound healing. In a prospective, double blind, randomized, placebo-controlled trial conducted by Ala et al,44 40 demographically similar hospitalized patients with Stage 2 pressure ulcers were randomly treated with sucralfate gel or placebo. Ulcers were evaluated using the Pressure Ulcer Scale for Healing45 (PUSH) with no statistically significant differences in healing noted or between groups in the average PUSH score decrease (6.36 ± 2.11 vs 5.89 ± 1.41, P = 0.42). Although the average healing time was less in the sucralfate group (6.05 ± 2.17 vs 7.78 ± 3.42), the difference was not statistically significant (P = 0.07).
Dodd et al46 used micronized sucralfate versus salt-and-soda mouthwashes in the management of 30 patients with radiation-induced mucositis; no significant difference was found between the 2 methods of treatment.
Sucralfate is a safe and well-tolerated drug. Although the oral form should be used with caution in patients with renal disease, the topical form, due to its low concentration and lack of absorption through the skin, has not been found to create any adverse effects.47 Sucralfate also may be used on the skin of patients of all ages; because sucralfate in topical formulations acts as a physical barrier with proved safety and no noticeable absorption, it may be used as a potential treatment for diaper dermatitis. In a double-blind, randomized clinical trial, Sajjadian et al48 investigated the efficacy of topical sucralfate versus topical zinc oxide in diaper dermatitis. Sucralfate and zinc oxide were formulated as 20% ointments with the same excipients. All patients were randomly treated topically with either sucralfate (n = 25) or zinc oxide (n = 21) for 7 days. Diaper dermatitis severity scores were obtained before treatment and at days 3, 5, 7 by the authors. Sucralfate 20% ointment was significantly superior in healing diaper dermatitis at days 5 and 7 (P <.05 and .01, respectively) and showed a significantly shorter healing time (3.24 ± 2.02 days) in comparison with zinc oxide 20% ointment (5.42 ± 2.39 days) (P = .002). The current study results showed that topical sucralfate has a positive histopathological effect on the healing process. However, day 4 results suggest an early more vigorous inflammatory response in the sucralfate group as compared to control rats; this is not necessarily clinically desirable, as the authors have seen it result in more pronounced scarring. This observation needs to be explored in future studies.