Topical Doxepin Significantly Decreases Itching and Erythema in the Chronically Pruritic Burn Scar

Introduction Severe pruritus or itching is a common and disabling problem in patients with a healed burn wound and affects 40 to 50 percent of burn patients.[1–4] Itching is most common in a burn that takes over three weeks to heal. The chronically pruritic burn wound markedly impairs quality of life for the burn victim, and itching can last for well over a year. The mechanism is not clearly defined, but increased histamine release from the wound is a likely etiologic factor, as is the case with a number of other skin disorders.[1–4] The source of the histamine would be the increased mast cell population typically present in the chronically pruritic wound.[5,6] Any wound manipulation or increase in wound temperature exacerbates the itching. The mechanism of the itch is considered to be the activation of the wound surface C nerve fibers.[8–11] The C fibers are typically considered to be pain fibers, and itch has been categorized as a form of pain.[8,9] Itch nerve fibers that are extremely sensitive to histamine have also been reported.[10–12] Histamine also increases surface wound blood flow, which would explain the raised red surface usually present on the chronically itching wound.[1–4] The current standard pharmacologic management of itch is the use of oral antihistamines with the frequent addition of sedatives. However, this approach is successful in less than half of the chronically itching burn patients.[1–7,13,14] Doxepin, a tricyclic compound used for clinical depression, has been found to have very potent H1 and H2 histamine receptor blocking properties.[15,16] Doxepin, which is currently available in a five-percent topical cream (Prudoxin®, Healthpoint, Fort Worth, Texas), has been found to be approximately 50 times more potent than hydroxyzine and nearly 800 times more potent than diphenhydramine as an antihistamine.[15,16] Doxepin cream has been found to control the pruritus of atopic dermatitis, eczema, urticaria, and other skin disorders. Although plasma levels of doxepin usually are not detected, some somnolence has been reported in about 10 percent of patients while using doxepin.[17–20] The authors recently reported doxepin cream to be highly effective in controlling the itching and erythema of more acute pruritic burn wounds up to three months from time to healing.[21,22] Also, doxepin use eliminated the itch stimulus in over half the wounds prior to the end of the three-month period indicating an attenuation of the causative stimulus. Oral antihistamines had a minimal effect. Although data is lacking, the authors would expect the chronic pruritic burn to be more refractory to management, which, therefore, deserves a separate study. The purpose of this study was to determine whether doxepin cream would be effective for controlling itch and erythema compared to oral antihistamines and sedatives. The authors studied patients currently being managed in the authors’ outpatient burn clinic. The initial body burn had to be less than 35 percent of total body surface, as larger burns have prolonged wound-related discomfort, which would be difficult to separate from itch. Pruritic wounds had to be healed for at least four months. The pruritic burns were partial thickness in depth and required three to four weeks to heal.[1–5] Deeper burns are excised and grafted, and these wounds in general are not a cause of chronic pruritus. Finally, the authors studied patients already complaining of itch and already using an antihistamine, as the focus of this study was treatment, not prevention. Methods Thirty-one burn patients being followed in the outpatient clinic who complained of itch in healed burns of 4 to 12 months of age were candidates for this Institutional Review Board-approved study. Criteria were that the burn wound must be healed. In addition, the pruritic wound could not exceed 20 percent of total body surface, and the total initial burn could not exceed 35 percent of the body. Larger burn injuries usually have other causes of discomfort, which are hard to distinguish from itch. All patients were already using oral antihistamines and skin moisturizers. After an initial assessment of the degree of burn wound itch and erythema, each patient was randomized into a standard care group or doxepin cream group for a three-month study period. Standard treatment consisted of an oral antihistamine. The dose and type were adjusted during the study to attempt to improve efficacy. The most common agents used were diphenhydramine and hydroxyzine. A skin moisturizer was applied two to three times a day in both groups. The doxepin cream is not a good skin moisturizer. The moisturizing product of preference for the patient was used. No skin moisturizer available has antihistamine properties. The doxepin group applied the cream in a thin layer to the itchy areas four times a day, preferably every six hours. This dosing was not modified. Twenty minutes later the moisturizer of choice was applied. No oral antihistamines were used in the doxepin group. Measurements. An initial assessment of the degree of itch and erythema was made by the research team, which included the burn clinic physician director and nurse research coordinator. This team obtained all the subsequent data for the entire study period and were therefore not blinded to the outcome measures. A linear visual analog scale of 0 to 10 was used to quantify the degree of itch.24 The scale is also used for pain. The degree of erythema reflecting increased blood flow was assessed using the rating system described by the Vancouver scar scale.[25] Erythema was graded 0 to 3, 0 being no erythema and 3 being marked red to purple in color. Digital photography was used on initial assessment and also weekly to monitor erythema. Measurements were obtained after patients were sitting quietly for 20 minutes in a room with an environmental temperature of 68 degrees F to avoid any cold- or heat-induced color changes, which would alter the score. Patients were provided instructions in the use of the itch rating tool and were asked to log the least and greatest itch on a daily basis. These values were used by the investigators to determine the average itch score and adjust the antihistamines and other agents in the standard care group. Measurements were obtained at weekly clinic visits. The treatment modality in each group was continued for three months or until the itch stopped, no longer requiring treatment. The patients were still monitored weekly for the entire three-month period to assess the wound status. Moisturizers were also continued. Any complications were documented. Statistical analysis. Within-group and between-group differences were determined by ANOVA. The Dunnett’s t-test allows for different time periods to be compared. Regression analysis was used to determine correlation coefficients. Results The characteristics of the two groups are presented in Table 1. A total of 31 patients were randomized into the two groups over a 12-month study period (2001–2002). The patients were a select group, as all had itching on entry into the study. The mean age of the burn was 7±3 months. The major causes of the initial burn were scalds accounting for 50 percent and flash flames for 40 percent. Mean time to healing was 23 days. The mean itching burn size was 13±5 percent of total body surface area. Patients had significant itch on entry into the study with a mean score of 5 out of 10. Wound erythema was also significant, typically being red in color. No wound infections were evident during the study. Mean group data on the response of itch and erythema over the three-month period is shown in Table 2. There was an immediate and significant decrease in itch and erythema in the doxepin-cream treated group compared to the standard care group at all time periods. Also, 75 percent of the patients in the doxepin group had their itching stop before the end of the study compared to only 20 percent of patients in the standard care group, a significant group difference. The correlation coefficient between degree of itch and degree of erythema was r = 0.75, a significant correlation. This correlation does not reflect cause and effect, but rather that the two variables exist together. There was no significant correlation between the length of time the burn was itching and the response to doxepin. The doxepin cream appeared to work in all cases to decrease itch unrelated to the length of time the wound was present. An example of the effect of topical doxepin on a pruritic wound is shown in Figures 1 and 2. Complications included mild to moderate somnolence in 50 percent of patients in the oral antihistamine group. A mild, transient somnolence was seen in 10 percent of the doxepin patients, which usually resolved after two to three days, even with continued use. Transient mild discomfort was noted in three patients using the doxepin cream due to placement of the cream onto an open area in the wound caused by scratching. No discomfort was noted when the doxepin cream was placed on a closed wound. There was no significant correlation between the degree of somnolence and the anti-itch properties of the cream (r = 0.37). Discussion Chronic burn wound pruritus is a serious problem often causing a severe impairment in quality of life.[1–7] The itch lasts months to years, markedly impairing sleep, work, leisure activity, and overall quality of life. The incidence of itch in adults with healed partial-thickness burns requiring two to four weeks to heal is reported to be between 40 and 80 percent, while the incidence in children approaches 100 percent.[1–5,13] Chronic itching in the healed burn wound is of considerable concern, as the patient typically is already using oral antihistamines, sedatives, and other methods with minimal success. The wound invariably has surface erythema. The refractory nature of the wound would suggest that a successful treatment may be difficult to find. There have been no studies comparing the itch of new versus older burn wounds. Itch appears to begin with epidermal closure, and the stimulus appears to be from the surface nerves.[1–5,23] In a large number of dermatologic disorders, the most common being atopic dermatitis, the source of itch has been found to be due to a histamine release in the wound.[17] A number of other mediators found in the burn wound likely act through increasing the release or potentiating the response of histamine.[13] Although histamine is likely causative in the itching burn wound, oral antihistamines are only effective in the minority of cases. The topical use of a tricyclic antidepressant compound to control skin itch is now a recognized treatment for itch, as this class of agents is known to have very potent antihistamine properties, blocking both H1 and H2 receptors.[15–19,26] Doxepin is recognized to be the safest of this class of drug; some somnolence is its major side effect.26 Doxepin has potent antihistamine properties, and when used in a water soluble cream form is very effective against a wide range of skin itching disorders.[15–19] Plasma doxepin levels in these studies are usually nondetectable. When detected, levels are 25 times less than the levels needed for its central nervous system effect.[7] The authors have recently reported that a five-percent doxepin cream is very effective at controlling post-burn itching in the freshly healed burn, compared to any other method.[21,22] Erythema was also significantly diminished. The itching focus also disappeared in 75 percent of the doxepin group prior to the end of the study compared to 20 percent of the oral antihistamine group. This fact would indicate that the doxepin cream in some way altered the wound, possibly by decreasing mast cell numbers or the stimulus to release histamine release.[22] The authors found in the current study that the doxepin cream was as effective in controlling itch and removing erythema in the chronic pruritic burn wound as in the more acute burn wound. In addition, the itch that had been present for months resolved in 75 percent of the patients before the end of the three-month study, again indicating that the doxepin alters the wound so as to remove the itch focus. The only side effect was a mild transient somnolence in 10 percent of patients, the degree comparable to an oral antihistamine. There was also no correlation between the degree of somnolence and the anti-itch activity. A placebo effect is possible but less likely given the fact that wound erythema was also decreased. Blood flow is unlikely to be affected by a placebo action. The authors can conclude that topical doxepin significantly decreases the itching of the chronically pruritic burn wound. Erythema is also decreased and correlates with the control of itch. In addition, the use of doxepin cream over a three-month period decreased the degree of subsequent itching when the cream was stopped compared to oral antihistamines.