Introduction Severe pruritus or itching is a common and disabling problem in patients with healed burn wounds. Itching is most common in burns that take about three weeks to heal. The mechanism is not clearly defined, but increased histamine release from the wound is a major 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 healed burn wound.5,6 Any wound itching, 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, extremely sensitive to histamine, have also been reported.10–12 There are also a number of studies indicating that histamine increases surface wound blood flow, which may explain the erythema usually present in the 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 burn patients with itch.1–7 Other approaches, such as massage therapy and cool baths, are only transiently beneficial, and the continued itching may result in significant levels of discomfort and impaired quality of life.13,14 Doxepin hydrochloride (HCl) is one of a class of agents known as dibenzoxipine tricyclic compounds used for clinical depression. Doxepin has also been found to have very potent H1 and H2 histamine receptor blocking properties.15,16 Doxepin HCl is currently available in a five-percent topical cream (Prudoxin®, Healthpoint, Ltd., Fort Worth, Texas). Each gram contains 50mg of doxepin HCl. Doxepin 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 dermatological disorders, with results superior to the use of more standard oral antihistamines.15–20 Serum levels of doxepin with the use of the cream in these disorders are usually immeasurable but, when detected, are over 25-fold lower than the serum level required for the doxepin to have any therapeutic effect on central nervous system function.17–19 The purpose of this study was to determine whether doxepin cream would be effective for controlling itch and erythema in the burn wound. A preliminary study has shown considerable success.21 The authors elected to study minor and moderate burn injuries managed in the outpatient burn clinic, as larger burns would likely have wound-related discomfort, which would be difficult to separate from itch. The burns were to be partial thickness in depth and require two to four weeks to reepithelialize, because these are the most likely wounds to itch.1–5 It is the authors’ policy to excise and graft deeper dermal burns, i.e., those likely to require more than four weeks to heal because of the poor quality of the healed skin. The authors studied patients already complaining of itch and using antihistamines, because the focus of this study was treatment not prevention. Methods Minor burn patients being followed in the outpatient clinic who complained of itch in their healed wounds were candidates for this approved study. Criteria were that the burn wounds be between six weeks and three months old, as peak itching is usually evident during this period in burns mid-dermal in depth. The burns would also have to be completely reepithelialized. In addition, the pruritic wounds could not exceed 15 percent of total body surface. Burns larger than 15 percent are considered to be major burns, which require admission and typically have significant wound-related discomfort in addition to 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 placed 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. In addition, a skin moisturizer was used at least three times a day. 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. Twenty minutes later, the moisturizer of choice was applied. Any residual pain in both groups was treated with ibuprofen, which is effective for wound discomfort but not for itch.23 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. A linear visual analog scale of 0 to 10 was used to quantify the degree of itch.24 The scale was 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°F to avoid any cold- or heat-induced color changes, which could 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 and no longer required treatment. Any complications were documented. Statistical analysis. Within-group and between-group differences were determined by ANOVA. The Dunnett’s t-test allowed 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 41 patients were studied, each for a three-month period. The patients were a select group, as all had itching on entry into the study. Itching is evident in over 50 percent of patients with healed burn wounds of this depth seen in the authors’ outpatient clinic. The mean itching burn size was about five percent of total body surface area. The major cause was scalds accounting for 70 percent, with chemical burns accounting for 10 percent, and flash flames for 20 percent. Mean time to healing was nearly three weeks. Patients had significant itch on entry into the study with a mean score of over 5 out of 10 and were already using oral antihistamines. Wound erythema was also significant on the wound surface, typically being red in color. 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-treated group compared to the standard care group at all time periods. Also, 55 percent of the patients in the doxepin group had their itching stopped before the end of the study compared to only 10 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 = 0.82, a significant correlation. This correlation does not reflect cause and effect but rather that the two variables exist together. Complications included mild to moderate somnolence in 80 percent of patients in the oral antihistamine group. A mild, transient somnolence, which usually resolved after two to three days even with continued use, was seen in 15 percent of the doxepin patients. A localized skin allergy was noted in one patient using the doxepin, which required his removal from the study. No discomfort was noted when the doxepin cream was placed on a closed wound. Discussion Burn wound pruritus is a serious problem often receiving inadequate attention.1–7 The itch lasts months to years, markedly impairing sleep, work, leisure activities, 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 25 percent and 80 percent, while the incidence in children approaches 100 percent.1–5,13 Itch is less likely to occur in skin-grafted sites.1–5,13 Itch appears to begin with epidermal closure, and the stimulus appears to be in the superficial area of the wound. Itch is reported by many to be a form of pain mediated by a common neural pathway. However, itch and pain appear to be activated by separate sensory modalities.8–11 The finding of very superficial C-fibers with selective activation by histamine suggests a specific itch pathway.12 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.17 A number of other mediators found in the burn wound, such as serotonin and tachykinins, can be involved likely through increasing the release or potentiating the response to histamine.13 Reports of severity of itch using a 10-point linear visual analog scale has averaged between 5 and 7 for the burn patients studied.1–7,13 This degree of itch has been reported in patients already using oral antihistamines, moisturizers, and other available methods.13 A number of approaches have been used to control post-burn itching, such as massage, cool baths, and distraction and relaxation techniques.11–13,22 However, the mainstay of treatment is the use of oral antihistamines, the most common being diphenhydramine and hydroxyzine, often in conjunction with sedatives and analgesics. Although some improvement in itching can be achieved in about half of the patients, itching usually remains significant.1–8 In our study, the patients studied were already using oral antihistamines and still had an itch score of at least 5 (on a scale of 0 to 10) and an erythema score of at least 2 (on a scale of 0 to 3) identifying the burn wound to be red in color.21 The use of a tricyclic antidepressant compound to control skin itch is now a recognized treatment, 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 with some somnolence being 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 The authors found that doxepin cream significantly decreased itch and erythema within 15 minutes of application compared to the standard pharmacological approach. The doxepin was effective over the three-month study and no tolerance was evident.11–16 Ideally, a placebo cream would be used to test efficacy in decreasing itching. The authors did not use a placebo, as patients with itch would have to discontinue use of antihistamines. Lack of placebo is a limitation of the study. It is not possible to clearly define the mechanism of action of the doxepin cream. But the ability to block a histamine response is the action most likely responsible. Erythema was also decreased.15–17 Increased wound surface blood flow has also been reported to be a histamine effect.3 Sufficient doxepin is unlikely to have been absorbed to lead to a central nervous system tricyclic effect, especially in small burns.17–19 Other possible pharmacologic mechanisms for the topical doxepin effect include local antagonism of adrenergic, muscarinic, and serotonin receptors.17–19 However, histamine release appears to be associated with all of these other potential mechanisms. In addition, the itch and erythema resolved in half of the burns before the end of the study indicating that continued doxepin exposure in some way altered the wound to decrease histamine release. An alteration of C nerve fiber sensitivity is also possible;12 however, erythema was also decreased, and changes in blood flow are not the result of changes in nerve or itch fibers but rather a decrease in the mediators released.13 The only side effect was a mild transient somnolence in 15 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 conclude that topical doxepin significantly decreases post-burn itching compared to the oral antihistamine. Erythema is also decreased and correlates with the control of itch.