Contemporary Options for the Management of Scars

Yvette C. Terrie , BSPharm, RPh
Jeffrey R. Marcus , MD, FAAP, FACS

By definition, a scar is the end result of the normal healing process. For many individuals, the effects of scarring are nonproblematic. Injuries that only involve the epithelium are not likely to cause significant scarring, but injuries that involve the dermis and deeper tissues have greater potential to leave a visible scar.¹ Scarring occurs along a continuum of expression both across and within populations. Normal scars can be faintly perceptible in some cases and prominent in others. We know that variation in normal scarring is associated with such factors as skin color, skin quality, age, and ethnicity. Scarring is a normal process, but several specific types of scars are abnormal and result from aberrant wound healing. Some individuals or populations may be more susceptible to developing such types of abnormal scarring.

Annually, an estimated 100 million individuals will develop some type of scar. Approximately 55 million will develop problematic scars as the result of elective surgeries, and 25 million will develop scars from operations after trauma or disease.² In addition, 11 million keloid scars and 4 million scars from burns exist, of which 70% occur in children.^2,3 The latter abnormal scars are often described as painful, disfiguring, embarrassing, and even functionally disabling.⁴ Patients may experience pruritus, psychological stress, and loss of motion from contracture.^4,5

Over the past 2 decades, researchers have gained significant insight with regard to the prevention, treatment, and management of scarring. An accurate assessment of the scar is a crucial step prior to initiating possible treatment and management.^2,5 Factors that need to be considered prior to electing to treat a scar include²:

1. Is the scar getting worse or showing signs of improvement?
2. The anatomical location of the scar.
3. Symptoms that the patient presents.
4. Presence and/or severity of functional impairment. (Does the scar affect mobility of joints?)
5. Stigma of the scar. (Evaluate the impact of the scar on the patient's quality of life.)
6. Likelihood of improvement with treatment.

Whereas the severity of a scar can be estimated subjectively, accurate representation (for the purpose of investigation) must be based on objective methodology. Objective assessment provides quantitative data and is a key element in the critical evaluation of treatment efficacy. Many objective tools are available for scar assessment. One example is the Vancouver Scar Scale.

The Vancouver scale is a clinical assessment tool that rates and scores scars according to pigmentation, vascularity, height/elevation, and pliability.^2,6,7 From this assessment, a score is obtained; the lower the score, the better the scar.² The scores can then be compared over periods of time and across potential treatment modalities.^2,6,7 Table 1⁸ shows the Vancouver Scar Scale. In this evolving field, it is important for health care professionals to keep abreast of treatment options and the clinical evidence that support their use. This continuing education article will review the stages of wound healing, the types of abnormal scars, and the treatment options currently available.

Table 1

Pathophysiology of Wound Healing and Scar Formation

For the purposes of this discussion, "injury" refers to any loss of skin continuity whether intentional (surgical) or unintentional (traumatic). The healing process is typically divided into 3 stages that begin immediately after an injury and continue for a period lasting weeks to months to years.^1,9,10 The stages of the healing process include inflammation, proliferation, and maturation (matrix remodeling).^1,9,10 The scar is the discernible end result of this process.^1,9,10

Inflammatory Phase
Although the exact role of the inflammatory response in the progression of scar formation is still not entirely clear, it is evident that early inflammation sets the stage for the production of scar tissue and may contribute to the end result.¹⁰ It appears that the development of the scar is programmed during and by certain parts of the inflammatory process.¹⁰

During the inflammatory phase, which lasts 3 to 4 days, the body responds to injury by preparing the wound for subsequent tissue replacement. This consists of 2 primary processes: hemostasis and inflammation.⁹ Hemostasis is initiated immediately as the first major function of the platelets.^1,11 In response to the initial injury, vasoconstriction in combination with clot formation and platelet aggregation occur.¹¹ The aggregation of platelets results in the formation of the primary platelet plug.¹¹ Aggregation and attachment to exposed collagen surfaces activates the platelets.¹²

Once aggregated, the platelets degranulate and release mediators that assist in the development of the fibrin clot, together with growth factors and chemoattractants.¹¹ The platelets are critical to the initial phase of healing, because they release cytokines such as platelet-derived growth factor, insulinlike growth factor-1, epidermal growth factor (EGF), and transforming growth factor-beta (TGF-beta) into the wound bed.^9,11 Neutrophils and macrophages travel into the wound and secrete additional growth factors, such as transforming growth factor-alpha (TGF-alpha), heparin-binding epidermal growth factor (HB-EGF), and basic fibroblast growth factor, which further the progression of the inflammatory process.¹¹

After hemostasis is achieved, the active inflammatory process is initiated by chemotactic factors that draw neutrophils into the wound. Under normal circumstances, neutrophils phagocytize debris and bacteria in the wound within 24 to 48 hours.⁹ Platelets also release mediators such as bradykinin, histamine, and prostaglandins into the wound area, thus initiating vasodilation among the surrounding vessels. This process then increases blood flow to the area, allowing further inflammatory and mediator cells to reach the site. As a result, the wound appears erythematous and edematous.^9,12 The final stage of the inflammatory phase is the epithelial migration into the wound.^3,9

Proliferative Phase
During the proliferative phase, the wound is filled with new connective tissue and covered with new epithelium. This phase involves the formation of granulation tissue, which is a collection of fibroblasts and newly synthesized collagen, new capillaries, and inflammatory cells.⁹ Granulation tissue begins forming approximately 3 to 5 days following injury and overlaps with the preceding inflammatory phase.¹² The synthesis of collagen by fibroblasts is directed by cytokines produced by stimulated macrophages.⁹ As granulation tissue is being processed, epithelial cells, which started to migrate during the inflammatory process, resurface the damage of the wound.⁹ The process of epithelialization then signals a down-regulation in proliferation. The final step in the proliferative phase includes the process of wound contraction and involves the mobilization and pulling together of the edges of the wound.⁹

Maturation Phase
The maturation phase, also known as the matrix remodeling phase, is the longest phase and begins at about 3 weeks after an injury.^9,10,12 During this phase, the wound is completely closed by connective tissue and resurfaced by epithelial cells. This phase can continue for as long as 2 years after an injury, depending on the extent of the injury.⁹ This phase involves an ongoing process of the synthesis of collagen with hightensile strength collagen.⁹ Peak tensile strength of a wound occurs approximately 60 days after an injury occurs.¹² The end product is the formation of a scar that has an estimated 70% to 80% of the original strength of the skin that it replaced.^9,12

Factors That Affect Wound Healing

Various factors can interfere with the wound-healing process, affecting any of the 3 phases.³ Multiple factors have been identified as contributing to impaired wound healing. Examples of these factors include advanced age, malnutrition, and impaired tissue perfusion and oxygenation. Oxygen availability is critical to the healing and is limited by smoking, diabetes, anemia, hypotension, peripheral vascular disease, and congestive heart failure.⁹ Radiation is a specific example of impaired perfusion due to microvascular fibrosis. Other examples of factors negatively affecting healing include infection, immunosuppressives, chemotherapy, steroids, and inadequate wound care.^1,9,13,14

Scarring

Scarring is part of the skin's natural wound-healing process and is a sign that a wound is healing. For the formation of a normal scar, the maturation phase involves gradual fading and flattening of the scar tissue which, on average, takes about 12 to 18 months, but can take up to 2 years.^1,9 Scarring follows local skin trauma through injury, disease, or surgery, inflammatory disorders (eg, acne vulgaris, mumps/measles/chickenpox infections), or lacerations/piercings (eg, cuts, bites, tattoos, vaccinations, surgery).⁵ Normal scars initially appear pink or red and raised, but then flatten and fade to varying degrees. Abnormal scars are thought to be caused by disturbances in the wound-healing process. During the maturation phase, the manifestation of abnormal scarring becomes apparent.¹⁵

As mentioned previously, many factors can affect the severity of scarring. These factors can be divided into 4 main elements: injury factors, patient factors, technical factors, and care factors.

Injury factors include the depth, orientation, contamination, mechanism, and extent of the injury. Tissue loss, crush injuries, and irregular tears of the skin are particularly problematic. Surgical incisions, on the other hand, are highly controlled. The injury itself is a significant determinant of longterm scar outcome. Patient factors were discussed earlier and relate to the individual's inherent ability to heal well and the potential predisposition to exuberant scar formation. It is worth mentioning that age plays a significant factor among all populations. During 2 periods of development, the process of healing typically results in less conspicuous scars. These are at 2 extremes—the very young and the elderly. Privileged healing does seem to occur during infancy and extends, perhaps to a lesser degree, for several years. By puberty, the qualities of the skin lend themselves to a more proinflammatory state. This exaggeration of the inflammatory and proliferative phase often results in unsightly and/or abnormal scars during this time. With increasing age, the qualities of the skin continue to change, as does the scar response. In later years, the skin becomes thinner and less elastic. The process of wound healing is less exuberant, and scarring during this period is again diminished.

Injury factors and patient factors cannot be willfully changed; therefore, a significant aspect of determining outcome is out of the control of the caregiver. The final 2 factors, however, can be influenced significantly, and these are the subject of interventions designed to optimize scar formation. Technical factors relate to the surgeon's ability to manage and repair the injury in the most optimal manner. Care factors relate to the manner in which an injury or wound are treated after surgical or nonsurgical treatment. Most types of scar treatments are directed at this aspect of the scar process.

Types of Abnormal Scars

Several types of abnormal scars exist, including keloids, hypertrophic scars, atrophic scars, widened scars, and contractures that can be differentiated by various characteristics (Table 2).

Table 2

Keloid and Hypertrophic Scars
The exact etiology of keloid and hypertrophic scar development remains unclear. Several theories suggest, however, that abnormalities in cell migration, proliferation, inflammation, and the synthesis and secretion of extracellular matrix proteins, cytokines, and remodeling can contribute to keloid and hypertrophic scar formation.¹²

Keloids
In the United States, keloids affect an estimated 15% of the population and are more prevalent among certain ethnic groups, such as African Americans, Asian Americans, Latin Americans, and other darker-pigmented ethnicities.¹⁶ Some studies suggest that keloids are related to an inherited metabolic alteration in collagen.¹⁶ Although keloids can occur at any age, they are rarely found in newborns or among the elderly and tend to have their greatest occurrence rate among individuals between 10 and 30 years of age.^1,5,17 Cosman et al reported that the average age of patients at the time of receiving initial treatment was 25.8 years, and the average age of onset was 22.3 years in women and 22.6 years in men.¹⁸ Furthermore, research has demonstrated that, because keloids typically have accelerated growth during both puberty and pregnancy and, in general, resolve upon menopause, both androgens and estrogen have been considered contributing factors to keloid formation.⁵ Other hormones that may be connected to the formation of keloids include thyroid hormone alterations and melanocyte-stimulating hormones.⁵

Keloids are defined clinically by 2 factors: first, the growth of the keloid extends beyond the boundaries of the initial wound/injury. Second, keloids are typically symptomatic over a prolonged course, described as painful and pruritic.¹⁹ Genetic predisposition coupled with some form of trauma or injury to the skin may play a pivotal role in the development of keloids.^5,17 Examples of skin injuries that may precipitate formation of keloid scars include surgery, ear piercing, abscess, abrasions, lacerations, tattoos, insect bites, burns, vaccinations, and any process that may cause inflammation of the skin, such as acne, chickenpox, or folliculitis.¹⁷ Butler et al states that the formation of keloids is a response to inflammation that is caused by keloidderived fibroblasts, which involve an abnormal secretion of proinflammatory mediators and an abnormal response to other inflammatory signals.¹⁶

Keloids occur more frequently on the shoulders, chest, earlobes, upper arms, upper back, and cheeks, although the reason for this occurrence is unknown.^20-22 Some theories postulate that these areas have increased susceptibility to formation of keloid scars since they are subject to elevated levels of muscle and skin tension.^23,24 The areas of the head and neck that are typically safe from keloid formation include the eyelids and the mucous membranes.²⁴

With the exception of trauma, exact etiologic factors responsible for keloid formation have not been fully understood.²⁵ Keloids are frequently associated with negative wound-healing factors, such as infection, excessive tension, foreign bodies, and repetitive trauma; however, keloids may form in simple clean wounds.²⁵

Many patients with keloids are affected both physically and psychologically and express a significant negative impact on their quality of life.²¹ In the results from one study, Lee et al evaluated 28 patients with keloids and reported that more than 80% of the patients reported keloid-associated pruritus, and an estimated 50% reported pain.²⁶

Hypertrophic Scars
Hypertrophic scars are more common than keloids. Hypertrophic scars may occur in persons of any age or at any site, and they tend to spontaneously regress. In addition, hypertrophic scars are more likely to respond to treatment.⁵ Hypertrophic scars typically develop within 8 weeks of skin injury, such as a burn wound infection. In general, their normal course includes a rapid growth stage for up to 6 months that can then be followed by regression during the next 12 to 18 months.²⁷

Differentiating Between Keloid and Hypertrophic Scars
Both keloid and hypertrophic scars are characterized by an accumulation of excess collagen and are not always easy to differentiate from one another.^16,21 It is important for health care professionals to distinguish between the 2 types of scars, because inappropriate therapy may cause formation of larger scars.³ Crucial differences between these 2 types of abnormal scars include histologic morphology, cellular response to growth factors, and scar appearance.²⁸

Keloids tend to grow beyond the borders of the original wound, invading the surrounding areas of the skin, and they typically do not resolve spontaneously. Hypertrophic scars stay within the boundaries of the original wound and tend to regress spontaneously.^1,5,13,25 In addition, hypertrophic scars are typically visible soon after an injury to tissue and are often related to a contracture across a joint surface, whereas keloids may develop as late as 12 months after an injury.^1,5,24 Hypertrophic scars appear as red, raised, nodular lesions occurring in areas of thick skin, and they may cause pruritus or pain. Keloid scars appear puckered and nodular and are reddish-purple in color and exhibit a prolonged, proliferative phase resulting in the appearance of thick hyalinized collagen bundles similar to those produced by hypertrophic scars.^17,27 Upon palpitation, keloids appear to be firmer when compared with hypertrophic scars and can also be painful and itchy.^1,28

Atrophic Scars
Atrophic scars are flat and depressed below the dermal area. They are generally small in size with an indented or inverted center.^2,3,16,29,30 They are most commonly the result of collagen destruction during the course of an inflammatory skin disease, such as from the result of acne vulgaris, varicella, and immunization sites.^3,28 Initially, atrophic scars appear erythematous and become increasingly fibrotic and hypopigmented as time progresses.³⁰

Widened Scars
Widened scars are described as stretched scars that normally occur in sites of higher tension.^1,5 The response to tension perpendicular to the wound edges is a widened scar regardless of whether there is separation or disruption of the wound.^1,5 Widened scars can occur at any age and have no predisposition to ethnicity, sex, or familial history. The arms, legs, and abdomen are the most common areas of the body that may form a widened scar.⁵ In addition, sun tanning can contribute to scar widening through attenuation of the tissues.⁵

Widened scars initially appear as a pale red color-typically flat, soft, symptomless scars often seen after knee or shoulder surgery, for example.^1,2,5 The stretch marks that often appear during or after pregnancy are a type of widened scar in which there is trauma/injury to the dermis and subcutaneous tissues but the epidermis is unbreached.⁵ Moreover, mature widened scars have no elevation, thickening, or nodularity, which distinguishes them from hypertrophic scars.²

Scars with Contractures
A contracture scar is characterized as a permanent shortening of a scar that can be disfiguring and disabling, because they can limit an individual's movement.² A contracture scar typically occurs when the wound occurs across a joint or when a large area of the dermal area has been damaged, such as when an individual experiences a severe burn.^1,2 Scar contracture is thought to be mediated by myofibroblasts, which are also thought to play a role in other similar disorders of tissue healing.

Treatment

If a scar causes functional or cosmetic concerns, then treatment may be warranted. The treatment of scarring can be categorized into 2 categories: invasive or noninvasive modalities.^1,7 Although advances have been made with regard to the nature of wound healing and scar formation and the modulation of these processes, a consensus in the literature regarding optimal treatment has not been reached.^1,10 The efficacy of many existing treatments is difficult to assess due to the lack of well-controlled clinical trials.^1,10 There remains a need for more in-depth clinical studies, particularly with regard to nonsurgical therapies in double-blind, placebo-controlled, multicenter, randomized trials with objective, evaluative measures.¹⁰

Invasive treatment options include intralesional corticosteroid injections (eg, triamcinolone), surgical excision, injection of interferons and other chemotherapeutic agents, radiotherapy, laser resurfacing, dermabrasion, cryotherapy, and chemical peels. Noninvasive treatment options include silicone gel sheets, silicone gel ointments/ creams, topical vitamin E, topical onion extract (and compounds derived from allivum), pressure/tissue compression, and topical retinoids. The main problem with most nonsurgical treatments is that little or no evidence of efficacy exists.¹ Many of these treatments are supported only by anecdotal or insufficient clinical data.^1,7 Several modalities are discussed below. Based on a 2002 publication, International Clinical Recommendations on Scar Management by Mustoe et al, however, evidence supports only 2 interventions: silicone gel sheets and intralesional corticosteroid injections.^1,7 These guidelines recommend that silicone gel sheeting should be the first line of treatment in the management of scars, particularly in the prevention of keloids and hypertrophic scars.⁷ In addition, it was recommended that silicone gel sheet therapy be considered as first-line prophylaxis following surgical excision.²¹

Noninvasive Treatment Options

Silicone Gel Sheeting and Silicone Gel Ointment
The use of silicone gel sheeting to prevent and treat hypertrophic and keloid scarring is still relatively new; it began in 1981 with the treatment of burn scars.^10,31 The therapeutic efficacy of silicone gel has been well-documented in the literature.^7,10 Studies show that early intervention with silicone gel appears to be ideal but that older scars have also showed improvement from treatment. When used appropriately, improvements in scar thickness, color, and texture have been noted.^17,32

Topical silicone gel sheeting and silicone gel ointments have been used with the intent to reduce the size, induration, erythema, and pruritus of preexisting hypertrophic scars and possibly prevent the formation of new scars.²⁷ Silicone is characterized as a soft, semi-occlusive scar cover composed of a cross-linked polydimethylsiloxone polymer that has extensibility comparable with the skin.²⁷

Although the exact mechanism of action of silicone gel is not fully known, several theories exist. Many researchers agree that silicone gel sheets act at the stratum corneum, which reduces evaporation and restores homeostasis.^10,27,33 Silicone gel sheeting has an evaporative water loss almost half that of skin.²⁷ In addition, many researchers postulate that silicone acts by creating a hydrated, occluded environment that reduces activity of the capillaries, thus decreasing fibroblast-induced collagen deposition and scar hypertrophy.^25,34 Studies also have shown that silicone gel sheets do not change the pressure, temperature, or oxygen tension at the site of the wound.²⁵ Results from at least 8 randomized controlled clinical trials and a meta study of 27 trials showed that silicone gel sheeting is a safe and effective treatment option for both hypertrophic and keloid scars.⁷

In a 2008 publication, Tandara and Mustoe tested the hypothesis that the use of silicone sheeting in vivo has a beneficial effect on scarring by reducing keratinocyte stimulation, with a resulting decrease in dermal thickness.³⁵ In the study, sheets of silicone adhesive gel were applied to scars in a rabbit ear model of hypertrophic scarring 14 days postwounding for a total of 16 days. Results from the study reported that the scar evaluation index was greatly decreased after silicone gel sheet application when compared with the untreated scars.³⁵ Total occlusion decreased scar hypertrophy by 80%, compared with semi-occlusion. The epidermal thickness index of untreated scars was increased by more than 100%, compared with uninjured skin. Furthermore, silicone gel treatment significantly reduced epidermal thickness by more than 30%. The findings showed that 2 weeks of silicone gel application at a very early onset of scarring decreased both dermal and epidermal thickness, which appears to be due to a reduction in keratinocyte stimulation.³⁵ The study also concluded that oxygen could be ruled out as a mechanism of action of silicone occlusive treatment. The hydration of the keratinocytes seems to be the key stimulus.³⁵

Silicone gel sheets should never be applied to open wounds and should be applied as soon as the skin shows signs of complete epithelialization and/or after surgical sutures have been removed, if applicable.³ The sheets should be worn for a minimum of 12 hours daily and may require use for as long as 6 months. The sheet can be removed for normal skin washing, and the product can be washed and reused. Many gel sheets will last for 14 to 28 days.¹ Silicone gel sheeting is an easy and pain-free therapeutic option for many individuals, especially children. From a practical standpoint, one difficulty with the use of silicone sheeting is the application to contoured/irregular body surfaces or surfaces that are difficult to conceal, like the face.

Silicone gel is gaining popularity, because it can be applied to a smaller area such as the face.⁵ Silicone gel has demonstrated significant reduction in scar volume when used over time. Additionally, some studies have shown an 80% to 100% overall improvement in hypertrophic scar formation.⁵ Chan et al evaluated the use of silicone gel in the prevention of hypertrophic scar development in median sternotomy wounds. The study concluded that the use of silicone gel in the prevention of hypertrophic scar development in sternotomy wounds was effective.³³ No incidence of adverse effects was reported, and patient compliance was satisfactory.³³ The topical use of silicone gel appears to improve the color, appearance, texture, and thickness of hypertrophic and keloid scars and decreases the incidence of itching.³ It has been shown to soften and reduce hypertrophic scars much more rapidly without interfering with pressure, temperature, or oxygen tension.³ Silicone gel is typically applied 1 to 2 times per day. It is colorless and odorless; it dries on the surface of the skin and is imperceptible. For these reasons, it is a particularly attractive and very welltolerated option for children.

Topical Vitamin E
Topical vitamin E (tocopherol) is classified as a lipid-soluble antioxidant.²⁷ To date, the effects of vitamin E on wound healing and improving the cosmetic effects of burns and other dermal injuries are due to anecdotal claims, with little scientific evidence to support them.^1,27 In a study conducted by Jenkins et al, the effects of vitamin E with regard to reducing scarring after reconstructive surgery were evaluated.^34,36 The study found no significant variances between the control group and the treatment group, and an estimated 20% of the study subjects reported a local reaction to vitamin E such as dermatitis.³⁶

Baumann and Spencer investigated the effect of vitamin E on the cosmetic appearance of scars. The results of the study demonstrated no benefit to the cosmetic appearance of scars after the use of topical vitamin E after surgery.³⁷ In addition, the study found that topical vitamin E might actually be harmful to the appearance of scars, because 33% of the study participants developed contact dermatitis.³⁷ Thus, the study concluded that the use of topical vitamin E should be dissuaded.³⁷

Onion Extract (Allivum Derivatives)
Allium cepa or onion extract is found in several nonprescription products marketed for scar treatment. Due to its simple use, widespread availability, botanical ingredients, and reasonable cost, many patients may elect to use scar treatment products containing this ingredient. Theories suggest that onion extract appears to exhibit antiinflammatory, bacteriostatic, and collagen down-regulatory properties and improves collagen organization in a rabbit ear model. Despite the popularity of this ingredient, a lack of clinical evidence exists regarding the beneficial effects of improving hypertrophic scars, however.²⁷

Jackson and Shelton evaluated the efficacy of topical onion extract gel on both the appearance and symptomatology of postsurgical scars, and the results were compared with those of a topical emollient ointment.³⁸ The study concluded that a significant decrease in erythema was visible in the scars of those using the topical emollient ointment and that the onion extract gel was ineffective in decreasing scar erythema.³⁸

Chung et al compared the effectiveness of onion extract gel and a petrolatum- based emollient with regard to improving the appearance and symptoms of new surgical scars.³⁹ The study concluded that although participants tolerated both treatments without incidence of allergic reactions, no significant differences were noted in the appearance of the scars when comparing both products.³⁹

Hosnuter et al evaluated the therapeutic activity of onion extract gel on both hypertrophic and keloid scars with an emphasis on elevation, redness, hardness, itching, and pain.⁴⁰ The study involved 60 patients divided into 3 groups. Group 1 was treated solely with onion extract gel; group 2 was treated with only silicone gel; and group 3 was treated with a combination of both onion extract gel and silicone gel sheet. After 6 months, the onion gel was more effective with regard to scar color, whereas the silicone gel sheet was superior in reducing the height of the scar. The most effective results were observed in group 3, where both onion extract gel and silicone gel sheeting were used.⁴⁰

In 2008, Draelos evaluated the ability of onion extract gel to improve the appearance of scars following excision.⁴¹ The study involved 60 participants who had symmetrical seborrheic keratoses of at least 8 mm in diameter on the right and left upper chest. The lesions were removed, and the surgical sites were allowed to heal for 2 to 3 weeks.⁴¹ During that time, the subjects were divided into 2 groups with each receiving either topical treatment of onion gel or no treatment at all. Results from the study concluded that the use of topical onion extract gel improved scar softness, redness, texture, and overall appearance at the excision site when assessed by the blinded investigator at study weeks 4, 6, and 10.⁴¹

Topical Retinoids
The use of topical retinoic acid has been successful in the treatment of keloids and hypertrophic scars. Panabiere- Castaings reported both a decrease in size and weight of lesions after a trial period of 12 weeks.⁴² The daily topical application of retinoic acid to both intractable hypertrophic and keloid scars has been shown to cause scar softening as well as decrease the size of scarring and the incidence of pruritus.⁵

It is important to note, however, that although rare, it is possible for topical retinoids to be absorbed systemically and cause adverse effects such as hypervitaminosis and teratogenicity.²⁷ Therefore, topical retinoid use should be limited or avoided, especially among certain patient populations (ie, pregnant women or those concurrently using oral vitamin supplements).²⁷ Furthermore, insufficient data exist regarding the effectiveness of topical retinoids on treating hypertrophic scarring.²⁷

Pressure/Tissue Compression
Since the 1970s, pressure therapy has been considered the preferred conservative treatment for the management of scars and the standard therapy for the treatment of hypertrophic scarring after a burn injury.^7,29 It can also be used for treatment of keloid scars.^3,7

A successful response rate ranging from 90% to 100% has been reported among patients treated with pressure therapy after keloid excisions, especially in those patients with ear lobe keloids.²⁴ The amount of pressure delivered should be between 24 and 30 mm Hg to avoid decreased peripheral blood circulation.²⁴

Pressure treatment is believed to accelerate wound maturation by several mechanisms, namely, a thinning of the dermis, decrease in edema, and a reduction of blood flow and oxygen.²⁷ Pressure therapy is particularly successful when applied while the scar is active; it loses some degree of efficacy after 6 months of treatment.^7,27

Typically, the materials used in pressure therapy are custom-made from an elastic material that contains a high spandex content. To prevent a decrease in the elasticity of the materials, they should be changed every 6 to 8 weeks.²⁷ To be effective, pressure must be applied continuously, and the garments are to be worn for approximately 1 year until the scar heals.^3,27

Various factors may be considered drawbacks of using pressure therapy, including its limited use in anatomic depressions, flexures, or areas of high movement, and the need to be worn at all times. The patient also may experience discomfort, and there is the possibility of occasional skin ulceration from uneven pressure distribution.²⁷ Many of these drawbacks can contribute to a decrease in patient compliance, with reports of noncompliance ranging from 8.5% to 59%.²⁷

Imiquimod Cream
Imiquimod 5% cream, which is classified as a topical immune response modifier, is FDA-approved for treating genital warts, basal cell carcinoma, and actinic keratoses. Imiquimod has been used in an attempt to reduce keloid recurrences after excision. Because of the success of imiquimod 5% cream in lowering keloid recurrences after operation, its role in the prevention of hypertrophic scars is currently under evaluation.²⁷ Imiquimod has been shown to improve hypertrophic scar quality after operation in a preliminary small, randomized, prospective clinical trial, but further clinical studies with a larger sample size and longer follow- up are needed to ascertain the role of imiquimod 5% cream in hypertrophic scar therapy.²⁷

Invasive Treatment Options

Corticosteroid Injections
Intralesional corticosteroid injections have been widely used to treat keloid and hypertrophic scars since the 1960s.¹⁰ Despite their use over a long period, however, the primary mechanism of action is still unknown.⁷ It is believed that steroids suppress the inflammatory phase of wound healing, decrease collagen production by the fibroblast, and decrease fibroblast proliferation.²⁴ Intralesional corticosteroid injections are considered the first line of therapy for the treatment of keloid scars and the second line of therapy for hypertrophic scars that have not responded to other treatments.^3,7 The most commonly used corticosteroid for scar treatment is triamcinolone.¹⁰ Multiple studies have shown 50% to 100% efficacy of intralesional injection of triamcinolone as a monotherapeutic agent in reducing scars.^7,10

Typically, the treatment of intralesional corticosteroids involves dosages that range from 10 to 100 mg administered every 3 to 6 weeks for several months.¹⁰ Length of administration depends on how well the scar responds to therapy. Because no standard of therapy exists, the patient's length of therapy is geared to the patient's response.³

Although the use of corticosteroids has been proven to be effective in decreasing scar formation, their use is associated with various adverse effects that occur in as many as 63% of patients. Adverse effects around the injection site include hypopigmentation, particularly in patients with darker pigmentation, dermal atrophy, telangiectasia (superficial blood vessels), widening of the scar, and delayed wound healing.^3,7 Intralesional corticosteroid injections also are associated with significant injection pain.^3,7

Other Invasive Therapies
Examples of other invasive therapies used for the treatment and management of scarring include surgical excision, radiotherapy, cryotherapy, laser therapy, chemical peels, and interferon injections. Whereas surgical excision may be beneficial and provide an immediate improvement in appearance, surgical excision of keloids alone is not always favorable, because the recurrence rate of scars can range from 45% to 93%.^21,24

The use of adjuvant therapies such as postexcisional steroid injections should be considered.²¹ Furthermore, data exist suggesting that preoperative steroid injection in combination with postoperative steroid injection offers a substantial reduction in recurrence associated with keloid excision. In addition, data exist suggesting the potential benefits of using topical mitomycin C as an adjunct to surgical excision; however, these are also small studies with short-term follow-up.²¹

Radiation can be used as monotherapy or in combination with surgical excision in order to prevent recurrence.⁴³ Success with monotherapy has not been acceptable, with recurrence rates reaching 100%. Some success has been shown with large doses of monotherapy; however, this may lead to malignant transformation 15 to 30 years later. Thus, large-dose monotherapy is no longer recommended.⁴³

Cryotherapy has been used for smaller hypertrophic scars, severe atrophic scars, and some keloids. The proposed mechanism of action is cell damage, resultant necrosis, leading to decreased scar bulk.²¹ Its use is restricted due to the occurrence of considerable pain and sometimes prolonged healing following treatment. Because multiple treatments are often required, the risk for hypopigmentation in darker-skinned patients is a significant obstacle.²¹

Atrophic scars have shown improvement with chemical peels, cutaneous laser resurfacing, dermabrasion, punch excisions, and the use of soft tissue biologic fillers.²

Emerging Therapies

Recently, several pharmacologic agents have been investigated as emerging and promising treatments for keloid scars. Although only a few clinical studies have been conducted, monotherapy with intralesional 5-fluorouracil (FU) or bleomycin tattooing have reported moderate to significant flattening of keloid scars in 88% of patients treated with 5-FU and in 92% treated with bleomycin.¹⁶ In addition, no recurrences in those scars that initially responded to these treatments were reported.¹⁶

The mechanism by which 5-FU reduces scarring has not been fully elucidated, but it has been shown that 5-FU inhibits fibroblast proliferation by blocking DNA synthesis and transcription through competitive inhibition of thymidylate synthesis.¹⁰

Adverse effects commonly associated with the use of 5-FU with up to 1 year of follow-up include transient hyperpigmentation (100%), tissue sloughing (21.4%-30%), transient burning sensation (7.1%), or pain (100%) at the injection site. No studies to date have reported systemic complications in patients treated with 5-FU for scar reduction. Long-term follow-up studies show no adverse effects.¹⁰

Bleomycin

Various studies have shown that intradermal injections of bleomycin, which is classified as a polypeptide antibiotic with well-known antitumor, antibacterial, or antiviral activity, have resulted in noticeable improvement in both keloid and hypertrophic scars.¹⁰ The exact mechanism by which bleomycin reduces scarring is not fully understood, but studies have shown that bleomycin inhibits collagen synthesis in dermal fibroblasts through decreased stimulation by TGF-beta1.¹⁰

Adverse effects commonly associated with its use include hyperpigmentation (75%) and dermal atrophy in the skin surrounding treated scars (10%-30%).¹⁰ To date, no systemic toxicity has been reported with low doses of bleomycin when used to treat hypertrophic scars. Future investigations will provide more information about the mechanism by which this drug acts and the effectiveness of this agent with regard to scars.¹⁰

Scar Prevention

Ideally, preventing abnormal scarring is better than treating it. The 2 aspects of the scar process that can be controlled are the technical aspects of wound repair and the postoperative management. From a surgical standpoint, the tissues of a laceration or incision should be handled delicately and be approximated meticulously. Initial dressings should be appropriately protective. Healing incisions on the trunk and extremities are often treated with a semi-occlusive dressing for up to 14 days. For facial incisions, dressings are used less frequently. Meticulous cleaning by patients and families is the single most important factor in control of the patient to affect wound healing and scarring. During the first 3 weeks following injury/repair, the focus should be on maintaining a clean incision.

For open wounds, achieving rapid epithelialization by providing a moist healing environment with ointment and semi-occlusive dressing is appropriate.^9,22 When epithelialization is prolonged past a time frame of 10 to 14 days, the likelihood of hypertrophic scarring increases dramatically.²² In burn injuries, early intervention is indicated, such as through the use of silicone and pressure garments after epithelialization has been complete.³

Just as many treatment approaches exist, many options potentially exist for prevention. For routine postoperative care of incision sites in visible locations, such as the face, the author favors an initial period (2-3 weeks) during which attention is focused on maintaining a clean surgical site. This is followed by 6 to 8 weeks of treatment using topical silicone gel. In the event of hypertrophic scar formation, silicone gel or sheets would be continued, and corticosteroid injection would be considered.

A combination of therapies to improve scar appearance probably holds the best possibility for successful treatment of both normal and abnormal scars. Future studies should continue to focus on evaluating the efficacy of various agents and exploring the potential role of emerging and novel agents for scar reduction.¹⁰

As more treatments and strategies for preventing scarring emerge, one of the best tools health care professionals can give patients is a thorough knowledge of the importance of immediate and proper wound care management, which can play a vital role in preventing or reducing the incidence of scarring. Again, the attention to maintaining a clean surgical/repair site cannot be overemphasized. Regarding counseling, patients with a history of keloid scars or familial history of keloids should be advised to avoid getting body piercings or tattoos, and they also should be discouraged from getting elective procedures at highrisk sites such as the upper arms, chest, or ears.^17,21

Because pharmacists are likely to encounter patients seeking counsel regarding wound care and the various scar treatments currently on the market, it is imperative for pharmacists to advise patients not to rely on the use of anecdotal information found on the Internet and to use products with well-demonstrated clinical efficacy. For the effective management of wounds and scars, it is essential for patients to be informed about the proper protocol regarding treatment and management. It is important for pharmacists to make patients aware of the availability of effective, noninvasive scar products—Table 3^27,44-51 lists topical scar products currently available-and encourage those patients with signs of abnormal scarring to seek the advice of their primary health care provider for proper treatment and to prevent further progression. Examples of when to seek medical attention include wounds that appear to enlarge, that are accompanied by discomfort or pain, show any signs of infection, or restrict movement of a joint.^1,9,10

Table 3

Depression

Joseph P. Vande Griend, PharmD, BCPS

This article will help patients with depression to understand their treatment options and know what to expect from their medications.

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Dr. Vande Griend is an assistant professor at the University of Colorado Denver School of Pharmacy, Aurora, Colorado.

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Everyone has felt down in the dumps at some point in life. For patients with depression, being sad or depressed does not go away quickly. It can last for a few weeks or longer. Patients with depression also can lose interest in areas of life they used to enjoy. They may have gained weight or lost weight. Other symptoms include trouble sleeping, being tired a lot, feeling guilty or worthless, and difficulty with focus. At worst, patients with depression may want to end their lives.

People with depression can have a poor quality of life. They may no longer be interested in their family, their job, or hobbies they used to enjoy. Depression also can affect a patient's overall health. A patient with depression and heart disease is likely to have more problems with their heart.

Depression affects both men and women. Women are almost twice as likely to be depressed. It can also affect children. It is most common, however, in patients 25 to 50 years old. Depression also can run in families. It is more common in patients living in a nursing home, hospitalized patients, and patients with many health problems.

What You Can Do if You Feel Depressed

If you have symptoms related to depression, talk to someone. Talk to your pharmacist, your regular doctor, or a family member or good friend. If you are depressed, visit your doctor. Feelings of depression that do not go away are not normal. Depression also is not a normal part of getting older. People who are depressed are not alone. In fact, nearly 1 of 10 people in the United States will become depressed at some point in their lives.

Table

Treating Depression

Depression is most often treated with medication. Talking to a therapist can also be useful. Taking a medication and talking to a therapist will provide the most benefit. Many different medications are used to treat depression. Medications used today for depression are effective. They have few side effects or drug interactions.

Old medications for depression had many drug interactions and side effects. One old class of depression medication was not very safe. Patients taking this drug could not eat aged cheeses, sauerkraut, or cured meat, and could not drink draft beer. Another older class of medication for depression has many side effects. These drugs cause constipation, drowsiness, dry eyes, and weight gain. These drugs also are not safe with certain heart conditions.

New depression medications have fewer side effects. They also can be taken safely with many other drugs. They treat depression as effectively as the old drugs. The new drugs are used first, instead of the old drugs for depression. The most common new medications are listed in the Table. Several are available in generic form at a lower cost.

Depression can affect a person's quality of life. It can make you sad, and make you lose interest in things you enjoy. Treatment for depression is available. Medication is most commonly used. It is most effective at treating depression when a patient understands the therapy and uses it correctly. When treated with medication for depression, be patient. Take your medication as your doctor tells you, and visit your doctor and pharmacist often. Be prepared for changes in your medication and lifelong treatment. Following this advice can help you beat the blues.

4 Tips for treating depression with medication

Medication for the treatment of depression can make the condition go away. Depression is most commonly treated with medication. Patients must understand their medication and how to use it correctly. This will help them feel better faster. The following information can help patients get the most from their medication:

1. It takes time for depression medication to work.
Depression medication takes at least 4 weeks to work. Many patients often stop the medication because they think it is not working, but they have not yet given it a chance to work. If you think the drug is not working, do not stop it. Continue taking the medication the way your doctor has instructed. If you feel worse with the medication, call your doctor. It can take up to 4 months for a depression medication to work best. Give the medication time to work. It can make you feel better over time.

2. See your doctor or pharmacist regularly.
Patients with depression are often jittery, anxious, or uneasy. Taking a medication to treat depression can make this worse at first. This will go away. If you feel really bad taking the medication, call your doctor. You can also talk with your pharmacist. Talk to your doctor or pharmacist before stopping a medication. They may give you a lower dose or try a different medication. They will make sure you have a good treatment for your depression. Your doctor and pharmacist also understand depression. Talking to them about your depression can make you feel better. They will help you get the most from any treatment.

3. Different medications may be needed to treat your depression.
Investigators did a large study on medication for the treatment of depression. In the study, every patient started on citalopram (see Table above). This medication is commonly used. It has few side effects and is easy to tolerate.

Patients in the study took this drug for 3 months. One of 3 patients no longer had depression after 3 months. Two thirds of patients required a change in medication. For some, the depression medication was switched. For others, another depression medication was added to citalopram.

This study showed that depression is not an easy fix. Very few people will no longer have depression after one medication. Your doctor will often need to change your medication. Finding the right medication for you may take time. Do not get frustrated, but continue to see your doctor or pharmacist. They can help find the medication that is best for you.

4. Depression may be a lifelong disease.
Depression often goes away but then comes back again. This is common. If depression is treated well the first time, it is less likely to come back. To prevent future depression, it is important to take your medication for as long as your doctor tells you. Even if you feel better, continue your medication until you are told to stop. You may need to take your depression medication for 2 to 3 years after you feel better. Some people will need to take depression medication for the rest of their lives. If you think you should stop, talk to your doctor or pharmacist. They will be able to explain to you how long you need the treatment.

Understanding and Managing Lactose Intolerance

W. Steven Pray, PhD, DPh
Bernhardt Professor of Nonprescription Drugs and Devices
College of Pharmacy
Southwestern Oklahoma State University
Weatherford, Oklahoma


12/15/2008

US Pharm. 2008;33(12):12-15.

The inability to ingest milk as an adult, known as lactose intolerance (LI), is characteristic of many ethnic groups. The pharmacist must have a full understanding of LI and the various products that can be used to help prevent this condition from producing uncomfortable symptoms.

Lactose Digestion
Lactose in milk is a rich nutrient for infants, who develop the ability to break it down into glucose and galactose by producing lactase in the brush border membrane of the small intestine.¹ Lactase levels remain high during infancy, until weaning from the breast occurs. Then there is a gradual loss in the ability to digest milk, due to a loss of ability to produce lactase. This is called primary LI, also known as hypolactasia or lactase deficiency.^2,3 Some people retain the ability to digest milk as adults; these individuals are referred to as lactase persistent or lactose tolerant.

Prevalence
Approximately 70% of the world's peoples are lactose intolerant.⁴ The incidence of primary LI is about 90% to 100% in Native Americans, Africans, and Asians. It is estimated to be 80% in African Americans, and 55% to 80% in Hispanics. The lowest incidence (10%-15%) occurs in those descended from northern Europeans, residents of the northwestern Indian subcontinent, and desert nomads.⁵

The theory for this sharp difference in prevalence relies on archeological and anthropological evidence suggesting that the ancestors of those with lactase persistence herded cows or camels and learned to ingest their milk as a survival measure. Those who were lactase persistent survived to pass that mutation on, eventually becoming the predominant state in that subculture.

Secondary Lactose Intolerance
Some patients with lactase persistence lose the ability to digest lactose as a result of environmental triggers, a condition known as secondary LI. Lactase production is confined to the upper third of the intestinal villi.⁴ Due to its superficial location, conditions that affect villi often disrupt lactase production. One example is intestinal infection. Rotavirus is a common cause of diarrhea in infants, often contracted in daycare. After the child recovers from the effects of the rotavirus, parents may notice the infant cannot ingest formula or milk like before. Infection with Giardia lamblia or enteropathogenic Escherichia coli may also be causal. Patients who experience secondary LI from an infection may be advised to slowly reintroduce lactose-containing products to ascertain whether lactase is again present. If it is not tolerated, lactose should be withdrawn and reintroduced later.

Secondary LI may also be caused by celiac disease, malnutrition, irritable bowel syndrome (IBS), or intestinal surgery.⁴ Tetracyclines, neomycin, cimetidine, and antithyroid medications have all been implicated as causes.

Manifestations
The manifestations of primary and secondary LI are virtually identical. When a patient with LI ingests milk, lactose that cannot be digested reaches the small and large intestines in intact form. Symptoms usually begin about 30 to 120 minutes postingestion. Lactose is osmotically active and causes the intestines to draw in and retain additional water with a meal. This osmotic activity produces the same type of manifestations as ingestion of saline laxatives, such as magnesium citrate or Fleet Phospho-Soda.

Initial symptoms of the excessive intestinal fluid include nausea, rumbling in the stomach, cramping, and abdominal discomfort or pain.⁶ The excessive fluids are moved through the bowel more rapidly. When they reach the large intestine, resident bacteria ferment the lactose, causing excessive production of hydrogen, short-chain fatty acids, methane, and carbon dioxide.⁷ Thus, the patient also experiences flatulence, bloating, and added abdominal discomfort. The end result is the collection of large amounts of gas and fluids in the distal bowel. The patient usually feels an urgent need to defecate. If the individual is unable to do so, intense pressure may overcome the anal sphincter's ability to retain materials, causing involuntary leakage of stool, staining of undergarments, and incontinence. If the patient is able to defecate, stools will often be diarrheal and watery.

Diagnosis
There are several tests that can be used to diagnose LI. In the lactose tolerance test, blood glucose is examined at several points after lactose ingestion to determine whether it was digested.^8,9 A hydrogen breath test measures intestinal absorption of hydrogen after lactose inges­ tion.¹⁰ The hydrogen level in the breath is normally nil. Elevated levels imply colonic maldigestion of lactose with resultant hydrogen production.

Tolerance Level
Adults who retain the ability to ingest dairy products can take full advantage of their nutrients (i.e., calcium, vitamins A and D). Those whose diets completely restrict milk intake are especially prone to osteoporosis and osteopenia, increasing the risk of bone fractures in later life.⁴ Many Americans lie in the middle of these two extremes in that they can ingest a specific amount of lactose without experiencing symptoms. Unfortunately, they may assume that they are completely lactose intolerant and voluntarily cease ingestion of all dairy products.

The pharmacist can provide advice on determining the individual lactose tolerance level, allowing patients to still obtain the nutrients found in dairy products. Patients should be advised to identify all milk-containing foods and avoid them scrupulously for about three weeks. If symptoms persist, there are two possibilities.⁴ Either they are still ingesting lactose, or they have another condition such as IBS. If further lactose restriction does not cause symptoms to abate, they must seek a physician diagnosis. If the symptoms do remit, they should remain on the lactose-free diet for three more weeks. Then, adhering to the same diet, the patient should ingest one-quarter cup of milk with breakfast. If symptoms recur, the patient is highly lactose intolerant and should adhere to the diet without introducing milk. However, if they tolerate the milk without symptoms, they should repeat the diet and milk for several days. They should then increase the amount of milk to one-half cup and repeat the cycle. Eventually, they will come to a level that is comfortable for them.

OTC Lactase Products
Pharmacists can also aid patients by suggesting that they purchase lactase-containing tablets. The most well-known product is Lactaid.⁴ It is available in two strengths. Lactaid Original Strength Caplets contain 3,000 FCC units of lactase. The suggested dose is three caplets swallowed or chewed with the first bite of a dairy product. Lactaid Fast Act is available as caplets or chewable vanilla tablets. Each dosage form contains 9,000 FCC units, with a suggested dose of one caplet/tablet with the first bite of dairy. Generic products are also available.

Milk Substitutes
Patients may also be advised by the pharmacist on nonpharmacologic methods to prevent LI. The major thrust is to substitute normal dairy products with lactose-free versions. There are a wide variety of milk substitutes on the market. They include the Lactaid brand, real milk products to which lactase has been added, producing altered milk that is useful for those with LI.⁴ All require refrigeration. The Dairy Ease line of products includes whole milk, reduced-fat, and fat-free options. Consumers can also try a line of soy substitutes, such as Silk Soymilk products, or rice-based milk substitutes, such as Rice Dream.

Milk Allergy
Some patients with LI mistakenly believe that they have developed a milk allergy. It is critical to differentiate LI from a milk allergy.¹¹ Patients with a true allergy to cow's milk must scrupulously avoid it to prevent a constellation of allergic reactions, including fatal anaphylaxis. However, LI is not due to an allergic reaction--it is a food intolerance.¹² With proper advice from pharmacists, patients with LI can still ingest milk and gain the benefits of its nutrients.

Patients With Headaches: The Pharmacist's Role

W. Steven Pray, PhD, DPh
Bernhardt Professor of Nonprescription Drugs and Devices
College of Pharmacy
Southwestern Oklahoma State University
Weatherford, Oklahoma

1/26/2009

US Pharm. 2009;34(1):12-15.

Pharmacists are often approached by patients who request assistance when choosing a headache medicine. For this reason, pharmacists should be able to recognize the headaches that are amenable to self-treatment and those that require referral to a physician.

Danger Signs With Headaches

Several signs indicate serious pathology that necessitate an immediate emergency room visit.^1,2 These signs include the sudden appearance of the first headache one has ever had in his or her life, especially in a patient over the age of 50 (possible subarachnoid hemorrhage or lesion); a headache brought on by exertion or exercise (possible aneurysm); loss of awareness of surroundings; decrease in mental functioning; the worst headache one has ever experienced; a headache that hits like a sudden thunderclap (possible subarachnoid hemorrhage); headache during pregnancy or the postpartum period (possible cortical vein or cranial sinus thrombosis); and a headache that awakens the patient from sleep.

Headaches to Refer

Headaches that require referral are those caused by serious underlying pathology, also known as secondary or organic headaches. Some are caused by trauma, known as posttraumatic headaches.³ The patient may have had a recent fall or blow to the head, or a whiplash injury to the neck. The headache generally begins within seven days of the event. Trauma may also cause an epidural or subdural hematoma, with the headache beginning within 24 hours and 24 to 72 hours postevent, respectively.

Headaches may also be due to medication overuse. Medication-overuse headaches are often daily in occurrence, migraine and/or tension in subtype, and caused by chronic, daily use of ergot derivatives or analgesics. These headaches occur in 1% to 2% of the population and are resistant to medical therapies and various nondrug medical interventions.^4,5 The ideal treatment is abrupt cessation of the causative medications, but this must be advised and managed by the patient's physician.

Space limitations preclude an exhaustive listing of other headache etiologies that require referral, but they include carbon monoxide exposure, sinus infections, and temporomandibular joint syndrome. Unless the pharmacist can determine that the patient's headache is clearly one of the self-treatable primary subtypes, it is prudent to refer the patient for a medical evaluation.

Primary Headaches

Primary (benign) headaches are neurological in origin and etiology, and may be self-treated under certain circumstances.⁶ They include chronic daily, tension-type, migraine, and cluster headaches.

Chronic Daily Headache: An estimated4% to 5% of people suffer from chronic daily headache (CDH), which are headaches that occur on 15 days or more each month.^2,7 CDHs are classified as primary (e.g., migraine, tension, or cluster) or secondary, due to such underlying causes as medication overuse, infection, tumor, or trauma.⁷ Because of the various possible etiologies, the patient who complains of CDH should first be referred for a full evaluation. If the physician rules out serious pathology, the pharmacist may suggest nonprescription products when appropriate.

Tension-Type Headache: Tension-type headache (TTH) is thought to arise when a patient is placed under undue strain, such as workplace demands that are difficult to fulfill or family obligations that appear to be overwhelming.⁸ TTH exhibits a clear and consistent gender preference, affecting only 38% of men but 45% of females.⁹ They are also known as muscle contraction headaches, a term that refers to the hypothesized etiology of sustained muscular tightness in the head, neck, and/or shoulders in response to life stressors. The patient complains of a bandlike tightness, pressure, or constriction around the forehead and temples that may radiate to or from the neck.¹ The pain is described as bilateral, nonpulsating, pressing, or tightening. TTH is not brought on or worsened by routine physical activities such as climbing stairs. Nausea and vomiting are uncommon.¹⁰ These headaches can last from 30 minutes to seven days, but may persist for months or years, depending on the nature and gravity of the patient's stressors and the individual's inability to successfully cope with them. The severity of a particular episode varies from mild to moderate.

Migraine Headache: Migraine affects about 12% of Americans, and at least 25% of females will experience it at some point.¹¹ The duration is one to 72 hours, with the migraine being more often unilateral, throbbing/pulsing, and moderate to severe in quality.¹⁰ Patients often report increased pain if they carry out routine physical activity, nausea/vomiting, and extreme sensitivity to sound and light (e.g., photophobia, phonophobia). Physical disability is also characteristic, as the patient avoids behaviors that worsen the migraine. Some patients report migraine with aura (i.e., visual, sensory, and/or motor changes that precede the onset of migraine pain). Visual changes are the most common aspects of the aura and include such phenomena as flickering lights, bright spots that obstruct vision, or lines across the visual field. Some patients also report loss of sight or defects in the visual field that disrupt vision.

Cluster Headache: Cluster headache is more common in males, with a male-to-female ratio as high as 9:1.¹ Attacks recur in clusters two to eight times a day for several weeks before abating for several months. This headache is unilateral, with a deep, boring pain behind the eye or in the periorbital region. Patients often state that the pain feels as though a red-hot fireplace poker were being pushed directly into the eye. Ancillary symptoms occurring on the same side include nasal congestion, rhinorrhea, ophthalmic tearing, sweating on the face or forehead, miosis, ptosis, and eyelid edema.

Treatment of Headache

The analgesic market presents the consumer with many choices of single-entity and combination products (e.g., aspirin and other non steroidal anti-inflammatory drugs, acetaminophen). Patients should be advised that the treatment limit for unsupervised self-usage of internal analgesics is 10 days for adult headache, unless the package label recommends a shorter time. Analgesics for headache include an alcohol warning advising against use if the patient consumes three or more alcoholic drinks daily.¹

Headache-Specific Nonprescription Products

While virtually all adult analgesics carry labeling for headache, manufacturers segmented the market several years ago by producing products with labeling and/or trade names specific for certain types of headache. The first were two products for migraine--Excedrin Migraine Tablets and Advil Migraine Liquid-Filled Capsules.^12,13

Products promoted specifically for migraine must include all of the general warnings required on other internal analgesics, but also a set of migraine-specific warnings that include far more detail than other internal analgesics.^12,13 Patients under 18 years should not take migraine-specific analgesics. Those over 18 years should take two capsules/tablets with a glass of water daily; they should not take any additional product for 24 hours and should contact a physician if symptoms persist. Patients should speak to their physician before using migraine-specific analgesics if they have never had migraine diagnosed; if their headache differs from the usual migraines; if it is the worst headache of their life; if they have fever and stiff neck; if headaches began after or were caused by head injury, exertion, coughing, or bending; if they experienced their first headache after the age of 50; if they have daily headaches; if they have asthma, bleeding problems, or ulcers; if they have migraine so severe as to require bed rest; if they have stomach problems such as heartburn, upset stomach, or stomach pain that do not go away or recur; and if they have problems or serious side effects from taking pain relievers or fever reducers.

Migraine products containing ibuprofen (e.g., Advil Migraine) carry additional labeling particular to all nonprescription ibuprofen products.They are not contraindicated in patients who have vomiting with their migraines, as is the case with Excedrin Migraine.¹³

Migraine combination products containing acetaminophen, aspirin, and caffeine (e.g., Excedrin Migraine) also carry specific warnings in addition to the general migraine warnings.¹² They warn patients that the product contains as much caffeine as a cup of coffee, and caution against use of caffeine-containing foods, beverages, or medications while using them to prevent nervousness, irritability, sleeplessness, and tachycardia. They warn against use if the patient has vomiting with migraines. Patients are urged to speak to a physician or pharmacist if they are taking medications for anticoagulation, gout, arthritis, or diabetes; if they are under a physician's care for any serious condition; taking any medication that contains aspirin, acetaminophen, or any other pain reliever/fever reducer; or if they are taking any other medication. Patients are urged to stop use and speak to a physician if an allergic reaction occurs, if the migraine is not relieved or worsens after the first dose, if new or unexpected symptoms occur, if ringing in the ears or loss of hearing occurs, and if stomach pain or upset gets worse or persists.

There are other headache-specific products, such as one for tension headache (e.g., Excedrin Tension Headache Geltabs) and one for sinus headache (e.g., Excedrin Sinus Headache Caplets).^14,15 The former contains 500 mg of acetaminophen and 65 mg of caffeine per geltab, and the latter contains 325 mg of acetaminophen and 5 mg of phenylephrine HCl per caplet. Unlike products labeled for migraine, these medications do not carry labeling that warns the patient about specific issues pertaining to either tension or sinus headache.

Unproven Products for Headaches

Numerous unproven products are promoted for treatment of migraine headaches. They include dietary supplements and homeopathic products. HeadOn Migraine is a tube of homeopathic product that is "applied directly to the head" to provide migraine relief.¹⁶ Its unproven formula contains diluted blue flag, potassium dichromate, and white bryony. Gelstat Migraine is a sublingual product containing diluted ginger and feverfew.¹⁷ None of the ingredients in either product is proven to provide relief for any type of headache, and when they are subjected to homeopathic dilutions, their efficacy is further in question. These unproven products should neither be stocked nor recommended.

Refractory Epilepsy

Mitra Habibi, PharmD
Clinical Assistant Professor, Pharmacy Practice
College of Pharmacy
University of Illinois at Chicago
Chicago, Illinois

3/18/2009
US Pharm. 2009;34(3):HS8-HS14.

Seizures are brief, paroxysmal, and abnormal neuronal discharges in the brain. About 10% of the population will experience a seizure at some point during their lifetime. In most of these individuals, seizures will not recur after the underlying cause has been corrected. Epilepsy, which is the recurrence of unprovoked seizures, occurs in about 1% of the population. There are approximately 200,000 new cases each year.^1,2

Most newly diagnosed epileptic patients will become seizure free on their initial antiepileptic drug (AED) therapy; however, about 30% continue to experience seizures despite trials with multiple AEDs and are diagnosed as having refractory epilepsy.^3-6 Studies show that patients who fail their first AED are less likely to become seizure free with each subsequent trial of another AED. This indicates that some patients have difficult-to-control epilepsy from the start. Conversely, some patients only show evidence of refractoriness to AEDs after several years of therapy.^5-7

Some early indications that a patient might be resistant to treatment include young age at onset, multiple seizures prior to receiving treatment, seizures occurring in clusters, seizure type, abnormal neurologic exam, and developmental delay.^5,6

In general, these patients are referred to epilepsy centers to receive comprehensive epilepsy care and are treated with combinations of different AEDs. However, there is evidence that even combination therapy with the most efficacious AEDs results in 50% improvement in only 32% to 37% of these patients.⁶ Nondrug options available to these individuals include epilepsy surgery, vagus nerve stimulation (VNS), and ketogenic diet.

Causes of Treatment Failure

Misdiagnosis of seizure type is a common cause of poor outcomes and should be considered before a patient is labeled with refractory epilepsy. Seizures are divided into partial (onset limited to one cerebral hemisphere) or generalized (onset involving both cerebral hemispheres). Partial seizures are further divided into simple partial (consciousness preserved), complex partial, or secondarily generalized (consciousness impaired). Generalized seizures are classified as convulsive or nonconvulsive types and are divided into several major categories (TABLE 1). Partial seizures are the most common type of seizure and the most difficult to control. Treatment failure can be the result of inappropriate selection of an AED for the specific type of seizure. For example, carbamazepine is a potent and efficacious AED and can be used to treat many types of seizures; however, it is well known to aggravate myoclonic and absence seizures.^2-4,6

Poor compliance or noncompliance is also a common cause for treatment failure.^4,6 In this case, selecting an AED with a better side-effect profile and a more simplified daily regimen may improve compliance and outcomes. To prevent seizure recurrence, patients should be educated early on about certain precipitating factors such as sleep deprivation, excessive alcohol consumption, intercurrent illnesses, and use of medications, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, or bupropion, which may lower seizure threshold.

Antiepileptic Drug Therapy

Over the past 15 years, 11 new AEDs have been approved in the United States (TABLE 2), expanding the number of combinations available to manage difficult-to-treat epilepsies. The new generation of AEDs offers similar efficacy compared to the older drugs (i.e., carbamazepine, phenytoin, phenobarbital, primidone, valproic acid), but with better side-effect profiles and fewer drug–drug interactions. The appropriate combination and optimal use of these drugs require knowledge of their mechanisms of action, pharmacokinetics, and pharmacodynamics.⁷

The mechanisms of some of the new AEDs are not completely understood. However, AEDs are generally grouped based on three mechanisms of action: 1) modulation of voltage-gated calcium, sodium, or potassium ion channels; 2) enhancement of gamma-aminobutyric acid (GABA)–mediated inhibition; and 3) reduction of the excitatory glutaminergic neurotransmission by blocking either the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-d-aspartate (NMDA) subtypes of the glutamate receptor.^8,9

Evidence shows improved efficacy or increased tolerability when AEDs with different mechanisms of action and side-effect profiles are combined. Data suggest that combining certain medications may result in therapeutic synergy and benefit patients with generalized tonic-clonic and partial seizures. These medications include a sodium-channel blocker with a GABA-ergic inhibitor, two drugs with GABA-ergic properties, and an NMDA antagonist with an AMPA antagonist. Combinations meeting these criteria include phenytoin/valproic acid, valproic acid/carbamazepine, valproic acid/lamotrigine, carbamazepine/topiramate, phenobarbital/topiramate, felbamate/topiramate, oxcarbazepine/topiramate, and lamotrigine/topiramate.^3,9,10

New Developments: A number of drugs in different stages of development may offer an alternative in patients with refractory epilepsy. Some of these are synthesized to enhance and improve the activity and adverse effect profiles of existing AEDs, including brivaracetam (levetiracetam analog), valrocemide (valproate analog), licarbazepine (oxcarbazepine analog), and fluorofelbamate (felbamate analog). Others have unique structures and may exert their activity through a novel mode of action.⁷

Two such drugs, lacosamide and rufinamide, were recently approved by the FDA.^11,12 Lacosamide, a functionalized amino acid with a dual mode of action, is indicated as adjunctive therapy in treatment of partial seizures in patients aged 17 years and older. It is available as both a tablet and for injection; the IV formulation is approved for temporary use when the oral administration is not feasible. Rufinamide is a triazole derivative and is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in adults and in children as young as 4 years. It is available in tablet form for oral administration. In clinical trials, patients in rufinamide and lacosamide groups showed significant improvement in seizure frequency compared with placebo. Both medications were relatively well tolerated and the most common adverse effects reported included dizziness, nausea, and headache.^11,12

Pharmacoresistance

The development of refractoriness to AED therapy is not very clear; however, two hypotheses have been proposed. Based on the target hypothesis, changes and alterations in AED targets such as ion channels or neurotransmitter receptors may lead to poor drug response.^13-16 The transporter hypothesis postulates that overexpression of multidrug transporters such as P-glycoprotein in the blood–brain barrier may impair drug penetration into the brain and cause multidrug resistance in epilepsy. These changes may be intrinsic (i.e., genetically determined) or acquired (i.e., secondary to recurrent seizures). These hypotheses have been investigated in animal models as well as the brain tissue of refractory epileptic patients; however, support for their clinical relevance is lacking.^13-16

Epilepsy Surgery

Brain surgery is an alternative treatment for patients with refractory epilepsy. The best candidates for surgery are individuals with focal epilepsy whose seizures arise from one area that is not critical for brain function. Because of significant advancements made in imaging and surgical techniques, it is possible to identify and remove the origin of seizures (seizure focus) more accurately. For carefully selected patients, epilepsy surgery can bring seizure freedom or a significant reduction in seizure frequency.^3,17

There are two main types of surgery in epilepsy. The most common type is resective surgery, which consists of removing the seizure-generating focus. Resection of the mesial (medial) temporal lobe sclerosis (scar) accounts for about 75% of adult surgical procedures. In this procedure, the scar tissue or the seizure focus is surgically removed. On average, 48% to 84% of these patients have reported seizure freedom after this temporal lobectomy. The second and less common type is a palliative procedure to prevent the progression of seizure by interrupting the nerve pathways. In corpus callosotomy, the corpus callosum connecting the two hemispheres of the brain is disconnected, preventing progression and generalization of the seizure. This is an effective procedure—there have been reports of 80% reduction in generalized tonic-clonic seizures and 50% reduction in complex partial, myoclonic, and absence seizures.^3,17,18

Other Therapies

Vagus Nerve Stimulation: Other therapies available to patients with refractory epilepsy include VNS and ketogenic diet. VNS is a nonpharmacologic tool that can be considered as an adjunctive therapy for patients with refractory partial seizures who are not candidates for epilepsy surgery or are unwilling to undergo such procedures. The pulse generator of this device is implanted subcutaneously in the left infraclavicular region and is connected to the left vagus nerve. Studies show 50% improvement in seizure frequency in 37% of patients in their first year of therapy; however, seizure freedom is rare.¹⁹

Ketogenic Diet: Ketogenic diet is a high-fat, low-carbohydrate diet that has shown efficacy in treatment of refractory epilepsy. Although the mechanism of its antiepileptic activity is not completely understood, new evidence suggest that the production of ketone bodies may diminish hyperexcitability of neurons and improve seizure control.²⁰ However, its potential complications, such as metabolic acidosis, hypoglycemia, dehydration, and hyperlipidemia, should be discussed before considering this diet.

Conclusion

Despite the availability of new drugs and the expansion of our options for treating epilepsy, at least 30% of newly diagnosed individuals remain refractory to current treatment. Improved understanding of the causes of refractoriness and development of novel agents hold the promise of therapeutic outcomes in the near future.

Patients with refractory epilepsy are usually treated with multiple AEDs, and because of the chronic nature of this disease, comprehensive care for these individuals should include their sociopsychological needs as well as the management of the chronic side effects of these medications. Pharmacists with a good knowledge of the pharmacokinetic and pharmacodynamic properties of AEDs can play a significant role in the management of individual drug therapy and subsequently improve patient outcomes. This can be achieved by adjusting medication doses based on serum levels and patients’ response and tolerance, anticipating drug–drug interactions and adverse drug reactions, and improving compliance by educating patients about their medications.

Pediatric Otitis Media: Managing Ear Infections in Children

W. Steven Pray, PhD, DPh
Bernhardt Professor of Nonprescription Drugs and Devices
College of Pharmacy
Southwestern Oklahoma State University
Weatherford, Oklahoma

3/18/2009
US Pharm. 2009;34(3):12-15.

Most pharmacists have been confronted by a parent whose child has an apparent ear infection, usually otitis media. The parent understandably wants to relieve the child’s pain, but nonprescription products are of no use in ear pain or otitis media, which greatly limits the scope of advice the pharmacist can offer the parent. However, the pharmacist should understand various facts about the condition in order to answer the parent’s questions.

Prevalence of Pediatric Otitis Media

The annual number of cases of otitis media in all segments of the population is unknown, but is estimated to be approximately 2.2 million (otitis media with effusion) to 5 million (acute otitis media).^1,2 Focusing exclusively on pediatric cases, experts estimate that 75% of children will suffer one or more episodes by the age of 3.^3-5 Furthermore, approximately one-half of those who do contract an ear infection will experience three or more ear infections by the age of 3 years.⁴ These startling statistics are further buttressed by the fact that ear infections are the most common illnesses experienced by babies and young children and are the number one cause of consultations with physicians, and that otitis media is the most common cause of hearing loss in children.^3,6,7

Otitis media is responsible for at least $5 billion each year in medical costs and lost wages.⁴ Acute otitis media requires more than 20 million antibiotic prescriptions yearly, and it has been identified as the most common justification for prescribing antibiotics in children.^8-10 Approximately 20% of children develop a form of acute otitis media that is recalcitrant to treatment, being characterized by increased persistency and recurrences.¹¹

Subtypes of Otitis Media

Otitis media is subdivided into several separate conditions. One is acute otitis media(AOM). The National Institute on Deafness and Other Communication Disorders (NIDCD) explained that AOM denotes a painful infection in which certain ear structures are infected and inflamed, with fluid and mucus being trapped in the ear.³

By contrast, the NIDCD defines otitis media with effusion (OME) as a noninfectious condition in which fluid and mucus are trapped in the ear, possibly following a bout of AOM, a condition also referred to as “glue ear” or serous otitis media.² This condition makes it more difficult to resist future infections and can also affect hearing.

The National Institutes of Health defines chronic otitis media as a subcategory of otitis media in which fluid persists, and there may or may not be infection with bacteria or viruses.¹² The agency also defines suppurative chronic otitis as a situation in which the eardrum undergoes repeated bouts of rupture or draining or in which middle ear or mastoid inflammation persists.

The medical literature utilizes a third term for a subtype of otitis media, recalcitrant or difficult-to-treat otitis media.^1,11 The patient begins with a case of acute otitis media, but antibiotic therapy fails to effect an improvement in signs and symptoms after 48 to 72 hours or more. In addition, the patient with this condition has had three or more episodes in the past six months, or has experienced four or more episodes in the year prior to the present incident.

Epidemiology of Pediatric Otitis Media

Children are the most common targets for otitis media, as the peak incidence is four to 24 months.¹ This is due to a combination of genetic, infectious, immunologic, and environmental characteristic and factors peculiar to pediatric patients.¹ For instance, the shape and caliber of the eustachian tube in children favor infection, as does the fact that children’s immunologic systems are immature and still developing.⁴

Breast-fed children have a decreased incidence of otitis media as opposed to those who feed from a bottle while lying down.^1,4 This may be due to a specific position assumed during breast-feeding, to the movements required in suckling, or to breast milk’s well-known ability to protect from infection.¹ Use of pacifiers increases the incidence of otitis media.

Attending day care is associated with an increased incidence of the condition. Being around air pollution or smokers is also a risk factor, much more so if the smokers are the parents themselves.^1,3 The risk is greater in babies of Native American, Alaskan, or Canadian Inuit background. Otitis media is more common in children of lower socioeconomic status, perhaps secondary to such contributing factors as crowded conditions, inappropriate hygiene, improper nutrition, and limited access to medical care.⁸

Etiology of Pediatric Otitis Media

Otitis media occurs as the culmination of a sequence of events. The inciting factor in most cases is another condition that also causes congestion and inflammation of the nasal mucosa, nasopharynx, and eustachian tube.¹ Thus, otitis media may follow such causative conditions as allergic rhinitis or an upper respiratory tract infection.

When the patient has an infection, bacteria are able to move through the lining or passageway of the eustachian tube to reach the middle ear.⁴ Infection causes inflammation of the middle ear lining, obstructing the eustachian tube at its narrowest segment (also known as the isthmus).^1,4 White blood cells and bacterial residue collect to form thick, yellowish pus in the middle ear. Middle ear secretions and air cannot exit as they normally do, and they collect (effusion).

Eustachian tubes in children are smaller and straighter than those in adults.³ This anatomic distinction lessens the ability of water to drain from the ear, predisposing children to otitis media.

Adenoids, located in the throat in close proximity to the eustachian tubes, are also prone to infection and inflammation, which can block eustachian tube openings and cause the same problems as when the common cold is the cause.³ Adenoids in children are larger than those in adults, predisposing them to adenoid-induced eustachian blockage.

Microbiology of Pediatric Otitis Media

When effusion fluids from pediatric patients with acute otitis media are examined, the usual organisms isolated are Streptococcus pneumoniae (40%-50% of cases), Haemophilus influenzae (30%-40% of cases), and Moraxella catarrhalis (10%-15% of cases).¹ When a child has experienced persistent or recurrent acute otitis media, the most common offender is penicillin-resistant strains of S. pneumoniae.

Manifestations of Pediatric Otitis Media

Physicians establish a diagnosis of acute otitis media using three diagnostic criteria: 1) acute, rapid onset of symptoms; 2) middle ear effusion as noted by bulging of the tympanic membrane; and 3) signs and symptoms consistent with inflammation of the middle ear.¹³ Infants and young children may display such nonspecific manifestations as diarrhea, vomiting, anorexia, fever, headache, irritability, cough, rhinitis, listlessness, and pulling or tugging at the ears.¹ Overt ear pain is less common in children under the age of 2 years, but more common in adolescents and adults.

Complications of Pediatric Otitis Media

If the problem persists for a sufficient period, the child’s hearing is seriously compromised due to an inability of the tympanic membrane and middle ear bones to vibrate normally.⁴ Eventually, the child’s speech and language are affected.³ This occurs because the child must hear normally to allow him or her to interpret normal speech and imitate it as language and speaking skills evolve. Severe ear pain is common, and rupture of the tympanic membrane is a possibility.⁴ Infection can extend to areas such as the mastoid or brain.^4,12

Treatment of Pediatric Otitis Media

The goals of treating pediatric otitis media are to resolve symptoms and reduce the risk of its recurrence.¹ Antibiotics are the most often recommended medication in active otitis media, with analgesics for ear pain.⁴ Unfortunately, about 34% of streptococcal infections are now resistant to penicillin, and 22% are resistant to multiple medications.⁹

A set of guidelines from the National Guideline Clearinghouse states that amoxicillin should be the first choice for all cases of acute otitis media.¹⁴ The recommended dose is 80 mg/kg/day in two equally spaced, divided doses for five to 10 days in those aged less than 4 years, increased to 40 to 60 mg/kg/day for those aged 4 years and above. If the patient is allergic to amoxicillin, the guideline suggests a single dose of azithromycin dosed at 30 mg/kg. If the infection fails to respond to amoxicillin after 72 hours, the guideline recommends administration of
amoxicillin/clavulanate dosed at 80 mg/kg/day of amoxicillin component, divided into two equally spaced daily doses for 10 days, or azithromycin 20 mg/kg daily for three days.

If the child has OME, antibiotics are not indicated, as there is no infectious component. However, the child must have periodic examinations to ensure that the effusion has cleared, and possible appointments with otolaryngologists to assess the impact of hearing loss on language delay.¹⁴ If fluid persists for more than three months and the child has hearing loss, physicians may place tubes in the eardrum in the procedure known as a myringotomy.

Precautions in Pharmacist Recommendations

The patient with any type of ear pain or suspected otitis media must be referred to a physician or pediatrician for assessment. It is improper for the pharmacist to recommend any nonprescription product, such as decongestants (e.g., pseudo ephedrine), antihistamines, or analgesics and suggest that the patient will thereby be able to avoid an appointment with a physician.

Pharmacists may field questions about the use of olive oil (sweet oil) in the ear when the child has ear pain or an apparent ear infection.¹³ The patient may volunteer that the person who recommended this old home remedy also said the olive oil should be warmed prior to instillation. Placing warm oil in the ear may temporarily soothe the ear that is pained with otitis media. However, the pharmacist should explain that the source of the ear pain and infection is beyond the tympanic membrane. Olive oil cannot (and should not) pass through an intact tympanic membrane. Its use delays securing appropriate care for the child, and applying it only gives a false sense of security to parents and caregivers.