Pharmacists resource on healthsensei

Optimizing Individualized Management of OSTEOARTHRITIS

2009-08-31T10:56:00.000-07:00

Release Date: June 1, 2009

Expiration Date: June 30, 2011

FACULTY:

Leonard M. Fromer, MD, FAAFP – Program Chair
Associate Clinical Professor;
University of California, Los Angeles;
Los Angeles, California

Steven B. Abramson, MD
Professor of Medicine and Pathology;
Vice Dean for Education, Faculty and Academic Affairs;
Director, Division of Rheumatology;
New York University School of Medicine and The NYU-Hospital for Joint Diseases;
New York, New York

Kenneth C. Jackson, II, PharmD
Assistant Dean for Program Development;
Associate Professor;
Pacific University School of Pharmacy;
Hillsboro, Oregon

Laurajo Ryan, PharmD, MSc, BCPS, CDE
Clinical Assistant Professor;
University of Texas at Austin College of Pharmacy;
University of Texas Health Science Center;
San Antonio, Texas

Diagnosis and Management of Osteoarthritis

Osteoarthritis (OA) is a leading cause of disability in North America. Many persons with OA are not diagnosed, however, and therefore are not effectively treated. In fact, many patients do not even seek out a formal diagnosis for their OA symptoms. Instead, they simply make a presumptive self-diagnosis and self-treat. In one study, 25% of patients over 55 years of age reported knee pain of at least 4 weeks’ duration in the previous year, yet only 15% of them had consulted their family physician for this symptom.¹There is obviously room for substantial improvement in the identification and treatment of individuals with OA.

Pharmacists have the potential to play an important role in improving care for these patients.²Pharmacists are more influential in identifying and managing OA patients than generally recognized. Individuals in the community have easy and direct access to pharmacists and often consult with them on the use of over-the-counter (OTC) analgesics.²Such consultation is likely responsible for a large portion of the use of OTC analgesics among people with OA who have never received a formal diagnosis. Similarly, pharmacists are likely to refer individuals to their physicians when OTC analgesics are ineffectual. Pharmacists are thus ideally positioned to identify patients with OA and to provide advice about therapy. A recent study demonstrated that pharmacists are capable of identifying more than 80% of patients with OA.²In their nondispensing (ie, advisory) role, pharmacists have the potential to improve patient outcomes related to medication use.³^,⁴Clinical pharmacists have also long been involved in interdisciplinary care teams, whereby they play a significant role in therapy selection. It is only more recently that these contributions from pharmacists have gained wider recognition from the rest of the medical community and the population in general. As pharmacists increase their knowledge of the issues in OA management, their involvement in interdisciplinary care models holds the potential to greatly improve the care of patients with OA.

This article presents information on OA relevant to the expanded role of pharmacists in OA management. It focuses on the epidemiology and pathophysiology of OA, the presentation of patients with this disease, and treatment alternatives for the management of OA-related pain.

Assessing the Impact of OA

The prevalence of OA in the United States is very high, and it can be expected to increase as the population ages. The estimated lifetime risk for symptomatic OA of the knee is 44.7%, and this risk increases to 56.8% in individuals who have a history of knee injury.⁵The Centers for Disease Control and Prevention estimate that OA affects 13.9% of the US population [.greaterequal]25 years of age and 33.6% of individuals [.greaterequal]65 years of age.⁶The most common site of OA is the knee; knee OA affects 16% of the population [.greaterequal]45 years of age.⁶However, OA also occurs frequently at other sites, including the hand (8% of individuals [.greaterequal]60 years of age) and hip (4.4% of people [.greaterequal]55 years of age).⁶

It is important to recognize the link between OA and age because clinicians will encounter a growing number of people with OA as the population ages. Age and other risk factors for OA are summarized in FIGURE 1.⁷Obesity is a significant risk factor for the development of symptomatic OA of the knee. The lifetime risk for OA of the knee is 30.2% in individuals who have normal body weight or are underweight (body mass index [BMI] <25>2), but it is 46.9% in those who are over-weight (BMI 25 to <30>2).⁵This risk increases to 60.5% in obese individuals (BMI [.greaterequal]30 kg/m²). Presence of metabolic syndrome (a combination of abdominal obesity, elevated triglycerides, low levels of high-density lipoprotein cholesterol, high blood pressure, and hyperglycemia) is also associated with high risk for OA. An estimated 62.6% of individuals with OA have metabolic syndrome.⁸

A long-term history of exercise may increase the risk for OA, but the exact nature of the association is controversial. Contrary to the common misconception that exercise may damage joints, available evidence suggests that, in the absence of injury, exercise may decrease the risk for OA.⁹In the elderly, changes in the mechanical loading of the knee that result from alterations in gait may contribute to the increased prevalence of OA of the knee in this population.¹⁰A significantly increased risk for the development of OA of the hip has been attributed to an occupational history of heavy physical stress and to a history of major musculoskeletal injuries.¹¹

Osteoarthritis results in a high disability burden for patients. Osteoarthritis is among the top five causes of disability: 80% of patients with OA have some degree of movement limitation, 11% require help with personal care, and 25% are unable to perform major activities of daily living.⁶Patients with OA have reduced quality of life relative to the general population, as about 40% rate their health as fair or poor.¹²

Patients with OA are at increased risk for significant psychiatric comorbidities, which may contribute to their impaired quality of life. Affective disorders (eg, depression and anxiety) are common in patients with OA, and the risk increases with the severity of the OA symptoms.¹³Sleep disorders are also common in OA. In addition, opioid analgesics, commonly used for relief of pain in OA, carry at least some degree of risk for diversion and abuse.¹⁴Fear of these risks is frequently cited as a reason for undertreatment with these agents.¹⁵The under-treatment of pain leads to an increased risk of psychiatric comorbidities, increased suffering from the pain of the disease, and a continued decrease in quality of life.

The high prevalence of OA and the substantial disability associated with this disease result in very high direct and indirect costs for this condition. The Arthritis Foundation has estimated that the annual direct and indirect costs of OA in the United States total $128 billion each year.¹⁶Results from a cohort study of 1258 patients with disabling OA of the hip or knee indicated that the mean annual per-patient direct costs were $2,300, and the indirect costs (mainly from loss of wages) were $12,990. The costs for OA increased with patient age and OA severity, as measured by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC).¹⁷

The overall cost of treating OA increases with rising comorbidity. Results from one survey among 140 patients with OA indicated that annual treatment costs increased from $2,038 for patients with no comorbidities (36.4% of the cohort) to $4,455 for patients with [.greaterequal]3 comorbidities (20.7% of the cohort).¹⁸

Important Pathophysiologic and Clinical Aspects of OA

Osteoarthritis is not a diagnosis of exclusion. It can be readily diagnosed on the basis of physical examination, patient history, and radiologic evaluation.¹⁹

The most common presenting symptom in patients with OA is pain, occurring in one or more joints, with joint involvement usually being symmetrical. Patients often complain of morning stiffness that resolves with activity. As the disease progresses, joint stiffness may become more prolonged and joint enlargement is also likely to be present. Crepitus (a grating sensation in the joint) and limitations in movement may occur in later-stage disease.¹⁹

The medical history for a patient with suspected OA should include questions about pain, arthralgia, morning stiffness, joint swelling, and weakness. It is also useful to gain information about potential secondary causes of arthritis, which may include obesity, repetitive use, previous trauma, crystal deposition (eg, gout), infection, acromegaly, and rheumatoid arthritis.¹⁹Inheritable metabolic diseases (eg, alkaptonuria, hemochromatosis, Wilson disease), hemoglobinopathies (eg, sickle cell disease), and neuropathic pain disorders may also lead to joint damage or dysfunction, underlying orthopedic disorders, and bone disease.¹⁹

A thorough medication history is another important line of questioning. Patients with OA often have a long history of using various prescription and OTC products, as well as complementary and alternative therapies. The pharmacist can offer a valuable service to patients by advising them on which therapies have proven efficacy. The pharmacist can also warn patients of the various adverse effects and drug interactions possible with these agents. In their discussions with patients, pharmacists can emphasize the importance of letting the rest of the care team know about concomitant therapies they may be taking, and the pharmacist can even ensure that the other care team members are aware of this history. Additional assessments focusing on the patient’s global functioning, mood, quality of sleep, and other quality-of-life factors should also be obtained to plan for comprehensive care (FIGURE 2).²⁰

Physical examination may reveal apparently normal joints in early-stage disease, but gait may be abnormal if weight-bearing joints are involved. Signs and symptoms that may be present upon physical examination in later-stage OA may include visible and/or palpable osteophytes, joints that are warm to palpation, effusion in superficial joints, range-of-motion limitations secondary to bony restrictions and/or soft tissue contractures, and crepitus.²¹

Radiography is not mandatory for a diagnosis of OA, although it should be used to evaluate involved joints in children, in patients with histories that suggest specific etiologies (eg, trauma), and in individuals who have progressive joint pain, pain at night, or a family history of inflammatory arthritis.¹⁹Plain film radiographs are useful in differential diagnosis and for monitoring the progression of the disease.²²However, plain radiographs may not reveal significant abnormalities in patients with early-stage disease.²¹Magnetic resonance imaging is capable of detecting early changes in the joints of patients with OA, but it is seldom used for diagnosis of this disease.²²

There are no definitive clinical laboratory tests for the identification of patients with OA.²¹Erythrocyte sedimentation rates and levels of C-reactive protein are generally normal in patients with OA, and the synovial fluid does not contain elevated numbers of leukocytes (>2,000/mm³).²³Synovial fluid evaluation is not generally necessary, but it may be useful for determination of leukocyte counts and crystal detection in the differential diagnosis of OA versus infection and gout. Investigation of various biomarkers has provided some insight into possible mechanisms of bone turnover in OA (eg, cartilage oligomeric matrix protein, antigenic keratan sulphate, hyaluronan, human cartilage glycoprotein-39, type III collagen Npropeptide, and urinary glucosyl-galactosyl pyridinoline), but, as yet, none of these is clinically useful.²³

As mentioned, pain is one of the cardinal symptoms of OA. Assessment of patients’ pain severity is thus an important part of the initial evaluation. The measurement of pain involves many facets, including intensity, location, duration, quality, and aggravating or alleviating factors. The chronic pain associated with OA can be assessed with any of a large number of scales, including the WOMAC, the Brief Pain Inventory (BPI), and the McGill Pain Questionnaire.²⁴The WOMAC also measures functionality, which is not directly a pain assessment. In essence, the WOMAC uses a pain scale to answer questions related to pain and function.

Pathophysiology of OA

Osteoarthritis involves three tissues— bone, articular cartilage, and the synovium—all of which undergo alterations in response to mechanical stress. Mechanical stress, in addition to trauma, joint mis-alignment, surgery, and even genetic predisposition, are all believed to contribute to the development of OA. Much research effort has been devoted to attempts to link these factors to the changes in joint tissues characteristic of OA. It is now known that both osteocytes and chrondrocytes respond to mechanical pressure. Under normal circumstances, this results in increased collagen synthesis and formation of extracellular matrix. However, abnormal mechanical stress can result in the production of substances that can degrade cartilage, such as inflammatory cytokines, including tumor necrosis factor–[.alpha] (TNF-[.alpha]), interleukins (interleukins 1[.beta], 6, and 8), and proteases (eg, matrix metalloproteinase).²⁵

Inflammatory events also contribute to the pain characteristic of OA. Inflammatory molecules, including prostaglandin E1 and leukotriene B4, can sensitize nerve fibers in joints, increasing the response to both painful and nonpainful stimuli. Other inflammatory molecules (eg, bradykinin, histamine, serotonin, prostacyclin) released in joints can cause fibers to signal pain even when the joint is still.²⁶

It has also been suggested that angiogenesis (formation of new blood vessels) may contribute to the progressive joint damage and pain in OA. Inflammatory cells, such as macrophages, can stimulate angio-genesis by releasing vascular endothelial growth factor (VEGF); TNF-[.alpha] also stimulates release of this growth factor from chrondrocytes. Stimulation of new blood vessel formation by VEGF can lead to ossification and the formation of osteophytes. The presence of new blood vessels can lead to pain as a result of structural reorganization of the joint.²⁶

Increased understanding of molecular events involved in the pathobiology of OA has prompted the development of disease-modifying OA drugs. Many of these agents (eg, matrix metalloproteinase inhibitors, TNF-[.alpha] inhibitors, interleukin-1 inhibitors) are aimed at blocking the actions of the inflammatory cytokines and degradative enzymes involved.²⁵^,²⁷These drugs may also decrease the pain experienced by OA patients.

Pharmacotherapy for Pain Management in the Patient With OA

Pain control should be a primary focus in the overall management of patients with OA because it has been repeatedly shown that the achievement of significant pain relief is associated with significant improvements in quality of life for this population.^28,29A very wide range of analgesic agents has been employed for pain management in patients with OA. The most commonly used oral medications are acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclo-oxygenase 2-selective agents (COX-2 inhibitors), and opioids. Each class of agents is associated with risks for specific adverse events. An important point to remember is that drug interactions are common with all of these agents, and particularly in the older patient population, in whom polypharmacy is common. Recommendations from the American College of Rheumatology (ACR) for the management of pain in patients with OA are summarized in TABLE 1.³⁰

Table 1. Pharmacologic
Therapy for Patients With OA*³⁰

Oral

Acetaminophen
COX-2-specific inhibitor
Nonselective NSAID plus misoprostol or a proton-pump inhibitor**
Nonacetylated salicylate
Opioids (including tramadol)

Intra-articular

Opioids
Glucocorticoids
Hyaluronan

Topical

Lidocaine
Capsaicin
Methylsalicylate

* The choice of agent(s) should be individualized for each patient, as noted in the text.
**Misoprostol and proton-pump inhibitors are recommended in patients who are at increased risk for upper gastrointestinal adverse events.
COX-2 = cyclo-oxygenase-2; NSAID = nonsteroidal antiinflammatory drug.
Adapted from Zhang W. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000 September;43(9):1905-15. Copyright ©2000. Reproduced with permission of John Wiley & Sons, Inc.

Oral Agents

Acetaminophen Acetaminophen is recommended as first-line treatment for OA by the ACR.³⁰It is modestly effective for relieving pain and decreasing stiffness, but it often fails to control severe pain.²¹^,³¹Meta-analysis of results from randomized clinical trials has shown that acetaminophen is less effective overall than NSAIDs in terms of pain reduction, improvement in global assessment, and improvement in functional status.³²Hepatotoxicity is the most important adverse effect of acetaminophen. The drug should be used with caution in patients who have liver disease and in those who chronically abuse alcohol, regardless of whether or not they have hepatic dysfunction.²¹

NSAIDs and Selective COX-2 Inhibitors Both NSAIDs and selective COX-2 inhibitors provide significant pain relief in patients with OA. However, nonselective NSAIDs are associated with an increased risk for gastrointestinal bleeding (1% to 3% of patients).²¹Selective COX-2 inhibitors were developed to selectively inhibit COX-2 and preserve the activity of COX-1, which catalyzes the synthesis of prostaglandins that protect the gastric mucosa. Selective COX-2 inhibitors are as effective as traditional NSAIDs for the treatment of OA pain.²¹

Both conventional NSAIDs and selective COX-2 inhibitors have become the subject of significant controversy because of evidence linking their use to cardiotoxicity. Therefore, it is recommended that these agents be used for only limited periods of time, particularly in patients with cardiovascular disease.²¹^,³¹A meta-analysis of studies investigating the link between NSAIDs or COX-2 inhibitors and heart failure showed that both classes of agents increase the risk of heart failure similarly.³³

Although the overall risk was considered to be relatively small, the risk increases with pre-existing cardiac disease. The Working Group on Pain Management recommends that NSAIDs and selective COX-2 inhibitors be avoided in patients at risk for cardiac or renal disease.³⁴Product labeling approved by the Food and Drug Administration, along with several guidelines such as those published by the Osteoarthritis Research Society International (OARSI), do not distinguish between NSAIDs and selective COX-2 inhibitors in terms of cardiac risks.³⁵^,³⁶

Opioids, Including Tramadol

Tramadol and full-agonist opioid analgesics are recommended for the treatment of moderate-to-severe pain related to OA.³⁴

Tramadol is a centrally acting agent that exhibits two distinct mechanisms of action: binding to [.proportional]-opioid receptors and blocking the neuronal uptake of serotonin and norepinephrine.²¹

Meta-analysis of clinical trial results indicates that tramadol or tramadol plus acetaminophen decreases pain intensity, produces symptom relief, and improves function in patients with OA, but these benefits are modest.³⁷The most common adverse events in patients treated with tramadol include constipation, nausea, dizziness, headache, somnolence, and vomiting.²¹

The essential mechanism of action of full-agonist opioid analgesics, as the nomenclature implies, occurs through binding to opioid receptors. These drugs do not have the analgesic ceilings of the other agents (eg, acetaminophen, NSAIDs/COX-2, tramadol) and are also considered a viable option for the treatment of moderate-to-severe OA pain.³⁴Opioid analgesics may be considered a component of rational polypharmacy for patients with OA pain that worsens or that cannot be controlled by acetaminophen, NSAIDs, or tramadol, either alone or in combination. Adverse effects of opioids include respiratory depression, sedation, dizziness, and constipation. With the exception of constipation, tolerance to these effects often develops with continued treatment.²¹

Both patients and physicians alike share concerns about diversion and abuse of opioid analgesics.³⁸^,³⁹Approaches that have been taken to decrease these risks include the development of extended-release formulations and other abuse-resistant formulations.⁴⁰Extended-release opioid formulations may also increase convenience for patients as well as provide better round-the-clock pain control.⁴¹Programs that involve agreements with patients regarding the use of opioids and also adherence monitoring have been shown to reduce opioid abuse up to 50%.⁴²

Agents Directed at Neuropathic Pain It is now recognized that OA-related pain may have a neuropathic component (ie, resulting from nervous system reorganization and resultant abnormal pain signaling). Agents that have been used in the treatment of neuropathic pain, although not yet studied extensively in OA, include anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, N-methyl-D-aspartate antagonists, and ion channel blockers.⁴¹

Intra-articular Agents Intra-articular agents are primarily used to decrease inflammation and improve function in patients with OA, but they have also been shown to relieve pain. Intra-articular injections of corticosteroids are used primarily in patients with OA of the knee. In studies, they have been shown to provide significant pain relief versus placebo. However, this pain relief is short lived, reaching maximal effect at 2 to 3 weeks postinjection.³¹

Viscosupplementation with hyaluronic acid-based products provides pain relief similar to that achieved with NSAIDs and with a longer duration of action than with intra-articular corticosteroids.³¹Intra-articular injections of opioids and the inter-leukin-1 receptor antagonist anakinra have also been demonstrated to provide pain relief in patients with OA of the knee. The pain relief with anakinra appears to be long lasting (up to 3 months), while that with opioids is short lived (lasting only several days). However, the studies on intra-articular anakinra and opioids involved small numbers of subjects, and, in the case of anakinra, no placebo comparison was made.²¹^,³¹Further studies of these agents are needed.

Topical Agents

Topical agents are effective for the treatment of OA, and they have the added benefit of reducing the risk for interaction with other drugs that the patient may be taking. Elderly individuals, who are most at risk for the development of OA, are also the segment of the OA population most likely to be taking a large number of medications.⁴³^,⁴⁴Topical analgesics are thus particularly suited for use in elderly patients because they decrease the risk for systemic adverse effects.⁴⁴Topical NSAIDs, lidocaine, capsaicin, and salicylate/menthol have all been shown to be effective for the treatment of peripheral pain.⁴⁵Topical NSAIDs appear to be as effective as oral drugs for relieving OA-associated pain, and they are less likely than oral agents to result in systemic effects, including gastrointestinal, cardiac, and renal events.²¹

Many studies have proven the efficacy of topical NSAIDs in the short term, up to 2 weeks. One study of patients with OA of the knee showed greater efficacy in pain relief with topical diclofenac for up to 12 weeks versus placebo.⁴⁶Longer-term studies with diclofenac are lacking. Lidocaine 5% patches have also been demonstrated to be safe and effective for the treatment of OA pain; the most common adverse event occurring with these patches is local skin irritation.²¹Two published studies, each of 2 weeks’ duration, have demonstrated the efficacy of lidocaine patches in reducing the pain of OA.⁴⁷^,⁴⁸A third study showed similar efficacy between lidocaine patches and oral celecoxib for up to 12 weeks.²¹Capsaicin relieves pain by depleting neurotransmitters in primary sensory fibers and reversibly decreasing their density. Capsaicin has been used effectively in patients with OA. Its most common adverse effects are a burning, tingling sensation and allodynia at the application site.⁴⁴

Adjuvant Therapies

Sleep disturbances and mood disorders are common in patients with OA and should be treated if present.⁴⁹^,⁵⁰Medications suitable for the treatment of sleep disorders in OA patients include nonbenzodiazepine agonists (zolpidem, zopiclone, zapelon) and benzodiazepines (lorazepam, temazepam).⁴⁹Various classes of agents are suitable for treating depression. These include tri-cyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and others.⁵¹

Emerging Treatments and Concepts for Pain Treatment

New agents for pain management in patients with OA are in development. These include the new abuse-resistant formulations of opioid analgesics mentioned previously.⁴⁰An antibody directed against nerve growth factor, tanezumab, has been shown to improve WOMAC scores better than placebo in patients with OA. In addition, a bradykinin-B₂receptor antagonist has been found to be effective for the treatment of OA of the knee following intra-articular injection.²⁷Novel topical agents in development may be particularly useful in elderly patients when drug-drug interactions related to polypharmacy need to be avoided.

Table 2. Nonpharmacologic
Therapy for Patients With OA³⁰

Patient education
Self-management programs (e.g., Arthritis Foundation Self-Management Program)
Personalized social support through telephone contact
Weight loss (if overweight)
Aerobic exercise programs
hysical therapy, range-of-motion exercises
Muscle-strengthening exercises
Assistive devices for ambulation
Patellar taping
Appropriate footwear
Lateral-wedged insoles (for genu varum)
Bracing
Occupational therapy
Joint protection and energy conservation
Assistive devices for activities of daily living

Reprinted from Zhang W. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000 September;43(9):1905-15. Copyright ©2000. Reproduced with permission of John Wiley & Sons, Inc.

Nonpharmacologic Interventions in OA
Addressing Risk Factors

Age- and genetics-related risk factors for OA cannot be modified, but others, such as obesity, metabolic syndrome, and joint injuries, can be. Weight reduction alone will significantly decrease pain scores and increase ambulation speed in obese patients with OA of the knee.⁵²OA is associated with high loads on joints and misalignment that can result in progressive injury. Use of walking aids, bracing, and taping can decrease pain and improve function in patients with OA.⁵³

Educational and Physical Interventions

Other nonpharmacologic interventions are also recommended for patients with OA (TABLE 2).³⁰These include self-management and exercise programs (both aerobic and muscle-strengthening), occupational and physical therapy, use of appropriate assistive devices, Tai Chi, acupuncture, diathermy, and balneotherapy.³⁰^,^54-56

Nutraceuticals

Nutraceuticals and specific foods have been used extensively to relieve symptoms of OA, but there is generally only modest evidence from controlled clinical trials to support their use. Glucosamine is an essential component of proteoglycans that are a key component of cartilage, and chondroitin is a glycosaminoglycan found in cartilage and connective tissue. A recent review of the literature supports the conclusion that both of these agents provide significant pain relief in patients with OA.⁵⁷Dimethyl sulfoxide and methylsulfonylmethane have also been employed to treat OA, but available data cannot support a positive recommendation for the use of either agent.⁵⁸Foods and food-derived compounds that have been studied in the treatment of OA include ginger, avocado, and soybean. In a randomized, controlled trial, ginger was not found to provide a statistically significant difference from placebo in relieving pain. The efficacy of an avocado and soybean compound is, however, supported by results from clinical trials. The combination of avocado and soybean has been shown to provide symptom relief and decrease NSAID use in two well-controlled clinical trials.⁵⁹

Current OA Treatment Guidelines

Major guidelines for the treatment of OA carry similar recommendations for using a combination of nonpharmacologic and pharmacologic strategies. All of the guidelines also recommend a stepped approach to pharmacotherapy for pain management. Acetaminophen is first-line treatment. Nonsteroidal anti-inflammatory drugs, administered at the lowest effective doses, are recommended for patients who do not respond to acetaminophen. Opioids are reserved for patients in whom NSAIDs are contraindicated, ineffective, or poorly tolerated.^30,35,36,60The pyramid in FIGURE 3 depicts the recommended step-wise approach to OA management.⁶¹

New Opportunities and Perspectives in OA Management

Current approaches to the management of patients with OA emphasize the importance of patient-centered therapy that takes into account patient needs and preferences and allows patients to make informed decisions about their care and participate in the development of a management plan. Care should be holistic and include consideration of the patient’s social situation and support network, as well as comorbidities. Patients should be followed closely by the treatment team.²⁰

As emphasized in all of the guidelines, interventions for OA should be based on severity of disease.⁶¹Generally, a combination of nonpharmacologic and pharmacologic treatments will be required to achieve optimal outcomes in most patients.³⁵Combinations of topical and oral pharmacologic agents may be useful for optimizing pain relief in some patients.³⁵

Specific approaches to care include the patient-centered medical home model and the regular, planned-care model. The patient-centered medical home model emphasizes the employment of a treatment team led by the patient’s personal physician to provide patient-centered care. This approach focuses on making care convenient for the patient and ensuring continuity by providing the patient with access to one physician.⁶²The regular planned-care model also uses a team-based approach and emphasizes regularly scheduled OA management that is not limited solely to urgent interventions or the treatment of pain.

Pharmacoeconomic Considerations

The cost-effectiveness of different pharmacologic approaches to the management of OA has been evaluated in a large number of studies. Available evidence suggests that acetaminophen, followed by an OTC NSAID, is the most cost-effective option for achieving pain relief for patients with pain related to OA of the knee.¹³Unfortunately, there are no published comparisons of the cost-effectiveness of different oral and topical treatments for OA across the entire range of disease and pain severity. Moreover, cost-effectiveness studies comparing pharmacologic and nonpharmacologic treatments for OA are similarly lacking.

OA ABBREVIATION LIST
ACR BMI BPI COX-2 NSAIDs OA OARSI OTC TNF-a VEGF WOMAC	American College of Rheumatology body mass index Brief Pain Inventory cyclo-oxygenase 2 nonsteroidal anti-inflammatory drugs osteoarthritis Osteoarthritis Research Society International over the counter tumor necrosis factor-a vascular endothelial growth factor Western Ontario and McMaster University Osteoarthritis Index

Other issues related to cost of care and outcomes for patients with OA include formulary restrictions and substitutions, the impact of benefit design, and the economic impact of adherence to therapy. Results from one retrospective analysis indicated that a three-tiered copayment coverage for anal-gesic agents in which selective COX-2 inhibitors were placed in the highest tier resulted in reduced use of these drugs; this reduced usage extended to patients at high risk for gastrointestinal events.⁶³Thus, an approach to drug coverage aimed at decreasing cost may have the unintended effect of increasing the risk for adverse events among some patients. Results from another retrospective study revealed an inverse relationship between the number of NSAIDs on formularies and the risk for hospitalizations among patients with OA. This suggests that more restrictive formularies may engender increased health care resource utilization.⁵⁷In one study, an increase in copayments for OA medications resulted in a significant increase in the number of patients who simply discontinued treatment.⁶⁴This change in pharmacy benefit was associated with a $971 increase in total treatment costs for patients with OA.

Conclusions

Osteoarthritis is a very common condition in the United States, and it causes significant pain and disability for a very large number of people, particularly the elderly. Optimal management of patients with OA requires integrated therapy involving both pharmacologic and nonpharmacologic interventions. All current treatment guidelines for the management of pain in patients with OA recommend a stepped approach to pharmacotherapy, beginning with acetaminophen as first-line therapy, followed by NSAIDs and opioids, if necessary. Pharmacists are essential members of the diagnostic and treatment team for patients with OA. Pharmacists also provide important support in treatment decision making for patients who may not receive adequate advice from other health care professionals.⁶⁵

An Update on the Current Treatment of HIV

2009-08-31T10:28:00.000-07:00

Release Date: August 1, 2009

Expiration Date: August 31, 2011

FACULTY:

Ami Teague, PharmD, BCPS, AAHIVE
Assistant Professor of Pharmacy Practice,
McWhorter School of Pharmacy,
Samford University, Birmingham, Alabama

GOAL:

To familiarize pharmacists with the current treatment options for human immunodeficiency virus, the adverse effects and main drug interactions with antiretrovirals, and the appropriate monitoring parameters of therapy.

Among the more than 20 chemical entities available to treat human immunodeficiency virus (HIV), there are six different classes of medication with different mechanisms of action. Through the use of combinations of drugs from these different classes, patients living with HIV can have very promising futures.

The Department of Health and Human Services (DHHS) provides guidelines on when and how to treat HIV.¹Though the idea of when to start antiretroviral therapy has changed over the years, recent data show that patients benefit when medication is initiated before the CD4 (antigenic marker on helper T cells) count falls below 350 cells/mm³.²Originally the thought was to treat as soon as possible, but as long-term adverse effects and resistance to antiretrovirals were identified, researchers began to look further into the benefits and risks of starting treatment at different clinical points. These clinical points include CD4 count and viral load, though less emphasis has been put on the viral load in recent guidelines. HIV-associated nephropathy (HIVAN) and pregnancy are also compelling indications to initiate antiretroviral treatment regardless of CD4 count. Other factors important in deciding when to treat include personal preference and the patient’s social history. Because adherence is critical, the patient must personally be ready to initiate therapy. Social aspects such as homelessness, addictions, unsupportive and/or unaware family and friends, and psychiatric illness should play a role in this decision.

Nucleoside Reverse Transcriptase Inhibitors

The first drug approved to treat HIV was zidovudine, a member of the nucleoside reverse transcriptase inhibitors (NRTIs). These medications are active once they are phosphorylated within the cell and inhibit the reverse transcriptase enzyme by mimicking naturally occurring nucleotides. Reverse transcriptase would normally allow for the conversion of viral RNA to DNA after the virus enters the host cell. This class of antiretrovirals is often referred to as the backbone of a regimen. The typical first-line regimens given to patients who have not been previously treated for HIV (treatment naïve) include two medications from this class. The DHHS guidelines recommend tenofovir and emtricitabine as the preferred NRTI backbone in treatment-naïve individuals.¹

Tenofovir is considered a part of the nucleoside reverse transcriptase class, but it differs from the others because it is a nucleotide (rather than nucleoside) and does not require phosphorylation to be active. Tenofovir is dosed once daily and is usually well tolerated by patients. It is coformulated with emtricitabine in a single tablet, which can be taken once daily. Tenofovir should be used cautiously in patients with renal dysfunction. There have been cases of acute increases in serum creatinine with administration of tenofovir as a result of acute tubular necrosis.³

Zidovudine, mentioned above, is known for its role in pregnancy. Because it has been studied in pregnancy with good outcomes, all women who are pregnant and are taking antiretrovirals should receive zidovudine as a part of their treatment regimen. In addition to its use during pregnancy, zidovudine is given intravenously to HIV-positive women during labor to decrease the risk of transmission of HIV to the baby during the delivery process. Neonates born to HIV-positive mothers are also given zidovudine liquid for the first 6 weeks of life.⁴Following the above recommendations can decrease the risk of vertical transmission of HIV from mother to baby from almost one-third to close to 1%.

Abacavir is the only NRTI that does not require dosage adjustment in the presence of renal dysfunction. It also carries the risk of a hypersensitivity reaction (HSR). When a product that contains abacavir is dispensed, a warning card is provided to the patient. This card lists the signs and symptoms of this HSR, including fever, rash, and shortness of breath. Now, a test is available that can screen for patients at highest risk for experiencing abacavir hypersensitivity. HLA-B*5701 is a gene that was found to be associated with this HSR.⁵Being HLA-B*5701 positive, however, does not guarantee a reaction. In patients who are found to be HLA-B*5701 positive, abacavir should be avoided and added to their allergy profiles. There has been some controversy surrounding the association with abacavir use and cardiovascular risk. The D:A:D Study Group showed a correlation between the use of abacavir within the previous 6 months and an increased risk of myocardial infarction in its observational cohort; however, a pooled analysis of clinical trials by the manufacturer of abacavir did not demonstrate an increased risk compared with controls.^6,7Because the data are inconclusive, patients and providers must weigh the benefits and possible risks when initiating abacavir.

All medications in the NRTI class carry a black box warning for lactic acidosis. This is a rare but serious, and sometimes fatal, complication that has been found more likely with certain drugs in this class compared to others. The thymidine analogues stavudine and zidovudine, along with didanosine, are thought to carry a higher risk due to their increased mitochondrial toxicity. All antiretrovirals can cause the initial feeling of fatigue and headache, and many carry a degree of nausea potential. Lamivudine and emtricitabine, which are both cytosine analogues, should not be used together because they are essentially identical in action and resistance profile, and stavudine and zidovudine should not be used together because they compete for phosphorylation and are therefore antagonistic to each other. As with other disease states, medications with similar side-effect profiles should be used with caution. An example in the NRTI class would be the use of didanosine and stavudine, which in combination can cause an increase in risk of peripheral neuropathy and pancreatitis. Didanosine should be taken on an empty stomach as opposed to the other NRTIs, which can be taken without regard to food. It is wise to avoid using two NRTIs that are analogues of the same endogenous nucleotides in the same antiretroviral regimen. Besides the interaction between the two thymidine analogues, the adenosine analogues didanosine and tenofovir are involved in a drug interaction requiring dose adjustment, and also produce results that are suboptimal in relation to treatment response. TABLE 1 lists all marketed antiretrovirals, including those from the NRTI class, brand name, normal dosing, and the most common adverse effects associated with each.

Table 1
Antiretrovirals by Class
NAME	DOSAGE	COMMON ADVERSE EFFECTS
Nucleoside Reverse Transcriptase Inhibitors
Abacavir (Ziagen)	300 mg bid or 600 mg daily	Hypersensitivity reaction, headache, nausea
Didanosine (Videx EC)	400 mg daily	Pancreatitis, peripheral neuropathy
Emtricitabine (Emtriva)	200 mg daily	Hyperpigmentation of palms and soles of feet
Lamivudine (Epivir)	150 mg bid or 300 mg daily	Headache, nausea
Stavudine (Zerit)	40 mg bid	Peripheral neuropathy, lipoatrophy
Tenofovir (Viread)	300 mg daily	Nausea, flatulence, nephrotoxicity
Zidovudine (Retrovir)	300 mg bid	Nausea, anemia, myopathy
Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz (Sustiva)	600 mg QHS	Vivid dreams, drowsiness
Etravirine (Intelence)	200 mg bid	Nausea, rash
Nevirapine (Viramune)	200 mg daily x 14 days, then 200 mg bid	Hepatotoxicity, rash
Protease Inhibitors
Atazanavir (Reyataz)	400 mg daily^a 300 mg with 100 mg RTV daily	Hyperbilirubinemia, nephrolithiasis
Darunavir (Prezista)	800 mg with 100 mg RTV daily^a 600 mg with 100 mg RTV bid	Rash, headache, nausea, diarrhea
Fosamprenavir (Lexiva)	1,400 mg bid^a 1,400 mg with 100-200 mg RTV daily^a 700 mg with 100 mg RTV bid	Rash, nausea, diarrhea
Indinavir (Crixivan)	800 mg with RTV 100 mg bid	Nephrolithiasis, hyperbilirubinemia
Lopinavir/ritonavir (Kaletra)	800/200 mg daily^a 400/100 mg bid	Nausea, diarrhea
Nelfinavir (Viracept)	1,250 mg bid	Diarrhea
Ritonavir (Norvir)	See other PIs	Nausea, diarrhea, paresthesias
Saquinavir (Invirase)	1,000 mg with RTV 100 mg bid	Nausea, diarrhea
Tipranavir (Aptivus)	500 mg with RTV 200 mg bid	Rash, nausea, diarrhea, headache, hepatotoxicity
CCR5 Inhibitor
Maraviroc (Selzentry)	150-600 mg bid	Rash, cough, fever, hepatotoxicity
Fusion Inhibitor
Enfuvirtide (Fuzeon)	90 mg (1 mL) SC bid	Injection-site reactions
Integrase Inhibitor
Raltegravir (Isentress)	400 mg bid	Nausea, headache, CPK elevation
Combination Products
Zidovudine and lamivudine (Combivir)		300/150 mg bid
Zidovudine, lamivudine, and abacavir (Trizivir)		300/150/300 bid
Lamivudine and abacavir (Epzicom)		300/600 mg daily
Tenofovir and emtricitabine (Truvada)		300/200 mg daily
Tenofovir, emtricitabine, and efavirenz (Atripla)		300/200/600 mg QHS
^a Only for use in treatment-naïve patients. CPK: creatine phosphokinase; PI: protease inhibitor; QHS: every night; RTV: ritonavir; SC: subcutaneously.

Nonnucleoside Reverse Transcriptase Inhibitors

In a treatment-naïve patient, many times the NRTI backbone described above is paired with a nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI). The NNRTI class includes efavirenz, nevirapine, etravirine, and the rarely used delavirdine. These drugs work to inhibit reverse transcriptase but by a different mechanism than the above NRTIs. NNRTIs inhibit reverse transcriptase by binding directly to the enzyme adjacent to the active site. Efavirenz paired with tenofovir and emtricitabine has been manufactured into one pill that patients can take once daily, typically at bedtime. This particular combination provides for a very convenient regimen but is not optimal for all patients. The NNRTI class has a low resistance barrier, and around 5% of treatment-naïve patients may initially present with resistance to this class of medications because only a single mutation is required to confer resistance to three of the four drugs in this class, and these three medications exhibit cross resistance.⁸The percentage of resistant antiretroviral-naïve virus may vary from one geographic region to another. NNRTIs are metabolized through the cytochrome P450 system and have many drug interactions.

The current guidelines recommend efavirenz as the preferred NNRTI for treatment-naïve patients.¹Efavirenz is a mixed inducer/inhibitor of cytochrome P450 enzymes. It has a unique set of central nervous system side effects that includes drowsiness and vivid dreams. Because it typically causes sedation, it is dosed at bedtime. Increased fat intake around the time of administration increases the absorption of efavirenz and results in more intense side effects. For this reason, it is recommended that it be taken on an empty stomach or with a light, low-fat snack. It is the only antiretroviral that is a known teratogen and should be avoided in pregnant women or women of childbearing age who are not on adequate birth control. Another unique fact about efavirenz is that it may cause a false-positive cannabinoid drug test. This may be important in those patients with jobs that require drug screening/testing because a letter from the physician or pharmacy noting this possible lab interaction would disclose the patient’s HIV status. Like many other antiretrovirals, especially PIs, efavirenz may have a negative effect on a patient’s lipid profile.

Nevirapine is the only antiretroviral that is initiated at a lower dose and then later titrated up to the maintenance dose. Patients are instructed to take nevirapine once daily for the first 2 weeks of treatment before increasing the dosage to twice daily. Because nevirapine carries a risk of hepatotoxicity, laboratory tests are conducted to assess liver function before the dose is increased. These first 2 weeks of therapy are also used to monitor for rash since nevirapine has been known to cause Stevens-Johnson syndrome, a serious, life-threatening skin rash. Individuals with higher CD4 counts are at increased risk for hepatotoxicity with nevirapine. It is recommended that women with CD4 counts greater than 250 and men with CD4 counts greater than 400 not be initiated on nevirapine.¹

Only etravirine, the newest NNRTI, has a more extensive resistance profile; this means that it takes more than one mutation to cause resistance. However, the etravirine studies for FDA approval were not done in treatment-naïve patients, and as a result this medication is reserved for therapy in treatment-experienced patients and in combination with more than just the above-mentioned NRTI backbone. However, etravirine is contraindicated with the PIs atazanavir, tipranavir, and fosamprenavir or with any unboosted PI. Etravirine is a substrate of the CYP enzymes 3A4, 2C9, and 2C19. It acts as an inducer of 3A4 and an inhibitor of 2C9 and 2C19. Etravirine should be taken with food to improve concentrations.¹

Protease Inhibitors

The use of PIs, the first of which was FDA approved in 1995, had a positive influence on mortality rates in HIV-infected patients. PIs inhibit the protease enzyme that is used to cut proteins into the usable portions needed to make new functional virions. If these proteins are left uncut, they leave the virion without the proteins necessary to infect other cells. A PI can be paired with NRTIs to make a PI-based regimen. The newest guidelines highly recommend that all PIs be combined with ritonavir. Ritonavir is a PI exhibiting strong inhibition of CYP3A4. When first manufactured, it was used as a PI at full dose, but its gastrointestinal and lipid effects make it a less desirable PI compared to other medications available in this class. Today, it is used in small doses (usually 100 mg per dose of the main PI) to “boost” other PIs by inhibiting their metabolism, resulting in higher concentrations for longer periods of time. According to the DHHS guidelines, the preferred PI-based regimens are all ritonavir-boosted. These preferred regimens include boosted atazanavir, darunavir, fosamprenavir, and lopinavir.¹Nelfinavir is the only PI that cannot be boosted by ritonavir and should be taken with food to increase absorption. According to the FDA, saquinavir, darunavir, lopinavir, and tipranavir must be given with low-dose ritonavir. Lopinavir is not available as a single entity and is the only PI that is coformulated with ritonavir. Ritonavir-boosted regimens should be taken with food to improve tolerability. As a class, PIs may increase the risk of bleeding in patients with hemophilia and may have altered kinetics in pregnancy. PIs have been associated with long-term metabolic effects including increased triglycerides, increased blood glucose, and fat redistribution, sometimes called lipodystrophy. To treat these subsequent conditions, lifestyle modifications including diet and exercise and, many times, drug therapy are required.

In general, PIs are inhibitors of CYP3A4. The only exception is the PI tipranavir, which is an inducer. Because of this unique characteristic, tipranavir must be given with a higher dose of ritonavir for boosting. Tipranavir also carries a black box warning for intracranial hemorrhage. TABLE 2 includes a list of drugs whose use is contraindicated with PIs as a class, though there are individual PIs that have additional severe drug interactions. There are also interactions that are not contraindications but require dose modifications. A common example is the use of phosphodiesterase (PDE₅) inhibitors or erectile dysfunction drugs with PIs. When used together, the dose of the PDE₅inhibitor must be decreased and the interval between doses extended (i.e., sildenafil 25 mg no more than every 48 hours). Several PIs, including fosamprenavir, darunavir, and tipranavir, contain a sulfa moiety and could potentially cause a reaction in an individual with a sulfonamide allergy. The cross-sensitivity is rarely seen clinically but should be kept in mind, especially for patients with a previous severe reaction to sulfa-containing drugs.

Table 2

Drugs That Are
Contraindicated With PIs

Ergot alkaloids
Simvastatin, lovastatin
Midazolam, triazolam
Inducing anticonvulsants
Rifampin
St. John’s wort
Fluticasone^a

^aFor patients on ritonavir-boosted regimens and includes nasal and inhaled formulations. PIs: protease inhibitors.

Atazanavir is thought to have the least effect on lipids and may be a better choice in a patient with baseline dyslipidemia. The hyperbilirubinemia associated with atazanavir is usually subclinical and only notable as an increase in a laboratory value. However, scleral icterus may sometimes be present, and a patient may desire a medication change because of cosmetic concerns. While not originally thought to be an adverse effect of atazanavir, case reports of nephrolithiasis have been associated with atazanavir, and its package insert was updated in 2007 to include this as a precaution. Atazanavir, in addition to fosamprenavir, can be given without ritonavir, unboosted, although this dosing is not preferred by the current HIV treatment guidelines and is only an option in treatment-naïve individuals.¹Atazanavir does interact with most acid-reducing agents including antacids, H₂-blockers, and proton pump inhibitors (PPIs). Antacids should be administered 2 hours before or 1 hour after atazanavir administration. H₂-blockers may be administered simultaneously or at least 10 hours after boosted atazanavir administration. PPI use is not recommended with atazanavir in treatment-experienced patients. However, in treatment-naïve patients a maximum dose equivalent to omeprazole 20 mg daily may be used but must be separated from atazanavir administration by 12 hours.⁹Indinavir can also cause hyperbilirubinemia in addition to nephrolithiasis. Patients taking atazanavir and indinavir should be counseled to increase fluid intake to decrease the risk of nephrolithiasis.

Other Therapies

One of the two newest antiretrovirals, maraviroc, is the only CCR5 inhibitor on the market. When HIV infects a cell, the viral protein gp120 must first bind to a CD4 receptor on the lymphocyte cell surface. Next, it binds to a coreceptor, CCR5 or CXCR4. Some HIV viruses can use one or the other coreceptor and some can use either. There is a tropism assay available to assess a particular patient’s virus tropism. Testing is required before initiation of maraviroc because it is only effective against pure CCR5 tropic virus. If a patient has CXCR4, dual, or mixed tropic virus, maraviroc should not be used. CCR5 tropic virus is common in treatment-naïve patients, but the incidence of pure CCR5 virus decreases with time. Pure CXCR4 virus is rare, but many patients will have dual or mixed tropic virus. Maraviroc has many drug interactions. When used along with strong CYP3A inhibitors, maraviroc is dosed at 150 mg bid. In conjunction with strong CYP3A inducers, the maraviroc dose is 600 mg bid. When neither a strong inducer nor a strong inhibitor is present in the patient’s medication regimen, the normal dose is 300 mg bid.¹⁰

Enfuvirtide is a fusion inhibitor and is supplied as a powder for injection. It binds to gp41, which would normally initiate fusion of the virus into the lymphocyte cell surface. Once enfuvirtide is reconstituted with sterile water, it is given as a subcutaneous injection twice daily. Two doses can be reconstituted at the same time and the unused dose placed in the refrigerator. Refrigerated doses must be used within 24 hours of reconstitution. Enfuvirtide is usually reserved for patients who have already tried initial and subsequent sets of antiretrovirals that were discontinued for various adverse effects or resistance. The most common side effect is injection-site reactions that produce knots under the skin that disappear with time. Patients should be encouraged to rotate injection sites and never inject into one of these preexisting knots. Sites used for this subcutaneous injection are the same as used for insulin—the abdomen, thighs, and upper arms.¹¹

Raltegravir, another new medication used to treat HIV, inhibits the enzyme integrase. Integrase’s role would normally include creating available ends on newly created viral DNA, aiding entry of this DNA into the cell’s nucleus, and then splicing viral DNA into the host DNA inside the nucleus. Because raltegravir is not metabolized by the cytochrome P450 system, it has minimal drug interactions. Raltegravir undergoes UGT1A1-mediated glucuronidation. There is a documented interaction with rifampin due to rifampin’s induction of UGT, resulting in the need to increase the raltegravir dose to 800 mg twice daily from the normal 400-mg twice daily dose.¹²Raltegravir is usually well tolerated.

One goal of antiretroviral therapy includes achieving an undetectable viral load, many times reported as less than 50 copies/mL depending on how low the assay can measure. Another goal includes increasing the patient’s CD4 count to a level that is near that of an uninfected individual, which decreases the patient’s risk of acquiring opportunistic infections. It is recommended that a patient’s antiretroviral regimen include at least three drug entities that are active against the patient’s HIV. In some treatment-experienced patients who have exhausted many previous antiretroviral options, it may be necessary to have only two active antiretrovirals in their regimen. It is more common to see regimens that include two NRTIs and one NNRTI or two NRTIs and one ritonavir-boosted PI; however, it is not uncommon to see drugs from all three of these classes used in one regimen or two PIs (in addition to ritonavir) in the same regimen. Of course, there is also incorporation of medications from some of the more unique classes such as an integrase inhibitor, CCR5 inhibitor, or fusion inhibitor. Careful attention to drug interactions is required when combining many of these medications due to their involvement with CYP450.

There are certain antiretroviral combinations that are never recommended to treat HIV infection. Monotherapy with a single antiretroviral, for example, is not recommended. Out of necessity, monotherapy with zidovudine was used after its marketing because it was the only available antiretroviral. Monotherapy sets the stage for resistance to occur and is virologically inferior to combination regimens. Therapy with dual or triple NRTIs alone is also discouraged. The 2NN Study demonstrated that regimens that included two NNRTIs had more adverse events when compared to regimens that included just one of the NNRTIs.¹³It is also important to remember antiretroviral combinations that should not be used due to overlapping toxicities or drug interactions.

Resistance testing is recommended in treatment-naïve patients, during pregnancy, and in instances of treatment failure not attributable to lack of adherence or adverse effects. Genotype results can be obtained faster than phenotype results and include a list of all mutations found in the patient’s HIV virus. Phenotyping compares response of the patient’s virus to each antiretroviral with the response of a wild-type virus. These results are reported in fold changes of IC₅₀.

Guarding Against Opportunistic Infections

Once patients with HIV experience immunosuppression based on decreases in CD4 count, they are at risk for many opportunistic infections. Medications can be given to prevent several of these infections. Pneumocystis jiroveci pneumonia (PCP) is seen more than 90% of the time in patients with a CD4 count less than 200 cells/mm³. Therefore, it is recommended that patients with CD4 counts under 200 cells/mm³receive prophylaxis to decrease their risk.¹First-line prophylaxis would be sulfamethoxazole/trimethoprim (TMP) 800/160 mg daily. If a patient has a sulfa allergy, dapsone 100 mg should be used as an alternative. There is a small percentage of sulfa-allergic patients who will also have a reaction to dapsone. In these circumstances, atovaquone or inhaled pentamidine may be used. For patients with a CD4 count less than 50 cells/mm³, prophylaxis for Mycobacterium avium complex (MAC) is recommended. Azithromycin 1,200 mg once weekly is typically used, but clarithromycin 500 mg twice daily is also acceptable. Patients with CD4 counts less than 100 cells/mm³and positive toxo immunoglobulin (Ig)G are at increased risk for Toxoplasmosis gondii. The first-line regimen to protect against PCP, sulfamethoxazole/TMP 800/160 mg daily, also provides prophylaxis for toxoplasmosis. If a patient is on an alternative PCP prophylaxis regimen and meets toxoplasmosis prophylaxis criteria, care should be taken to ensure that adequate toxoplasmosis coverage is added.¹⁴

Role of the Pharmacist

Important patient counseling points for antiretroviral regimens include confirming that the patient understands the goals of treatment and stressing adherence. Just as it is useful for patients with hypertension to know their current blood pressure or those with diabetes to know their most recent glycosylated hemoglobin level and the goals associated with each, it is important for a patient with HIV to know his or her CD4 count and viral load and what the goals of therapy are for these numbers. With the newer formulations of many of the antiretrovirals, storage is not a concern. However, there are a few formulations that must be refrigerated prior to dispensing, and the patient must be advised to keep the product at room temperature or cooler. These products include ritonavir capsules (Norvir), lopinavir/ritonavir liquid (Kaletra), and tipranavir capsules (Aptivus) and are stable outside of the refrigerator for 30, 60, and 60 days, respectively.^15-17

Pharmacists have the unique opportunity to be able to educate HIV-infected patients about their antiretroviral medications; monitor all of a patient’s medications, including OTC drugs and herbals, for drug interactions; and provide patients with advice and services to increase medication adherence. As persons infected with HIV continue to live longer lives and take many complex medication regimens, pharmacists will continue to become a more vital component of their health care team. Pharmacists will need to be diligent in medication history review with each patient before dispensing medications. Services to help patients become more adherent include simple ideas such as refill reminders and daily pill boxes. All of these important tasks are vital to the care of HIV-infected patients.

Herpes Zoster (Shingles) and Postherpetic Neuralgia Management

2009-06-27T11:41:00.000-07:00

Release Date: May 1, 2009

Expiration Date: May 31, 2011

FACULTY:

Nora Osemene, MS, PharmD
Associate Professor and Chair
Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Texas Southern University, Houston, Texas

FACULTY DISCLOSURE STATEMENTS:

Dr. Osemene has no actual or potential conflicts of interest in relation to this activity.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

Herpes zoster infection (shingles) results from the reactivation of varicella zoster virus infection. Within the spinal ganglia and sensory nerves lay clinically dormant varicella zoster virus acquired during the primary varicella (chickenpox) infection.¹The reactivation of the varicella zoster virus is associated with progressive decline in varicella zoster—specific, cell-mediated immunity related to aging or conditions with diminished immunity such as cancer and diabetes. This reactivation and the accompanying inflammation lead to central nervous system dysfunction, which is manifested as debilitating pain. Low levels of immune globulin have been shown to predispose patients to recurring herpes zoster infection.

While varicella virus infection mostly affects the young, shingles and its complications mainly affect older persons. In excess of 60% of people older than 60 years, especially those with diminished immunity due to diabetes and cancers, are afflicted by herpes zoster. More than 50% of people who live to be 85 years will develop shingles. About 20% of people with herpes zoster develop postherpetic neuralgia (PHN).²The pain associated with postherpetic neuralgia is very debilitating and lasts long after the herpetic rash is cleared. Postherpetic neuralgia is very resistant to treatment and results in decreased quality of life.

PATHOPHYSIOLOGY AND PRESENTATION

Varicella virus infection is the primary infection in patients with compromised immunity. The virus gains entry into nerve cells in the sensory dorsal root ganglia.³The mechanism of the virus's entrance into the dorsal ganglia and the nerve cells is not completely understood. Initially, the host is able to produce varicella zoster virus—specific, cell-mediated immunity during the infection. This ensures that the virus remains latent within the host ganglia. Periodically, endogenous and exogenous boosting of the immunity against varicella results in the virus remaining dormant for decades. Eventually, reactivation of the virus occurs as a result of decline in virus-specific, cell-mediated immunity. Normal age-related decline and diseases such as malignancies and HIV impact the reduction in cell-mediated immunity and the reactivation of dormant varicella virus. The reactivated virus travels down the sensory nerve, causing pain and skin lesions (FIGURE 1). Shingles usually develops in stages.^4,5

Early Stage

The initial stage of shingles precedes the active stage with a conundrum of symptoms that last several days or weeks before the shingle rash appears. Patients with early signs of shingles complain of headaches, hypersensitivity to light, flulike symptoms without fever, itching, tingling, and burning or pain around the affected area. The affected nerves are usually found on the trunk of the body but may sometimes be distributed on the face, neck, arm, leg, or abdomen. The lymph nodes may be swollen and tender as well. These symptoms last a short time and are followed by skin rash.

Active Stage

The rash develops from maculopapular lesions forming a beltlike pattern on the patient's trunk, but the band of rash may appear anywhere on the body including the eyes. Some patients get very mild rash or none at all. The rash evolves into vesicles and blisters that are extremely painful, often described as like a piercing needle in the skin, accompanied by anxiety and flulike symptoms. These vesicles become crusted within 7 to 10 days and are shed, leaving scarring and pigmented changes on the skin. Pain is the primary complaint with active-stage shingles and the symptom for which patients seek medical care. The pain is described as persistent, with a burning or stinging sensation.⁶In patients who are immunocompromised, zoster initially presents in a typical fashion. However, the rash in these patients tends to be more severe with prolonged duration. One specific risk for patients who are immunocompromised is dissemination of the zoster rash. Cutaneous dissemination generally occurs only among immunocompromised patients, occurring in up to 37% of zoster cases in the absence of antiviral treatment. While cutaneous dissemination is not life-threatening, it is a marker for potential virus seeding of the lungs, liver, gut, and brain and can cause pneumonia, hepatitis, encephalitis, and disseminated intravascular coagulopathy in 10% to 50% of episodes.

Complications

Many complications can occur with herpes zoster infection. In 10% to 25% of cases, patients contract herpes zoster ophthalmicus (HZO). Keratitis occurs in approximately two-thirds of patients with HZO, often causing corneal ulceration. Other complications include conjunctivitis, uveitis, episcleritis and scleritis, retinitis, choroiditis, optic neuritis, lid retraction, ptosis, and glaucoma. Extraocular muscle palsies can also occur. Prolonged or permanent sequelae of HZO include pain, facial scarring, and loss of vision. Occasionally, zoster can cause motor weakness in noncranial nerve distributions, called zoster paresis. The weakness develops abruptly within 2 to 3 weeks after onset of the rash and can involve upper or lower extremities. Diaphragmatic paralysis has also been described. Rarely, patients will experience acute focal neurologic deficits weeks to months after resolution of the zoster rash, involving the trigeminal distribution contralateral to the initial rash. This ischemic stroke syndrome is termed granulomatous angiitis. Mortality from this syndrome is substantial. Other rare neurologic complications of herpes zoster include myelitis, aseptic meningitis, and meningoencephalitis. The risk for neurologic zoster complications is generally increased in immunocompromised persons. The most common chronic complication of shingles remains PHN.

Postherpetic Neuralgia

The main symptom associated with postherpetic neuralgia is pain, which persists for a long period beyond the resolution of the shingles rash. The features of PHN pain vary from mild to excruciating in severity, can be constant or intermittent, or triggered by trivial stimuli. Patients complain of pain in response to nonnoxious stimuli such as pressure from clothing, bed sheets, or the wind. Approximately half of patients with zoster or PHN describe their pain as horrible or excruciating, ranging in duration from a few minutes to constant on a daily basis. The pain, which is characterized as burning and lancinating, is chronic, intractable, and distressing. It can disrupt sleep, mood, work, and activities of daily living, adversely impacting the quality of life and leading to social withdrawal and depression. The pain is stipulated to be due to persistent C-fiber nociceptor activity in the nerve cells, although studies have shown chronic neural loss and scarring in nerves affected by herpes zoster injury. What has not been established or shown is how the associated inflammation causes pain. The pain of PHN commonly affects the forehead or chest.

MANAGEMENT OF SHINGLES

There are three main objectives in the management of shingles. The first objective is to treat the acute viral infection. The second objective is to treat the associated pain in the acute phase and in PHN, and the third objective is to prevent the occurrence of PHN and other complications. To achieve these objectives, antiviral agents, oral corticosteroids, and pain management are utilized.

Antiviral Therapy

The choice of antiviral agent should be individualized with considerations for dosing frequency, clinical outcomes, and cost.⁷TABLE 1 shows the available antiviral agents and dosing schedule. Acyclovir is a DNA polymerase inhibitor. It is available for both oral and intravenous use. The main disadvantages when acyclovir is administered orally are low bioavailability and the 5-hour dosing frequency. Acyclovir's multiple-dosing requirements often lead to noncompliance. The parenteral route is available for patients who are unable to utilize the oral dosing route. Valacyclovir is a prodrug of acyclovir with less frequent administration of every 8 hours. Another advantage of valacyclovir compared to acyclovir is better bioavailability, producing comparable blood levels to parenteral acyclovir. Valacyclovir appears to be more efficacious in decreasing the severity of pain associated with acute herpes zoster and the duration of the PHN when compared to acyclovir. Famciclovir is also a DNA polymerase that is administered every 8 hours. Famciclovir has the advantage of having longer intracellular half-life compared with acyclovir and a superior biovailability compared to both acyclovir and valacyclovir. When antiviral therapy starts within 72 hours of the onset of herpes zoster, acyclovir, valacyclovir, and famciclovir have been shown to significantly shorten the periods of acute pain, virus shedding, rash, and acute and late-onset complications. Both valacyclovir and famciclovir have been shown to lessen the incidence and severity of PHN. No antiviral agents as of yet prevent the development of PHN.

Corticosteroids

Oral corticosteroids are useful in the treatment of acute herpes zoster.^8,9Clinical trials have shown variable results. Prednisone use in conjunction with acyclovir resulted in the reduction of the pain associated with acute herpes zoster. It has been postulated that the mechanism of the steroid effect is due to decrease in the degree of neuritis caused by the active infection, decreasing the resulting damage to affected nerves. Despite the usefulness of prednisone in managing the associated pain with herpes zoster infection, it has not been shown to decrease or prevent the incidence of PHN. The risk of immunosuppression may hinder the use of steroids in high-risk patients.

Pain Management of PHN

The main objective in the treatment of PHN is pain relief. Frequently, PHN does not respond well to treatment. The pain relief is partial, and pain may last the remainder of the patient's lifetime. The pain is chronic, intractable, and distressing for the patient. Pain therapy may involve the use of multiple agents including topical analgesics, tricyclic antidepressants, anticonvulsants, narcotics, and intervention therapy (TABLE 2).

Topical Analgesics

Capsaicin, an extract of chili peppers, is approved in the United States for treatment of PHN.^10,11Clinical trials have demonstrated capsaicin's efficacy compared to placebo in the management of PHN pain. The application of capsaicin to the skin produces a burning sensation, which triggers the release of substance P, a neuropeptide, from pain fibers. The depletion of substance P in the nerve fibers from repeated exposure to capsaicin results in analgesia. Capsaicin cream must be applied three to five times daily to achieve substance P depletion from the pain fiber and analgesia. The need for regular application of capsaicin must be emphasized to patients to maintain pain relief. Additionally, patients must understand that the pain may initially increase within the first week of initiating the therapy because it initially acts as an irritant by stimulating the nerve endings before desensitizing afferent C-fibers. It is important to educate patients on the need for thorough hand washing after each application of capsaicin. Hand washing prevents accidental transfer of capsaicin to other areas. Tolerability of capsaicin in the elderly may be a problem.

The lidocaine 5% patch has been shown to be easy to use, safe, tolerable, and efficacious in the management of PHN pain. Lidocaine is an amide-type local anesthetic agent that stabilizes neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses. In patients with PHN, the lidocaine 5% patch has demonstrated relief of pain and tactile allodynia with a minimal risk of systemic adverse effects or drug—drug interactions. Because of its proven efficacy and safety profile, the lidocaine 5% patch has been recommended as a first-line therapy for the treatment of PHN pain.¹²The systemic absorption of lidocaine from the patch is minimal in healthy adults even when applied for up to 24 hours, and lidocaine absorption was even lower among patients with PHN than among healthy adults at the recommended dosage. The highest blood lidocaine level measured was 0.1 mcg/mL, indicating minimal systemic absorption of this agent. Lidocaine-containing patches significantly reduce pain intensity throughout the dosing interval for up to 12 hours. Lidocaine patches were superior to both no treatment and vehicle patches in averaged category pain relief scores. Most adverse events were at patch application sites. No clinically significant systemic adverse effects were noted, including when used long-term or in an elderly population.

Oral Agents

Tricyclic Antidepressants: Tricyclic antidepressants (TCAs) are effective adjuncts in the management of PHN pain.¹³TCAs inhibit the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically, this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. TCAs relieve PHN pain by stabilizing nerve pathways that have undergone degeneration and interruption due to herpes zoster infection. TABLE 2 shows commonly used TCAs in the management of PHN. TCA therapy should be initiated with low doses to improve tolerability and be administered at bedtime. The dose can be titrated every 2 to 4 weeks until maximum tolerated dose to achieve results. TCAs act slowly and may require up to 3 months before achieving adequate response in patients. Combining TCAs with antiviral drugs during herpes zoster infection has been shown to decrease the intensity of PHN pain but does not prevent it. The main side effects expected from TCA therapy are sedation, dry mouth, postural hypotension, blurred vision, and urinary retention. These side effects are related to the anticholinergic activities of TCAs. Nortriptyline tends to produce less anticholinergic effects and is better tolerated. Cardiac conduction impairment or liver toxicity may develop in some patients, especially in elderly patients or those at high risk.

Anticonvulsants: Phenytoin, carbamazepine, gabapentin, and pregabalin are useful to control PHN pain.^14,15 Phenytoin is an anticonvulsant drug related structurally to barbiturates. Phenytoin produces its beneficial effect in PHN through its antinociceptive activity. The side effects to be concerned about, especially in the elderly, include nystagmus, ataxia, skin eruptions, hematological complications, and gingival hyperplasia.

Carbamazepine greatly reduces or abolishes pain induced by stimulation of the nerve. It depresses thalamic potential and bulbar and polysynaptic reflexes. Carbamazepine is chemically unrelated to other anticonvulsants or other drugs used to control PHN pain. The drawback to using carbamazepine is the serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome. These dermatologic adverse events commonly affect patients of Asian ancestry. Also, severe blood disorders such as aplastic anemia and agranulocytosis may occur. Complete baseline and periodic hematologic monitoring for the patient is essential.

Gabapentin prevents allodynia and hyperalgesia associated with PHN pain as well as the associated sleep disorder. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA), but it does not bind directly to GABA_Aor GABA_Breceptors. The adverse events with its use are dizziness, somnolence, and peripheral edema.

Pregabalin is a structural derivative of the neurotransmitter GABA and does not bind directly to GABA_Aor GABA_Breceptors. It binds with high affinity to the alpha₂-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues to produce antinociceptive effects.

Anticonvulsants have been shown to be equally efficacious; however, drug selection may involve trial and error. If there is inadequate response to one anticonvulsant agent, another agent should be tried. Doses required for the analgesic activity are lower than those used to treat seizures. These agents may be combined with TCAs or the lidocaine patch to improve pain relief. The risk of side effects, however, is increased with the use of multiple medications. The side effects that are associated with anticonvulsants include sedations memory disturbance, electrolyte abnormalities, liver toxicities, and thrombocytopenia. These side effects can be minimized by initiating therapy with low doses and slowly titrating doses upward over several weeks.

Opioid Analgesics: Opioids such as codeine, oxycodone, and morphine provide PHN pain relief by their interaction with opioid receptors in the central nervous system.¹⁶Specifically, they provide pain relief through inhibition of the ascending transmission of nociceptive signals, activation of descending inhibitory pain pathways, and modulation of limbic system activity. Opioid analgesics in combination with acetaminophen or nonsteroidal anti-inflammatory drugs may be useful as a last resort in patients with severe PHN pain unrelieved by other drugs. Opioid analgesic side effects include nausea, vomiting, constipation, dizziness, headache, and respiratory depression. Long-term use is of concern because of the abuse potential. Tramadol, a centrally active synthetic opioid analgesic, is a useful alternative because it lacks the abuse potential associated with other opioids.

Other Interventions

Transcutaneous Electric Nerve Stimulation: The application of electrical current through the skin for pain relief is known as transcutaneous electrical nerve stimulation (TENS). TENS has been shown to be beneficial in the management of PHN pain.¹⁷TENS produces analgesic effects by activation of opioid receptors in the central nervous system. High-frequency TENS activates delta-opioid receptors both in the spinal cord and supraspinally (in the medulla), while low-frequency TENS activates mu-opioid receptors both in the spinal cord and supraspinally. Further, high-frequency TENS reduces excitation of central neurons that transmit nociceptive information, reduces release of excitatory neurotransmitters (glutamate), increases the release of inhibitory neurotransmitters (GABA) in the spinal cord, and activates muscarinic receptors centrally to produce analgesia by temporarily blocking the pain gate.

Biofeedback: Patients may use biofeedback techniques that employ the mind to control body functions such as skin temperature, muscle tension, heart rate, and blood pressure.¹⁸Biofeedback may also be used to control problems such as chronic pain. There are two types of biofeedback techniques. The first type is electromyography. This type uses a device that measures muscle tension while the patient practices a relaxation technique such as meditation, progressive muscle relaxation, or visualization. The second technique is hand-temperature biofeedback. This type of biofeedback uses a device that measures the skin temperature of the hand. Patients can decrease their pain by increasing their body temperature through visualization or guided imagery.

Nerve Block: Nerve block injections have been shown to be useful in the management of PHN pain. Nerve blocks provide periods of dramatic pain relief, which promotes the desensitization of sensory pathways. In this technique, local anesthetics, steroids, and opioid medications are injected around the affected nerve to relieve pain. The nerve block with anesthetic may relieve PHN pain for several days, but the pain often returns.¹⁹Nerve block injections need to be repeated several times over the course of a week to be effective.

Herpes Zoster Vaccine: The medical and social costs of shingles and PHN are high, particularly in elderly people. The outcome of treatment of shingles is often unsatisfactory, although the antiviral medications reduce the duration of pain during the acute phase but do not prevent PHN complications and pain. A live, attenuated vaccine has been shown to reduce the incidence of shingles and PHN as well as reduce the burden of the illness in patients older than 60 years.²⁰The zoster vaccine licensed in the United States (Zostavax, Merck) is a lyophilized preparation of the Oka/Merck strain of live, attenuated varicella zoster virus, the same strain used in the varicella vaccines (Varivax, Proquad). The Oka strain was isolated in Japan in the early 1970s from vesicular fluid from a healthy child who had varicella; the strain was attenuated through sequential propagation in cultures of human embryonic lung cells, embryonic guinea pig cells, and human diploid cells (WI-38).²¹Further passage of the virus was performed at Merck Research Laboratories in human diploid cell cultures (MRC-5). The cells, virus seeds, virus bulks, and bovine serum used in the manufacturing are all tested to provide assurance that the final product is free of adventitious agents. The CDC Advisory Committee on Immunization Practices recommends routine vaccination of all persons age >60 years with one dose of zoster vaccine. Persons who report a previous episode of zoster and persons with chronic medical conditions (e.g., chronic renal failure, diabetes mellitus, rheumatoid arthritis, and chronic pulmonary disease) can be vaccinated unless those conditions are contraindications or precautions. Zoster vaccination is not indicated to treat acute zoster, to prevent persons with acute zoster from developing PHN, or to treat ongoing PHN. Before routine administration of zoster vaccine, it is not necessary to ask patients about their history of varicella (chickenpox) or to conduct serologic testing for varicella immunity.

In conclusion, age is the most important risk factor for developing shingles. More than 50% of the people who live to be 85 years old will develop shingles, and 80% to 85% of PHN complication occurs in patients older than 50 years. Thus, early management of shingles is essential to prevent the many complications, especially the chronic, debilitating, difficult-to-treat PHN pain that often results from the condition.

The Use of OTC Medications in Older Adults

2009-06-22T09:53:00.000-07:00

Miranda Wilhelm, PharmD
Clinical Assistant Professor
Department of Pharmacy Practice
Southern Illinois University Edwardsville
School of Pharmacy, Edwardsville, Illinois

J. Mark Ruscin, PharmD, BCPS
Professor
Department of Pharmacy Practice
Southern Illinois University Edwardsville
School of Pharmacy, Edwardsville, Illinois

6/18/2009
US Pharm. 2009;34(6):44-47.

With the introduction of the Beers Criteria, there has been a virtual explosion of literature regarding the inappropriate use of medications in older adults. The Beers Criteria focus on prescription medications, with only a few OTC medications being addressed (diphenhydramine, mineral oil, cimetidine).¹ However, this provides little guidance for practitioners when making recommendations with respect to appropriate medications, particularly among many available OTC products.

Older adults generally have more medical problems and use more medications, both prescription and OTC, when compared to younger adults. Many older adult patients self-treat using OTC medications. Older adults account for about 13% of the United States population and purchase 40% of all OTCs consumed.² Pharmacists, as one of the most accessible health care providers, have an opportunity to assist these patients when making decisions in the OTC aisle. As the baby boomers age, there will be even more opportunities for pharmacists to assist older adults with making appropriate OTC medication choices. To do this successfully, it is essential for pharmacists to be able to evaluate and assess patient symptoms. One quick and effective method for determining the needs of patients and to see if they are candidates for self-care is the QuEST/SCHOLAR process.^3,4 QuEST is a mnemonic for assessing and counseling the patient (TABLE 1). SCHOLAR is a mnemonic to assist with symptom assessment (TABLE 2). The purpose of this article is to provide the practicing pharmacist with a review of various OTC options, for some of the more common medical problems or disease states, that are generally safe for older adults.

Allergy

Allergic rhinitis has an estimated prevalence of between 9% and 40% in the U.S. adult population.⁵ It can be seasonal if occurring only during certain parts of the year, or perennial if symptoms occur year round. Mild-to-moderate symptoms are most often treated with antihistamines and decongestants. Cromolyn sodium is an intranasal mast cell stabilizer that prevents the release of histamine and other mediators of allergic rhinitis. The nasal spray is approved for the treatment and prevention of seasonal and perennial allergic rhinitis symptoms such as sneezing and runny, stuffy, and itchy noses. As a topical nasal spray, it exhibits a local effect with minimal systemic absorption. The most common adverse effects relate to the local action and include sneezing and nasal stinging and burning. Since it exerts only a local effect, no drug interactions are reported. No dosage adjustments are needed for renal or hepatic impairment. The minimal adverse effects and no drug interactions therefore make cromolyn sodium a good choice for treating allergic rhinitis in older adults.

Ketotifen is an ocular antihistamine, mast cell stabilizer, and eosinophil inhibitor that prevents the release of histamine and other mediators of allergic conjunctivitis. The ophthalmic solution is approved for the prevention of ocular itching due to allergic conjunctivitis. Previously available only by prescription, ketotifen is now available OTC. Most of the OTC eye drops contain an antihistamine and a decongestant to treat the itching and redness associated with allergic conjunctivitis. Ocular decongestants have the same problem of rebound congestion as the nasal decongestants. As a result, patients should be counseled not to use the products longer than 3 to 5 days consecutively. Ketotifen is not a decongestant and therefore does not have the rebound congestion problem. As a topical ophthalmic solution, it exhibits a local effect with minimal systemic absorption. The most common adverse effects include conjunctiva congestion, headache, and rhinitis. No systemic drug interactions have been reported with ketotifen since it has only a local effect. No dosage adjustments are needed for renal or hepatic impairment. The lack of rebound congestion and lack of reported drug interactions make ketotifen a good choice for treating allergic conjunctivitis in older adults.

Loratadine is a second-generation oral antihistamine. It is approved for the relief of seasonal and perennial allergic rhinitis symptoms, such as sneezing, itching, and rhinorrhea. As a large protein-bound lipophobic molecule with charged side chains, it does not cross the blood-brain barrier easily. This is what accounts for the lack of sedating effects. Unlike the sedating, first-generation antihistamines, loratadine does not activate alpha-adrenergic receptors or block cholinergic receptors. Therefore, it does not produce substantial anticholinergic adverse effects such as dry mouth, dry eye, urinary retention, and constipation, which are commonly seen with the sedating antihistamines. Older adults are also more susceptible to the cognitive side effects associated with antihistamines having anticholinergic effects. The lack of sedating and anticholinergic effects makes loratadine one of the better choices for treating allergic rhinitis in older adults.

Patients with more severe symptoms or with symptoms that do not resolve with a trial of OTC medications should be referred to their primary care provider (PCP). Patients should also be referred to their PCP if sinusitis is suspected.

The Common Cold

The common cold, which is caused by rhinoviruses or coronoviruses, cannot be cured with any available drug therapies at this time. As a result, recommended treatments are primarily symptomatic. The most common symptoms include sore throat, runny nose, congestion, sneezing, coughing, muscle aches, and fatigue. Although there is an abundance of OTC products available to treat cold symptoms, most products contain combinations of antihistamines, decongestants, expectorants, and cough suppressants. Many of these medications may not be appropriate for patients who have other medical problems (hypertension, diabetes) or take other medications.

Oxymetazoline is an alpha-adrenergic receptor agonist available as a nasal spray. It causes vasoconstriction of the mucous membranes resulting in decreased nasal mucosa edema. This promotes drainage and improves breathing. The nasal spray is approved for relief of stuffy nose symptoms associated with the common cold, sinusitis, hay fever, and nonseasonal, seasonal, and perennial allergic rhinitis. When administered intranasally, it exhibits a local effect with minimal systemic absorption. Unlike oral decongestants that can increase blood pressure, the topical decongestants do not have this effect; therefore, patients who are taking blood pressure-lowering medication would not need to worry about oxymetazoline raising their blood pressure. The most common adverse effects relate to the local action and include nasal stinging and burning, dryness, and sneezing. The use of oxymetazoline can result in rebound nasal congestion, so patients should be counseled not to use the product longer than 3 to 5 days consecutively. It has only a local effect, so little to no drug interactions are suspected. No dosage adjustments are needed for renal or hepatic impairment. Minimal adverse effects and no drug interactions make oxymetazoline a good choice for the short-term treatment of nasal congestion symptoms associated with the common cold in older adults.

In older adults, viral infections can increase the risk of developing secondary bacterial infections, such as bronchitis, pneumonia, or sinusitis. If one of these is suspected, patients should be referred to their PCP.

Osteoarthritis

Osteoarthritis affects nearly 50 million adults in the U.S., and the prevalence increases substantially with age.⁶ Pain due to osteoarthritis is one of the most common medical complaints among older adults.⁷ Limitations in physical activity and physical functioning are strongly associated with pain symptoms in osteoarthritis. Acetaminophen is a centrally acting analgesic. It is approved for the treatment of mild pain, fever, osteoarthritis, and migraine headaches. It is also approved for the temporary relief of headache, myalgia, back pain, dental pain, dysmenorrhea, arthralgia, or minor aches and pain associated with the common cold or influenza. Acetaminophen is the drug of choice for osteoarthritis when there is little to no inflammation involved. The American College of Rheumatology recommends acetaminophen as the first-line treatment option for osteoarthritis of the hip and knee.⁸ Compared to the alternative OTC pain relievers, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen has a more favorable adverse-effect profile. Older adults are at increased risk for the renal dysfunction, gastrointestinal irritation and bleeding, and exacerbations of hypertension that NSAIDs can cause. Acetaminophen's adverse effects are mainly seen at high doses used long-term or when the medication is used inappropriately (overdose). Acetaminophen should be used with caution in patients with hepatic impairment or history of alcohol use/abuse. It is the drug of choice for pain relief in patients with renal impairment, but dosage titration based on clinical effect is encouraged. When used as directed in doses not exceeding 4 g per day, acetaminophen is a safe and effective pain reliever for older adults. Despite its relative safety, some older patients may not get adequate analgesic effects from acetaminophen because of age-related changes in gastric motility, disease-related changes such as diabetic gastroparesis, or anticholinergic drug effects. Acetaminophen is primarily absorbed in the small intestine, and delayed presentation of the drug to the site of absorption may lead to inadequate analgesic effects.

Although not a pharmacologic agent, continuous low-level heat wrap therapy products are available in the OTC pain relief aisle. Low-level heat wrap therapy is approved for the treatment of arthritis and muscle pain. Low-level heat helps to relax sore and tight muscles, increasing flexibility and range of motion.⁹ With one application, the wraps provide heat for 8 to 12 hours. On the other hand, topical treatments such as counterirritants require application three to four times daily to maintain pain relief. Counterirritants, available as creams and ointments, can be messy, greasy, and are generally not acceptable to patients for long-term use. The heat wraps contain no medication, so there are no drug interactions and no dosage adjustments are required for renal or hepatic impairment. Neither heat nor occlusive dressings should be used in combination with other topical analgesics. Using the combination can increase the risk of systemic side effects. Low-level heat wraps provide a safe and effective alternative to OTC pain relief medications as well as an adjunct to oral therapy for older adults.

Heartburn

Heartburn and gastroesophageal reflux are very common symptoms in adults in the U.S., with an estimated 10% to 20% of adults having reflux symptoms on a weekly basis.¹⁰ Repeated exposure of the esophagus to refluxed stomach contents can lead to inflammation and erosions. However, for many patients, lifestyle changes and use of OTC acid-blocking medications can control symptoms and prevent complications of esophagitis.¹¹ Famotidine and nizatidine, as histamine₂-receptor antagonists, decrease gastric acid by blocking the effect of histamine on gastric cell receptors. They are approved for the prevention and treatment of mild-to-moderate, infrequent heartburn associated with acid indigestion or sour stomach. One dose taken 1 hour prior to anticipated heartburn or at the onset of heartburn can provide relief for up to 12 hours. This is useful for patients who experience heartburn at night. Histamine₂-receptor antagonists in general have a low incidence of adverse effects. Famotidine and nizatidine are not metabolized by the CYP450 system and, therefore, lack the drug interactions commonly seen with cimetidine. Ranitidine is metabolized by the CYP450 system, but to a lesser extent than cimetidine, so drug interactions are possible but are not seen clinically with OTC doses. The main drug interactions reported with famotidine and nizatidine are related to their acid-lowering effects. Medications that require an acidic environment to be absorbed, such as ketoconazole and itraconazole, will have reduced bioavailability. Dosage adjustments are needed for patients with renal impairment but not with hepatic impairment. The limited adverse effects and minimal drug interactions associated with famotidine and nizatidine make these two histamine₂-receptor antagonists, with dosage adjustments as needed, a good choice for patients with heartburn.

Omeprazole, as a proton pump inhibitor, decreases gastric acid by inhibiting acid secretion. It is approved for the treatment of frequent heartburn in patients experiencing symptoms 2 or more days per week. Omeprazole is not indicated for immediate relief of infrequent heartburn, and it may take up to 4 days for the full benefit to be seen. Omeprazole is taken once daily 30 minutes prior to the morning meal for 14 days and can be repeated after 4 months if symptoms return, or as directed by a physician. If heartburn symptoms persist or return before the 4-month time period, the patient should be instructed to consult with a physician. Omeprazole has a low incidence of adverse effects. No dosage adjustments are required for renal impairment, but dosage reductions are recommended for patients with severe hepatic impairment. One caution for pharmacists and something that patients should be aware of relates to drug interactions. Omeprazole has the same interaction as the histamine₂-receptor antagonists with regard to lower bioavailability of medications that require an acidic environment. Also, omeprazole is an inhibitor of the CYP450 system and therefore will interact with other medications metabolized by this system.

Patients who have frequent symptoms or symptoms that do not respond to OTC medications or who experience what is termed alarmsymptoms (continual pain, chest pain, dysphagia, odynophagia, weight loss, or choking) should be referred to their PCP.¹¹

Constipation

Constipation is a common problem among older adults, and many patients choose to initiate self-treatment. Although it is often considered a fairly benign issue, constipation not appropriately addressed can lead to bowel obstruction and hospitalization. Constipation is defined on the basis of stool frequency, stool consistency, and difficulty passing stools.^12,13 In the U.S., insufficient dietary fiber is a frequent underlying issue for many patients with constipation. Commonly used medications are also associated with constipation, including opiate analgesics, anticholinergics, and calcium or iron products. General nondrug approaches to improving constipation include dietary fiber (at least 10 g daily of crude fiber), adequate fluid intake, and exercise. Fruits, vegetables, and cereals are among the best foods to increase dietary fiber intake. There are numerous OTC medications to treat constipation, but not all are appropriate in all situations. For patients who have symptoms of obstruction (nausea, vomiting, abdominal pain or distention) or fecal impaction, OTC treatments should not be recommended, and these patients should be referred to their PCP for evaluation or disimpaction prior to the use of oral laxative agents.

Bulk-forming laxatives, including psyllium and methylcellulose, can be used to supplement dietary fiber if patients do not have adequate intake of dietary fiber. Bulk-forming laxatives are generally safe since they are not systemically absorbed. However, these agents must be taken with adequate fluid to prevent intestinal obstruction. Bulk-forming agents can be useful for ongoing treatment and for preventing chronic constipation. These agents are not optimal for patients who have acute constipation, as they can take several days to produce the desired effect. Some patients may experience abdominal distention and flatus with increases in dietary fiber, but these symptoms typically decline over time.

Emollient laxatives, such as docusate sodium, are not exceptionally effective for treating constipation but may be useful in situations where straining during defecation should be avoided, such as with hemorrhoids or following rectal surgery or a myocardial infarction.

Polyethylene glycol 3350 is an osmotic laxative that is generally safe to use for older patients with constipation. It does not cause electrolyte disturbances, as can be seen with other saline-type osmotic laxatives, including magnesium citrate or sodium phosphate. As a result, polyethylene glycol-containing products are safer for patients with significant renal dysfunction or with congestive heart failure. The laxative works by osmotic action and retention of fluid in the gastrointestinal tract, which leads to softening of the stool. Unlike some of the saline-type osmotic laxatives, which work quickly (hours), polyethylene glycol takes slightly longer to produce the desired effect (1 to a few days).

Acute constipation can be relieved with the use of glycerin suppositories. Glycerin is considered very safe, and the onset of action is usually less than 30 minutes. Occasionally, patients may experience mild rectal irritation.

Insomnia

Complaints regarding sleep increase dramatically with advancing age. Aging is associated with changes in sleep architecture, including decreased sleep efficiency, total sleep time, and restful sleep stages.¹⁴ Numerous factors can also impact sleep, such as pain, urinary symptoms associated with benign prostatic hyperplasia or overactive bladder, restless legs syndrome, sleep apnea, issues with sleep hygiene, or side effects of medications. It is very important to look for underlying causes of sleep problems before initiating medications to treat sleep symptoms. Improving sleep hygiene and healthy sleep habits (limit napping, avoid late-day exercise, avoid late-day caffeine and fluid intake, etc.) are also important to consider prior to initiating medications for sleep.¹⁵

Many OTC sleep products contain sedating antihistamines, such as diphenhydramine. These products are generally not recommended for older adults because of the anticholinergic side effects. The food supplement melatonin has been advocated for sleep in older adults, since aging has been associated with a decrease in this natural hormone secreted by the pineal gland.¹⁶ Supplementation with melatonin in older adults with low levels of melatonin does improve sleep efficiency.¹⁷ There have been several studies of melatonin in elderly patients with insomnia, but most have been small and the melatonin products have been varied, including both controlled-release and immediate-release products in dosages ranging from 0.5 mg to 6 mg dosed at bedtime.^18,19 One study also showed improvements in sundowning symptoms in patients with dementia and agitated nighttime behaviors.¹⁹ Melatonin is considered fairly safe, and reported side effects have been minimal in the available published studies.

Urinalysis: A Guide for Pharmacists

2009-06-22T09:47:00.000-07:00

Kirandeep Panesar,
BPharm (Hons), MRPharmS, RPh, CPh
Freelance Medical Writer
Orlando, Florida,
Consultant Pharmacist
Acacia Pharmacy,
Nairobi, Kenya

FACULTY DISCLOSURE STATEMENTS:

Kirandeep Panesar has no actual or potential conflict of interest in relation to this activity.

The evolving role of pharmacists as providers of health and health care information encompasses both in-pharmacy clinical testing and the provision of counseling on tests carried out in the more traditional laboratory setting. Clinical laboratory tests can be used to confirm or support a diagnosis, assess the severity of a disease (e.g., MRI for tumor size), monitor the response to treatment, monitor appropriate drug dosing, and help prevent toxic side effects and interactions.¹To facilitate the role of pharmacists in health promotion, a basic knowledge of clinical testing is useful for both institutional and retail pharmacists. This will assist pharmacists when counseling patients on preparing for laboratory procedures and receiving test results; adjusting drug therapy based on test results; providing in-pharmacy testing to promote patient health; and liaising with other health professionals to optimize patient therapy.

Urine testing provides a broad spectrum of information to health care providers and offers a noninvasive and therefore pain-free option to diagnostic testing for a number of conditions. Urinalysis has been used in diagnostic medicine for thousands of years, dating as far back as ancient Egypt, where there are descriptions of polyuria. “In the 7th century AD, Protosharis suggested that it was important to look at the color of urine and by 1674 Thomas Willis, a professor at Oxford University, recorded that the urine of his patients with diabetes tasted sweet.”²However, it is only with the introduction of the microscope in the 19th century that there have been major advances in this field. Dipstick testing, the application of modern chemical and microscopic techniques to constituent analysis, automation, and, most recently, monoclonal antibody and recombinant gene technology, have enhanced and improved urine examination.³

Today, urinalysis is a popular test in medical diagnosis and is frequently ordered with hospital admissions and regular checkups since it is relatively simple, inexpensive, and pain free. It may specifically be ordered in patients complaining of lower back pain, abdominal pain, and problems with urination or in pregnancy. Most importantly, testing urine samples may reveal disease conditions that would otherwise go unnoticed. For example, it has been shown that rising thyroid-stimulating hormone levels may be due to a rare condition called nephrotic syndrome and not to poor compliance with thyroxine therapy. This condition can be suspected with dipstick urinalysis and confirmed with biochemical testing and a renal biopsy.⁴

The test itself can be broken down into three components: visual examination (macroscopic analysis), dip-and-read tests, and microscopic analysis. There are a large number of dip-and-read tests now available for OTC purchase, and pharmacists will often be asked to provide instructions on the use of these kits. Additionally, pharmacists may be required to counsel patients on collecting urine samples, interpreting test results, and adjusting drug therapy based on these results.

COLLECTING URINE FOR TESTING

Obtaining a good urine sample is a tricky procedure, since the patient provides a majority of the samples. Consequently, patients need to be clear on how and when to collect the sample. Clean-catch of midstream urine collection is suitable for most test procedures. Some tests may require timed urine collection such as the 24-hour urine collection. In hospitals, urine samples from inpatients are frequently collected by catheterization. Recently, the accuracy of the 24-hour sample, a time-consuming and inconvenient procedure, has been questioned for testing proteinuria. Accordingly, the National Kidney Foundation recommends the use of spot urine samples that correct for creatinine concentration over the 24-hour sample.⁵

Patients who are required to collect their own samples should ideally be provided with a container specifically designed for urine collection, free of any chemicals that may affect the test results. When testing babies, the parent or caregiver should be given a urine collection bag. Specific advice for patients collecting urine is given in TABLE 1.

Table 1

Collecting Urine: Advice for Your Patients

For clean-catch or midstream urine collection

Use a container provided specifically for urine collection
Wash your hands before collecting the sample
Remove the lid of the collection container and place it with the inner surface up, making sure you do not touch the inside of the lid or the container
Clean the area around the genitals using a medicated swab or towelette
- Males should pull their foreskin back, if present,
and clean the tip of the penis
- Females should open the folds of the labia (vagina)
and clean from the front to the back
Urinate into the toilet or urinal for a few seconds, then pause
Continue urinating into the collection container until enough urine has been collected
Finish urinating into the toilet or urinal, if necessary
Carefully replace the lid and return the container for testing
If the sample is not being tested immediately, store it in a
refrigerator
Always wear gloves if helping another patient to collect urine

For 24-hour urine collection

Ensure that the specimen container is kept refrigerated at
all times
Start the urine test by urinating directly into the toilet. Do not collect this sample, but make a note of the time
and date on the storage container
For the next 24 hours, urinate into the collection container
and transfer the urine into the storage container
If you need to use more than one container during the
24-hour period, fill one container first before you start
filling the next one
At the end of the 24-hour period, urinate and transfer this
sample into the storage container. Make a note of the time and date for the end of this period on your container
Keep the sample refrigerated and return it to the testing
center as soon as possible

Urine samples should be tested immediately after collection to prevent false results. If immediate testing is not possible, the sample should be refrigerated and allowed to return to room temperature before testing. Samples that are stored incorrectly may give inaccurate results owing to reduced clarity because of crystallization of solutes; increased alkalinity (pH) due to the loss of CO₂; loss of ketone bodies and bilirubin (if present); dissolution of cells and casts; and overgrowth of contaminating microorganisms.

VISUAL EXAMINATION (MACROSCOPIC ANALYSIS)

Normal urine is a clear, pale yellow-colored fluid that has a slight odor of urea and is slightly acidic; any changes in the color, clarity, and smell of a urine sample can signal potential problems that may require further investigation. Dehydration results in an increase in the concentration of urochrome, the chemical that gives urine its distinct color, causing a darkening of the urine to an orange hue. Often, changes in urine color are a result of certain foods or drugs, and pharmacists should essentially rule out this possibility (TABLE 2). Blue urine is distinctive of the rare, inherited metabolic disorder termed the blue diaper syndrome. It is caused by incomplete breakdown and intestinal absorption of tryptophan in children.

Table 2
Factors That Can Change the Color of Urine
Color of Urine	Foods	Drugs	Diseases
Cloudy	Diet high in purine-rich foods	NA	Kidney stones, excessive cellular material, proteinuria, UTI accompanied by a foul odor
Orange	Vitamin C, carrots, carrot juice	Rifampin, warfarin, phenazopyridine	Dehydration due to increased concentration of urochrome
Red or pink	Beets, blackberries, rhubarb	Levodopa, chlorpromazine, thioridazine, propofol, rifampin	Hematuria
Blue or green	Asparagus	Amitriptyline, indomethacin, cimetidine, promethazine, triamterene	Blue diaper syndrome, pseudomonal UTI
Dark brown	Fava beans, rhubarb, aloe	Chloroquine, primaquine, metronidazole, nitrofurantoin, methocarbamol, senna, vitamin B complex	Liver disorders such as hepatitis, jaundice, and cirrhosis accompanied by yellow skin and pale stools; myoglobin; renal disorders that affect the kidney’s ability to excrete fluid and waste materials
Black	NA	Ferrous salts	NA
NA: not applicable; UTI: urinary tract infection.

The odor of urine may also provide some direction toward a diagnosis. Patients who have diabetes mellitus pass sweet, fruity-smelling urine caused by the excretion of acetone, and after prolonged bladder retention, alkaline fermentation causes an ammoniacal odor.⁶The urine of anorexic patients often smells like pear drops, and patients with urinary tract infections (UTIs) often pass urine with a pungent smell. Gastrointestinal-bladder fistulas in which feces may be deposited in the bladder commonly result in urine with a fecal odor; the formation of sulfur compounds in cystine decomposition disorders causes urine to have a sulfuric smell.⁶

DIP-AND-READ TESTING
How to Use the Test Strips

Dipsticks are very simple and convenient to use, but results can be easily misinterpreted since they are semi-quantitative. Semiquantitative analysis reports results as a range within which the actual result may lie, using a color chart or other qualitative reading. Reagent strips can be used to test pH, urine specific gravity (USG), UTIs, proteins, glucose, ketone bodies, bilirubin, and urobilinogen, and to confirm pregnancy and the presence of certain drugs (TABLE 3). However, the reliability of this method of testing is still controversial since the results may be highly inaccurate.

Table 3
Select Dip-and-Read Test Strips
Brand	Test
Clinistix	Glucose
Hemastix	Blood
Ketostix	Ketones
Bayer Multistix 10 SG	Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, protein, urine specific gravity, urobilinogen
Uristix	Glucose and protein
Uristix 4	Glucose, protein, nitrite, leukocytes
Clearblue, EPT, First Response	hCG hormone (pregnancy)
hCG: human chorionic gonadotropin.

When using a dipstick, the urine specimen should be collected in a sample bottle. Then the test area of the strip should be completely immersed in the urine sample and removed immediately. Shake off any excess urine by gently tapping the strip against the side of the specimen container. The strip should be left to react for the prescribed time. Finally, compare the color of the test area to the chart provided.⁷

Storage of Test Strips

Test strips should be stored at a constant temperature between 15°C and 30°C in a tightly closed container. The provided desiccant should not be removed from the container. Bayer Multistix 10 SG test strips exposed to the air for prolonged times have been shown to give false-positive results for glucose and false-negative results for microscopic hematuria (TABLE 4).⁸Furthermore, Gallagher et al found that out of nine reagents tested in the Chemstrip-9 dipstick (leukocyte esterase [LE], pH, protein, glucose, ketones, urobilinogen, bilirubin, blood, and nitrites), only the nitrite portion of the exposed dipsticks showed a rapid cumulative loss of specificity over time.⁹All other tests demonstrated reproducible results after exposure to room temperature and humidity for 1 to 15 days.⁹Therefore, even though manufacturers indicate that the strips should be stored in a tightly closed container and the desiccant should not be removed, all reactants may not lose their activity if exposed to air or humidity. However, it is a good practice to follow the label guidelines, and patients should be similarly advised. Discard any strips past their expiration date or any unused strips after 6 months of first opening.

Table 4
Factors That Can Change the Color of Urine
Dipstick Test	False-Positive	False-Negative
pH	Acidic urine: ingestion of proteins and acidic foods Alkaline urine: urine stored at room temperature, diet high in citrate, antiepileptic drugs, aged urine specimen	NA
USG	Dextran solutions, proteinuria	Alkaline urine
Leukocyte esterase	Contamination	Elevated USG, glycosuria, ketonuria, proteinuria, ascorbic acid, certain antibiotics (tetracycline, cephalexin, gentamicin, nitrofurantoin)
Nitrites	Contamination, exposure of dipstick to air, phenazopyridine	Elevated USG and urobilinogen level, nitrate reductase-negative bacteria, pH <6.0,>
Proteins	Alkaline or concentrated urine, phenazopyridine, ranitidine (Zantac)	Acidic or dilute urine
Glucose	Ketones, levodopa, exposure of dipstick to air	Elevated USG, uric acid, vitamin C
Ketones	Acidic urine, elevated USG, mesna, phenolphthalein, some drug metabolites (e.g., levodopa)	Delay in examination of urine
Blood	Dehydration, exercise, menstrual blood	Captopril, elevated USG, pH <5.1,>
Bilirubin	Phenazopyridine	Chlorpromazine, selenium
Urobilinogen	Elevated nitrate levels, phenazopyridine	NA
NA: not applicable; USG: urine specific gravity. Source: References 9-11.

Uses of Dip-and-Read Testing

Urinary Tract Infections: UTIs are characterized by an increase in the enzyme LE, nitrite, and protein levels. LE is a component of white blood cells that is normally found with bacteria, and nitrite levels rise in urinary infections since the pathogens reduce urine nitrate to nitrite.¹²Most dipsticks test for at least two of these chemicals depending on the brand used.

Numerous studies, meta-analyses, and reviews have been conducted to determine the accuracy of dip-stick testing for UTIs and compare the reliability of reagent strips to culture assays, but there remains a discrepancy over the results. Yuen et al reviewed the use of leukocyte esterase dipstick testing in children and concluded that it should not be used as a replacement for microscopic examination.¹³Conversely, a recent meta-analysis showed that a true negative can be concluded if both nitrites and leukocyte esterase test negative with a dipstick test.¹⁴Moreover, Gorelick and Shaw demonstrated that the results of a dipstick analysis for both nitrite and leukocyte esterase are comparable to those of a Gram stain test and “superior to a microscopic analysis for pyuria.”¹⁵

However, in patients with a high risk of contracting a UTI, it has been shown that a negative urine dip-stick test does not rule out the possibility of an infection.¹⁶More specifically in the long-term care setting, high rates of false-negative results for LE and nitrite with dipstick tests have been demonstrated.¹²With an aim to overcoming this discrepancy, Mariani et al have proposed a protocol to determine which results of screening urine specimens that are positive on a dip-stick culture would be confirmed by a properly performed microscopic urinalysis.¹⁷

In an attempt to contain costs and save time by eliminating the urine culture step, the use of immunochromatography strips using antibodies to detect infectious agents has been examined.¹⁸Even though immunochromatography has been found to be useful in urinalysis, this form of testing is yet to be fully developed. The newer dipslides offer a convenient way to perform a culture assay. They consist of a sterile paddle that is coated with agar on both sides, ready to use in a clear plastic tube.

Urinary pH: Health care professionals may use the urinary pH to select drug therapy for UTIs. The effectiveness of some antibiotics used to treat UTIs is affected by the urinary pH. Methenamine, for example, works only in an acidic environment, whereas streptomycin and neomycin work better in an alkaline environment.⁷Urinary pH may also be used to reduce the risk of kidney stones. Uric acid and calcium oxalate stones form well in acidic urine, whereas alkaline urine is optimal for the formation of calcium carbonate and calcium phosphate stones.

Desai and Assimos indicated that determining uri-nary pH is an important part of the initial evaluation of certain patients with nephrolithiasis.¹⁹Urinary pH manipulation therapy may be used to treat patients with cystine and uric acid stones, which results in the dissolution of uric acid stones. Monitoring the pH of patients receiving therapy for hypocitraturia is necessary to ensure that the pH does not go above 7.0, since overalkalinization can cause the formation of calcium phosphate stones.

Urinary pH is normally acidic, ranging from 4.5 to 8.0, but it is not as well regulated as blood pH due the absence of buffers in the urine. An elevated (alkaline) pH may be the result of:

Aged urine specimen; the loss of CO₂causes increased alkalinity.
Systemic alkalosis; this can be further confirmed by testing serum pH, which is a better indicator.
Urine left at room temperature; Cook et al demonstrated that urine stored at room temperature has a pH of >9.0 and that the pH of samples stored below -20°C was relatively stable.²⁰
Infection; bacteria break down urea to ammonia that combines with hydrogen ions and raises pH.
Certain medications (e.g., antiepileptics that have been shown to cause an increased tendency to form alkaline urine as the number of coadministered antiepileptics increases).²¹
Diet high in citrate.
Magnesium-ammonium phosphate crystals.

Acidic urine may be the result of ingestion of proteins or acidic foods. Urinary pH can also be used to detect renal tubular acidosis. In this condition, the patient is unable to acidify urine to a pH of less than 5.5 following the administration of an acid load and an overnight fast.

Therefore, it is important for pharmacists to emphasize that urine that is not tested immediately should be stored in a refrigerator and to encourage patients to take the sample to the clinic as soon as possible for testing. Home urinary pH is increasingly being recommended by urologists for patients with uric acid and calcium phosphate stones, as well as for patients on medication therapy for hypocitraturia. The study conducted by Desai and Assimos found that Chemstrip and litmus paper are more accurate than Multistix in determining urinary pH.¹⁹When recommending a suitable dipstick for a patient, pharmacists need to keep in mind that the litmus paper is significantly cheaper than the Chemstrip and is an adequate test for patients who are attempting to maintain therapeutic urinary pH levels.

Handheld urinary pH monitors are becoming available on the market, but their accuracy and cost-effectiveness have yet to be tested. These monitors will probably prove useful in busy clinical settings or for patients who need to monitor urinary pH for the long-term.

Hematuria: Hematuria is generally defined as the presence of three or more red blood cells per high-power field (HPF).⁶Hematuria causes pink or red urine and can be due to a number of factors ranging from strenuous exercise and UTIs to more severe conditions such as kidney or bladder cancers. Rarely, it is due to an inherited disorder known as porphyria, in which heme precursors are excreted in the urine. Exposure of the urine to sunlight in patients with porphyria will result in dark reddish urine that may slowly change to a brown color.

Hematuria is detected by the peroxidase activity of erythrocytes; however, hemoglobin and myoglobin can also catalyze this reaction, giving false-positive results.⁶Additionally, dipstick testing is highly sensitive and may pick up levels as low as one to two red blood cells per HPF.²²Further microscopic evaluation is recommended to confirm the findings of a dipstick test.

Urine Specific Gravity: USG is a measure of the amount of substances dissolved in the urine and is expressed in grams/mL. It indicates the kidneys’ ability to concentrate urine and the patient’s dehydration status, with normal values between 1.001 and 1.305. Decreased USG is observed in diabetes insipidus and overhydration. USG less than 1.02 for over 12 hours is indicative of generalized renal impairment, nephrogenic diabetes insipidus, and symptoms of inappropriate antidiuretic hormone. End-stage renal disease is characterized by specific gravity values between 1.007 and 1.010.

On the other hand, dehydration, contaminated urine, diarrhea, and heart failure will result in a higher reading for USG. Increased USG is also noted in patients who have been given low molecular weight dextrans or IV radiographic dyes for radiographic studies.

Protein: The glomerular capillary wall filters low molecular weight proteins that are then reabsorbed and metabolized by the proximal tubule cells. The normal value for protein levels in the urine varies from 0 to 30 mg/dL; the proteins consist of albumin, serum globulins, and proteins secreted by the nephron. Sustained protein-uria from 10 to 20 mg/dL may be a symptom of renal damage and requires further investigation. Most dip-stick tests detect protein by production if color with bromphenol blue is sensitive to albumin, but these tests may not detect low levels of gamma-globulin and Bence-Jones protein. If a positive result is obtained for proteins in the urine, further investigation should be performed to confirm the diagnosis.²³Other causes of proteinuria include excessive exercise, exposure to cold, postural changes, pregnancy, febrile illness, UTIs, and diabetes mellitus.

Options for a differential diagnosis include a 24-hour urinary protein excretion (TABLE 5), spot urinary protein-creatinine ratio, precipitation tests, and microscopy. It has been shown that ranitidine (Zantac) can cause a false-positive test for proteinuria with Multistix. The manufacturers of Zantac therefore recommend testing proteinuria with sulfosalicylic acid. This is a more sensitive precipitation test that can detect albumin, globulins, and Bence-Jones protein at low concentrations.

Table 5
Extent of Renal Damage as Indicated by Amount of Protein in Urine
Protein Reading	Extent of Renal Damage
<1.0 g/24 h 1.0-3.5 g/24 h >3.5 g/24 h	Mild Moderate Severe nephrosis

Glucose: Urine testing for glucose is useful for patients who find blood glucose monitoring difficult. Glucose levels should read below 130 mg/24 hours; higher values are often observed in diabetes mellitus, pregnancy, sepsis, tubular damage, Cushing’s syndrome, and liver and pancreatic disease. Most dipsticks employ the glucose oxidase reaction, are specific to glucose, and do not detect reducing sugars. To overcome this, patients may be tested further using the Clinitest that is based on Benedict’s copper reduction test.

Ketones: Ketone bodies are the breakdown product of fat, and their presence in urine (positive dipstick test) may be seen in patients with poorly managed diabetes mellitus, in anorexic patients, or in those who are dieting (e.g., with the Atkins diet). Dipstick tests or test tablets detect acetic acid through a reaction with sodium nitroprusside.

Urobilinogen and Bilirubin: Urobilinogen and bilirubin are only detected in the urine in liver dysfunction and indicate further evaluation. The Chemstrip-9 test uses diazonium dyes that turn red with urobilinogen and bilirubin. Kupka et al demonstrated that urine bilirubin and urobilinogen assays may offer a cost-effective way of predicting liver function abnormalities.²⁴

Pregnancy Testing: Initial pregnancy tests can be performed on urine samples and later confirmed with a blood test. The levels of human chorionic gonadotropin (hCG) hormone double almost every 2.2 days during the first trimester of pregnancy, and these levels can be detected in the patient’s urine. Detectable levels start at 5 mIU/mL during the first week of gestation and rise to 100,000 mIU/mL at 2 to 3 months.²

Pregnancy test kits use monoclonal and polyclonal anti-hCG antibodies placed sequentially to detect the presence of hCG via a color change. The test area of the test strip is held under a stream of urine and then allowed to sit for about 1 minute. The specimen migrates from the test area by capillary action to a pad containing monoclonal anti-hCG antibody. If hCG is present, it forms a complex with the antibody, which then moves further to the test line. The test line is spotted with polyclonal hCG antibody, which binds the complex and causes a color change if hCG is detected. Some kits come with a control test line that will change color whether or not hCG is detected; this helps the patients ensure that they have performed the test correctly.

Sometimes, the levels of hCG are too low to be detected and patients may get a false-negative result. It is therefore important to advise the patient that she may need to perform a second test if she is testing very early on in the pregnancy. Some manufacturers provide two kits in the package so that patients may repeat the test a couple of weeks later if needed. Additionally, patients should test the first-morning midstream urine, when the levels of hCG are the highest. Patients taking diuretics and promethazine may also obtain a false-negative, whereas patients on anticonvulsants, anti-Parkinson drugs, hypnotics, and tranquilizers may get a false-positive result as well. Other causes of false-positive results are very rare but may indicate trophoblastic disease.

MICROSCOPIC ANALYSIS

Microscopic analysis reveals cells, pathogens, and contaminants visible under a HPF, and casts that can be viewed under a low-power field (LPF). The reference range for leukocytes, erythrocytes, and epithelial cells is 0 to 4/HPF. Normally urine does not contain any erythrocytes, as they are too large to pass through the renal tubules. Any red blood cells in the urine indicate hematuria and are a sign of a potential abnormality. White blood cells and transitional epithelial cells are visible in normal urine and only signal a problem if their concentrations increase. On the other hand, renal tubular cells are present in very low amounts and have normally disintegrated by the time the urine is voided. Intact renal tubular cells are an indication of renal tubular disease.

The presence of bacteria and yeasts in normal urine should be further analyzed using a culture. They may be a normal part of the microbial flora (e.g., bacteria), contaminants (e.g., yeast), or a sign of an infection.

Hyaline casts are formed from mucoprotein in the distal convoluted tubule and the collecting duct in the absence of cells. High numbers (>1/LPF) may suggest proteinuria, but such casts are normally present in lower numbers in the urine of most patients. Cellular casts contain leukocytes, erythrocytes or renal tubular cells, and sticky protein, and their presence is a symptom of renal inflammation, hematuria, or severe renal disease, respectively. When renal tubular cellular casts remain in the nephron for some time before being flushed out, they become granular casts, and then finally waxy casts. The granular and waxy casts are an indication of increasing renal damage.

The urine of healthy patients will commonly contain crystals of calcium oxalate and triple phosphate; their concentration is dependent on the urinary pH. However, the presence of cystine, tyrosine, and leucine crystals is abnormal and needs to be investigated.

In many cases, analyzing a urine sample microscopically is fairly challenging, and it may be difficult to identify and count the components even with a trained eye. This said, microscopic analysis is an indispensable part of urinalysis that can confirm a number of diagnoses made with dipstick testing.

CONCLUSION

Pharmacists play a vital role in guiding patients through the vast amount of information available today. Since urinalysis is an essential tool in clinical testing, it is important for modern pharmacists to have a working knowledge of these analytical procedures. Opportunities for counseling exist during the recommendation for OTC tests, interpretation of test results, referral of patients for further investigation, and adjustment of patients’ drug therapy.

pressure ulcer

2009-04-24T23:12:00.000-07:00

Goldina Ikezuagu Erowele, PharmD
Clinical Pharmacy Specialist
Formulary Management & Pharmacoeconomics Services
Harris County Hospital District
Houston, Texas

Ruth Ebiasah, PharmD, MS
Clinical Pharmacy Specialist,
Palliative Care & Oncology
Holy Cross Hospital
Silver Spring, Maryland

In 2007, the National Pressure Ulcer Advisory Panel (NPUAP) redefined pressure ulcer as a localized injury to the skin and/or underlying tissue, usually over a bony prominence, as a result of pressure alone or in combination with shear or friction.¹The earliest documentation of pressure ulcers was made by Hippocrates in 400 BC. Paget, in his clinical lectures on bedsores in 1873, said that pressure ulcers sometimes erupt from beneath intact skin. Pressure ulcers are a significant clinical, quality-of-life, economic, regulatory, and legal problem for providers and patients alike.²Pressure sores are a serious and common occurrence in older people, and they will continue to be a major health care concern as the population ages.

PREVALENCE

The prevalence of pressure ulcers has been described extensively in various health care settings, including long-term care facilities, acute- and critical-care settings, and general surgical settings. In the United States, prevalence is estimated to be 1.3 million to 3 million.³Ranges in prevalence rates vary widely depending on the health care setting. According to the NPUAP, rates range from 10% to 18% in general acute care, 2.3% to 28% in long-term care, and 0% to 29% in home care.⁴Other reported data have indicated rates of 3% to 14% in hospital settings.⁵

Pressure ulcers are a major cause of morbidity and mortality in older people and are the most common care problem among nursing home residents, with prevalence estimated at 2.6% to 24%.^1,6In one longitudinal study, 17% of patients admitted to nursing homes had pressure sores at the time of admission.⁷Among patients who did not have a pressure ulcer at admission, the risk of developing one after admission was 13% in the first year postadmission and 21% by the second year.^2,5Additionally, it has been reported that the risk of developing a pressure ulcer following surgery is five times greater in patients older than 70 years of age than in those younger than 60 years.⁸

RISK FACTORS

The development of pressure ulcers is directly associated with the tissue's tolerance to pressure, as well as the intensity and duration of this pressure.⁹Risk factors for the development of pressure ulcers are classified as intrinsic or extrinsic (TABLE 1).^8-10

Intrinsic Factors

Intrinsic factors are those that internally influence the integrity of the skin. These factors include, but are not limited to, the following:

Immobility: All bed-bound patients are at risk for developing pressure ulcers. Limited activity, an immobilized body part, or total inability to move or ambulate is a central, underlying risk factor for the development of pressure ulcers.

Advanced Age: Patients older than 75 years appear to be at greatest risk, possibly due to age-related changes in the skin.¹¹Skin undergoes physical, structural, physiologic, and immunologic changes with increasing age. These changes may cause decreased barrier function, increased susceptibility to shearing forces, and decreased vascularity.

Impaired Sensory Perception: Conditions resulting in loss of sensation, pain perception, or level of consciousness (e.g., Parkinson's disease, Alzheimer's disease, diabetes mellitus, stroke, spinal-cord injury) may reduce mobility and cause loss of motor control, resulting in abnormal shear forces and friction on skin.⁹Additionally, medications that impair sensory perception or level of consciousness (e.g., sedative-hypnotics, narcotic analgesics) can contribute to the development of pressure ulcers.

Poor Nutritional Status: Poor dietary intake and dehydration may contribute to the development of hypoalbuminemia, anemia, or vitamin or mineral deficiency (e.g., vitamin C, zinc), leading to impaired wound healing.⁹

Comorbidities: Any disease that results in diminished or altered tissue perfusion (e.g., ischemic heart disease, peripheral vascular disease, renal insufficiency, or hypotension) can contribute to the development of pressure ulcers.

Incontinence: Fecal or urinary incontinence can result in prolonged moisture and bacterial contamination. This promotes the breakdown of skin and facilitates the development of pressure sores. Moisture from incontinence may increase the risk of pressure ulcer fivefold.⁸

Extrinsic Factors

Extrinsic factors are related to the degree of external forces that are applied to the skin surrounding the potential wound site.⁹These include pressure, frictional force, and shearing force.

Pressure: Pressure, the most important extrinsic factor, is created when the external surface against the skin and a person's skeleton compress soft tissue sufficiently to halt circulation.^8,9,12The normal capillary filling pressure is 20 mmHg to 30 mmHg; the pressure required to compress capillaries and interrupt circulation is generally considered to be 32 mmHg.¹⁰A patient lying on a hospital mattress can generate a pressure of 45 mmHg to 75 mmHg over such bony prominences as the sacrum, greater trochanters, and heels, where pressure ulcers commonly form.⁸If this pressure is sustained for more than 2 hours and exceeds capillary filling pressure within the deep tissue, a pressure sore may result.⁸

Frictional Force: Frictional forces act to pull on the skin while the weight of the body moves in the opposite direction. This may occur when a patient is repositioned in bed or transferred from bed to a wheelchair.

Shearing Force: Shearing forces are exerted when gravity causes the body to slide while in a fixed position, as when a patient is positioned with the head of the bed in a raised position, generally at greater than a 30° angle.^8,9

SCREENING

Since numerous risk factors exist for pressure ulcer, prediction-assessment tools are widely used to stratify patients' risk. There is insufficient evidence for one scale being superior to others. Currently, the Braden and Norton scales are the most widely used prediction tools for pressure ulcer.^13,14The Braden Scale, developed to foster early identification, comprises six sub-scales that rate sensory perception, skin moisture, activity, mobility, friction and shear, and nutritional status. The Braden Scale is performed upon admission, at least quarterly in long-term care facilities, after a major change in clinical status, or after return from the hospital. When the Braden Scale score is 16 or less, prevention protocols should be implemented. The Norton Scale rates physical and mental activity, mobility, and incontinence on a scale of 1 to 4. A score of 14 or less means that the patient is at risk.

PATHOPHYSIOLOGY

The skin consists of three major layers: the epidermis (outermost layer), the dermis (connective tissue containing nerves, blood vessels, and lymphatics), and the subcutaneous layer (containing adipose tissue).⁹Skin repair and regeneration are a natural bodily process involving several complex steps. These steps, which may overlap, are categorized as the inflammatory phase, the proliferative phase, and the remodeling phase.

Following hemostasis at the site of injury, the beginning of the inflammatory phase is marked by initiation of an inflammatory response and attraction of neutrophils to the area by degranulating platelets. Transforming growth factor (TGF) beta, tumor necrosis factor (TNF) alpha, and fibroblast cells are released from the damaged blood vessels, and these attract inflammatory cells to the wound site.¹⁵Responding neutrophils and macrophages synthesize additional growth and inflammatory factors and continue the breakdown and cleansing process.

The proliferative phase is characterized by the creation of an extracellular matrix and basement membrane degradation, in addition to the formation of new vasculature. This phase may last for up to 4 weeks in a clean, uncontaminated wound.⁹

After the third week, the remodeling phase begins; this phase can last for years after the initial injury. The tissue undergoes extensive remodeling as collagen and elastin are added and degraded by fibroblasts. The wound tissue's maximal tensile strength (approximately 80% of the tensile strength of the original tissue) is achieved by the 12th week, and the process of healing is complete.⁹

The aggravating event in pressure sores is purported to be an unrelieved external force—such as a mattress, wheelchair pad, or bed rail—or traumatic forces that may be present, including frictional and shearing forces. These forces cause circulatory interruption, resulting in ischemia and subsequent inflammation and tissue anoxia. Tissue anoxia leads to cell death, necrosis, and ulceration.

STAGES OF PRESSURE ULCER

Clinical assessment of pressure ulcer should be initiated by determining whether a patient is at risk and performing an examination for early signs of pressure-sore formation at the anatomical sites where such sores are most commonly encountered.⁸Pressure ulcers usually occur on the lower part of the body, predominantly the sacral region and heels. Other sites include the elbows, ankles, trochanters, ischia, knees, scapulas, shoulders, and occiput.⁹

Pressure ulcers are staged according to one of four categories. In February 2007, the NPUAP redefined these categories and added stages for deep-tissue injury and unstageable pressure ulcers.¹

Suspected Deep-Tissue Injury: This is a maroon or purplish localized area of discolored, intact skin or a blood-filled blister that is caused by damage of the underlying soft tissue by pressure or shear. The affected region may be preceded by tissue that is painful, firm, mushy, boggy, warm, or cool compared with the adjacent tissue. It may be hard to detect deep-tissue injury in patients with dark skin. Evolution may involve a thin blister over a dark wound bed. The wound may evolve further and become covered in thin eschar. Even with optimal treatment, evolution may be rapid and expose additional layers of tissue.

Stage I: This stage consists of intact skin with nonblanchable redness of a localized region, usually over a bony prominence. Dark skin may not have visible blanching, but its color may differ from the surrounding area. The area may be painful, firm, soft, warm, or cool compared with the adjacent tissue. It may be difficult to detect this stage in patients with darkly pigmented skin. This stage may be a heralding sign of risk.

Stage II: This stage involves partial-thickness tissue loss and presents as a shallow, open ulcer with a reddish-pink wound bed without slough. This stage of ulcer may also present as an intact or open/ruptured serum-filled blister. It may present as a shiny or dry shallow ulcer without slough or bruising (bruising signifies suspected deep-tissue injury). This stage should not be used to describe skin tears, tape burns, perineal dermatitis, excoriation, or maceration.

Stage III: This stage is characterized by full-thickness tissue loss. Subcutaneous fat may be visible, but bone, muscle, and tendon are not exposed. Slough may be present, but the depth of tissue loss is not obscured. Undermining and tunneling may be involved. The depth of an ulcer of this stage varies by anatomical location: Since the ear, the bridge of the nose, the occiput, and the malleolus do not have subcutaneous tissue, stage III ulcers in these locations can be shallow; areas of significant adiposity, in contrast, can develop ulcers of this stage that are quite deep. Bone and tendon are not visible or directly palpable.

Stage IV: Stage IV comprises full-thickness tissue loss with exposed bone, muscle, or tendon. Slough or eschar may be found on some areas of the wound bed. Undermining and tunneling often are involved. The depth of an ulcer of this stage varies by anatomical location, as described in stage III above. Stage IV ulcers can extend into the muscle or supporting structures (e.g., tendon, fascia, or joint capsule), rendering osteomyelitis a possibility. Exposed bone and tendon are visible or directly palpable.

Unstageable: Unstageable pressure sores involve full-thickness tissue loss, and the base of the ulcer is covered by slough (yellow, tan, brown, green, or gray), eschar (brown, tan, or black), or both, in the wound bed. Until enough of the slough or eschar is removed to expose the base of the wound, the true depth and stage of the ulcer cannot be determined. Stable (dry, intact, and adherent, with no erythema or fluctuance) eschar on the heels should not be removed.

THERAPEUTIC TREATMENT OPTIONS

Nonpharmacologic treatments include reduction of tissue pressure, frequent repositioning, and the use of surfaces that are protective and supportive.¹⁶Frequent repositioning (and selection of proper position) is extremely important. Bed-bound patients should be turned a minimum of every 2 hours, and they should be elevated as minimally as possible to avoid the shear forces on tissues that result from sliding down the bed. Lifting devices or bed linen should be used to reposition patients, rather than pulling or pushing the patient (which causes friction and shear forces). Patients placed in chairs should be repositioned every hour, and they should be encouraged to change position on their own every 30 minutes. Protective padding includes pillows or foam wedges that can placed between the knees, ankles, and heels when patients are lying on their sides; pillows, foam, and heel protectors can be used when patients are supine. Support surfaces under bed-bound patients can be changed to reduce pressure.

A change from standard mattresses is necessary when patients are unable to reposition themselves and periodic repositioning care is unavailable. Special mattresses are indicated for patients with stage I ulcers who develop hyperemia on static surfaces and for patients with stage III or IV ulcers. Air-fluidized or high-air-loss mattresses contain silicone-coated beads that liquefy when air is pumped through the bed. Advantages include cooling and reduction of moisture on surfaces. These mattresses are indicated for patients with nonhealing stage III and IV sores or numerous truncal ulcers.

PHARMACOLOGIC TREATMENT OPTIONS

The yearly cost of preventing and treating pressure ulcers is astronomically high, proving the dictum of preventive therapy being beneficial not only for the patient, but also for the economics of the health care system.¹⁷Conservative treatment of pressure sores includes appropriate wound care, debridement of necrotic tissue, optimization of nutrition, release of pressure, and minimization of muscle spasticity in order to provide the patient with the best opportunity to heal by secondary intention. Stage I and II pressure sores are treated conservatively. Some patients with stage III and IV pressure ulcers must be treated conservatively because of coexisting medical problems.¹⁸

Therapeutic measures for a pressure sore should be appropriate to its stage and should be consistent with the patient's therapeutic goals. Many therapeutic interventions follow the same principles as preventive interventions. In one study, independent predictors of healing included pressure ulcer size, older age, and receiving rehabilitation services.¹⁹Both immobility and incontinence were associated with poor healing of pressure ulcer.

Wound Care

Wound fluids may contain tissue growth factors that facilitate re-epithelialization. Thus, healing of pressure ulcers is promoted by dressings that maintain a moist wound environment while keeping the surrounding intact skin dry.²⁰The goal is to keep the ulcer bed moist to retain tissue growth factors while allowing some evaporation and inflow of oxygen to keep surrounding skin dry, facilitate autolytic debridement, and establish a barrier to infection.^9,12,18A moist wound environment is achieved by loosely packing the wound with saline-moistened gauze that is not allowed to dry (occlusive dressings are equally effective and reduce the nursing time required for wound care). Several types of dressings are available commercially; there are no clear recommendations for use of one type of dressing versus another, but individual circumstances may favor one form of dressing over another.²¹

Transparent films provide an effective barrier for retaining moisture; they are good secondary dressings when combined with another product for full-thickness wounds, and they may be used alone for partial-thickness wounds. Hydrocolloids generally are effective for retaining moisture and are useful for promoting autolytic debridement; they come in a variety of sizes and shapes for use on different parts of the body. A comparison study of transparent absorbent acrylic dressings and hydrocolloid dressings in the management of stage II and shallow stage III pressure sores demonstrated that the transparent film dressing improved the ability to assess the ulcer as well as patient comfort, although time to wound closure was nearly identical between the two groups.²²

Hydrogels, which are designed to maintain a moist wound bed, and can be used for deep wounds with little exudate. Both alginates and foams are highly absorptive and are useful for wounds with significant exudate.^9,23 A study of 110 elderly (mean age 83.5 years) patients in a geriatric hospital ward with stage III or IV pressure ulcers found that sequential use of a calcium alginate dressing for 4 weeks followed by a hydrocolloid dressing for 4 weeks was preferable to a hydrocolloid dressing alone for 8 weeks (control condition). In this study, the mean absolute surface area reduction (SAR) was significantly larger in the sequential-treatment group than in the group that had just the hydrocolloid dressing (7.6 cm²vs. 3.1 cm²at week 8). Similarly, at week 8, significantly more patients in the sequential-therapy group had a 40% SAR (75% vs. 59% for controls).²⁴ Iodine-solution wet gauze comes in a variety of forms and provides broad-spectrum antimicrobial coverage in the setting of a moist wound environment.¹⁸Further information about the various dressings used to treat pressure ulcers is given in TABLE 2.^9,10,15-17

Nutrition

Poor nutritional status or dehydration can weaken the skin and make a person more vulnerable to developing pressure ulcers. Nutritional screening must be a part of the evaluation of any patient with pressure sores. Dietary consultation is recommended for patients who are malnourished, and an evaluation of swallowing ability should be considered.

Nutritional interventions to prevent or treat pressure ulcers include providing additional nutrition and dietary supplements and encouraging adequate dietary intake by the patient. High-calorie foods and supplements should be used to prevent malnutrition.^12,18If oral dietary intake is impractical, enteral or parenteral feeding—if compatible with the patient's wishes—should be considered to achieve a positive nitrogen balance (≈30-35 calories/kg/day and 1.25 g-1.5 g protein/kg/day). Zinc supplementation supports wound healing, and replacement at a dose of 50 mg tid may be useful. Supplemental vitamin C (1 g/day) may be administered if intake is insufficient and deficiency is present, although data supporting its effectiveness in accelerating healing have been inconsistent.²⁵A 2003 Cochrane review of four trials found that although there is some evidence that nutritional interventions may be able to reduce the occurrence of pressure ulcers, more evidence is needed to identify effective dietary interventions.²⁶

Topical Growth Factors

Growth factors have been found in vivo and in vitro to show promise for tissue repair.²⁷Several growth factors, including TGF, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor, interleukin-1 and interleukin-2, and TNF, have been shown to mediate the healing process in acute wounds.²⁸

To date, no growth factor has received FDA-approved labeling for such use. Topical recombinant human BB platelet-derived growth factor (rPDGF-BB) has been found to stimulate the migration of neutrophils, macrophages, and fibroblasts into wounds; hasten the accumulation of glycosaminoglycans and fibronectin; and enhance collagen production.²⁹The commercially available rPDGFBB becaplermin has been the most extensively studied for wound healing in humans.

One trial enrolled 124 patients with stage III or IV pressure ulcers who were randomized to receive 100 mcg/g becaplermin gel once daily alternating with placebo gel every 12 hours (n = 31); 300 mcg/g becaplermin gel once daily alternating with placebo gel every 12 hours (n = 32); 100 mcg/g becaplermin gel twice daily (n = 30); or placebo (n = 31).³⁰Complete healing was significantly more frequent with 100 mcg/g or 300 mcg/g becaplermin once daily than with placebo (P = .005 and P = .008, respectively). A difference was not observed between the becaplermin 100 mcg/g twice-daily group and the placebo group. No sores in placebo recipients healed completely, compared with 3% in patients given becaplermin 100 mcg/g twice daily, 19% in the 300-mcg/g once-daily group, and 23% in the 100 mcg/g once-daily group. Interpretation of the results, however, may be confounded by the negative dose-response effect, a substantially lower rate of healing than observed for other standard treatments, and failure of any ulcers to heal in placebo recipients. Adverse effects were similar in all treatment groups and included skin ulceration, urinary-tract infection, rash, erythema, and fever.

In June 2008, the FDA issued a follow-up "Dear Healthcare Professional" letter regarding an earlier safety review of becaplermin. In March 2008, the FDA had announced that it had received information from a retrospective study and was investigating the possibility of an increased risk of cancer or mortality from cancer in patients with diabetes who used becaplermin, compared to patients who did not use becaplermin. The FDA completed its review of this study and noted an increased risk of mortality from cancer in patients who used three or more tubes of becaplermin gel. As a result, the becaplermin prescribing information was updated to include a new black box warning regarding this finding. It is important to note that while the study showed an increase in mortality from cancer, the number of mortalities was small, there was no overall increase in the incidence of cancer, and the observed malignancies were remote from the ulcer treatment site. The FDA recommends the use of becaplermin only when the potential benefits outweigh the risks.³¹

Pain Control

Primary treatment of pain is treatment of the pressure sore itself. Options for treatment should include nonsteroidal anti-inflammatories (such as naproxen or ibuprofen) or acetaminophen, which are used for mild-to-moderate pain. Opioids may be necessary during dressing changes and debridement. In cognitively impaired patients, changes in vital signs can be used as an indication of pain. Opioids should be avoided when possible because sedation promotes immobility.

THE PHARMACIST'S ROLE

The cornerstones of therapy for pressure ulcers remain elimination of the source of the pressure or friction and appropriate wound care. Prevention is imperative, because once a pressure ulcer forms, prolonged hospitalization and expensive therapy are distinct possibilities. The pharmacist's role in the prevention of pressure ulcers includes educating patients about the contributing factors and monitoring patient progress to ensure successful healing of the sore when therapies are initiated. Patient education about the proper use of prescribed discharge medications and preventive steps necessary to ensure that the ulcer will not occur again is quite important for reducing the health care burden of pressure ulcers on society.

Contemporary Options for the Management of Scars

2009-04-14T19:57:00.000-07:00

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.^2,5Factors that need to be considered prior to electing to treat a scar include²:

Is the scar getting worse or showing signs of improvement?
The anatomical location of the scar.
Symptoms that the patient presents.
Presence and/or severity of functional impairment. (Does the scar affect mobility of joints?)
Stigma of the scar. (Evaluate the impact of the scar on the patient's quality of life.)
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.¹⁰The 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

treating peanut allergy

2009-04-14T19:54:00.000-07:00

How to Determine If You Have an Allergy

It is important to see a doctor who specializes in food allergies to determine your individual risks. To make sure you are diagnosed properly, you may have to undergo a series of questions, blood tests, and a skin-prick test.

Exposure to even small amounts of peanuts may cause anaphylaxis (an-uh-fuh-lak-sis), or a severe allergic reaction. Symptoms such as itching, redness, swelling, shortness of breath, wheezing, nausea, abdominal pain, lightheadedness, or loss of consciousness may occur and usually begins within minutes after exposure to a peanut or peanut-containing product.

It is possible, however, to experience a delayed reaction, if symptoms do not appear immediately. Touching peanuts may result in hives, or areas of itchy and red skin, which may spread across your body. An allergic reaction also can occur if you inhale dust from peanut flour or mist from peanut oil cooking spray. Examples of peanut-containing products are listed in the Table.

Avoiding an Allergic Reaction

Avoidance is the best way to reduce your chances of experiencing a severe allergic reaction. It is important to read all food labels to look for peanut-containing products. Also, when dining out, ask the server about the types of oils in which the entrees are cooked. If your child has a peanut allergy, you should inform and educate school personnel, parents of your child’s friends, and other caregivers about foods the child needs to avoid.

Both children and adults are advised to wear a medical alert bracelet or necklace. This alert should list the specific allergy and possible reaction symptoms, and provide first aid instructions for others during an emergency.

Treating a Serious Allergic Reaction

Table

Peanut-containing Food Products

Peanut butter
Peanut flour
Ground or mixed nuts
Baked goods, such as cookies and pastries
Ice cream and frozen desserts
Energy bars
Salad dressing
Cereals and granola
Grain breads
Peanut oil
Marzipan

The emergency treatment during a severe allergic reaction involves several steps. First, an injection of epinephrine (EpiPen or EpiPen Jr) should be given to reduce the severity of the reaction. Second, taking liquid diphenhydramine (Benadryl) at a dose of 5 mg for every 10 lb of body weight, up to a maximum dose of 75 mg, also is recommended. Third, if not already done, emergency services should be contacted.

A visit to the emergency room is necessary because additional treatment may be needed. While at the hospital, the patient may be given medication such as albuterol in the form of a nebulizer, or special breathing machine, to open up your airways, as well as additional epinephrine injections and intravenous fluids.

After a severe reaction, you should be observed by medical personnel for at least 4 hours, as some patients may have another reaction that can be delayed for several hours. These secondary reactions are very dangerous and require immediate treatment. Upon leaving the emergency room, you may be given prescriptions for antihistamines (eg, diphenhydramine) and corticosteroids (eg, prednisone), which should be taken as the doctor prescribes. It is important to follow up with your primary care physician within 3 days.

EpiPen and EpiPen Jr

These injections, also known as auto-injectors, are designed to provide a quick dose of epinephrine for patients during severe allergic reactions. The EpiPen 0.3 mg is for patients weighing 66 lb or more. The EpiPen Jr 0.15 mg is for patients between 33 and 66 lb. The injection should begin to work quickly after it has been given. Some patients may feel a rapid heartbeat, slight nervousness, sweating, dizziness, and headache from the injection.

The EpiPen or EpiPen Jr should be kept nearby and ready for use at all times. The manufacturer recommends that you store these injections at room temperature, and they should never be exposed to extreme temperatures, such as in your vehicle’s glove compartment. The injection should be stored in the container provided to protect the medication from light. An expiration date will be printed on each product (eg, “DEC 08” = December 31, 2008). The EpiPen should be replaced before the expiration date, even if you did not use it. A window on the outside of the pen allows you to see the solution on the inside. If the solution is discolored or contains solid particles, you should replace the injection.

Make an Action Plan

Make sure your child knows what symptoms to look for and how to ask for help if he or she has an allergic reaction. All individuals with peanut allergies should develop an action plan with their medical provider detailing what should occur once they have been exposed to any peanut-containing product. Once the action plan is complete, copies should be made available for easy access.

How to Use the EpiPen

A short film on how to use the EpiPen is available at www.epipen.com/howtouse.aspx.

Unscrew the yellow or green cap from the carrying case, and remove the auto-injector from its storage tube.
Grasp the unit with the black tip pointing downward.
Form a fist around the unit with the black tip pointing downward.
With your other hand, pull off the gray safety release.
Hold the black tip near the outer thigh.
Swing and jab firmly into the outer thigh until it clicks so that the unit is making a 90° angle to the thigh. (The auto-injector is designed to work through clothing.)
Hold firmly against the thigh for approximately 10 seconds. (The injection is now complete, and the window on the auto-injector will show red.)
Remove the unit from the thigh, and massage the injection area for 10 seconds.
If you have not already done so, call 911, and seek immediate medical attention.
Place the used injector, needle-end first, into the storage tube, and screw the cap of the storage tube back on completely, and take it with you to the hospital emergency room.

How to Treat Common Skin Infections

2009-04-14T12:27:00.000-07:00

Elaine Wong, PharmD, and Lana Borno, PharmD

Helpful advice for your patients on treating bacterial skin infections.

Drs. Wong and Borno are assistant professors of pharmacy practice at Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York.

Bacteria can cause different types of skin infections. Three common skin infections that you and your doctor may encounter are: (1) cellulitis, (2) folliculitis, and (3) impetigo. Keep in mind that skin infections vary in presentation and treatment. Therefore, it is important to talk to your doctor to obtain an appropriate diagnosis and treatment plan.

Cellulitis

Cellulitis is an infection that involves the outer layers of the skin. It is commonly caused by bacteria known as beta-hemolytic streptococcus or Staphylococcus aureus. You may experience pain, swelling, tenderness, warmth, and redness in the infected area. If you have a severe case of cellulitis, you may experience fever, tiredness, and a lowering of blood pressure. If left untreated, pus may form and cells may die in the infected skin area. Cellulitis can involve any part of the body but most often affects the leg. It typically results from an injury to the skin, such as scratches or animal bites—these allow bacteria to enter the body and cause an infection. An additional cause of cellulitis is skin breakdown around the anal area, typically seen in children. This can lead to redness, swelling, and painful bowel movements.

Oral antibiotics are used to treat mild cellulitis; more severe cases must be treated with intravenous antibiotics in a hospital. Antibiotics that may be used include cephalosporins, dicloxacillin, clindamycin, or vancomycin. Swelling can be lessened by elevating the affected area, such as the legs or arms. To stop cellulitis from occurring again, it is important to keep applying lotion to the skin and to maintain good skin cleanliness.

Folliculitis

Folliculitis is a general term used to describe an infection of the hair follicles commonly caused by Staphylococcus aureus, resulting in red pimples. You may experience redness, tenderness, or swelling of the affected area. It also can spread to the deeper parts of the hair follicles and pus can form, also known as furuncles or boils. Carbuncles is a term used to describe a group of infected hair follicles. Folliculitis, furuncles, and carbuncles can be seen on any part of the body with hair, such as the face, scalp, thighs, underarms, and groin area. This includes areas that are bearded or shaved.

Mild folliculitis can be treated with topical antibiotics, such as erythromycin, clindamycin, or mupirocin. More severe infections, such as carbuncles and larger furuncles, may require a surgical cut and drainage of the affected area. After drainage, it is important to clean the area with antibacterial soap; then you should apply the antibiotic ointment to the affected area of the skin. If needed, your doctor may prescribe oral antibiotics such as cephalosporins or dicloxacillin. Keep in mind that your doctor may recommend monthly treatments with mupirocin ointment if you have folliculitis that occurs repeatedly.

Impetigo

Impetigo is a contagious skin infection commonly caused by Staphylococcus aureus. Although this infection may occur in adults, it is most often seen in children aged 2 to 5 years and is usually spread through direct contact with another person who has the infection. You may experience tenderness, itching, sores, or blisters that can rupture and form honey-colored crusts. It can affect different parts of the body such as the face, arms, or legs. It also can affect moist parts of the body, such as the armpits, neck folds, and diaper areas.

Impetigo can be treated with a topical ointment or oral antibiotic. Mupirocin is a typical ointment that may be prescribed by your doctor. Oral antibiotics such as penicillins or cephalosporins are used for more severe infections. To prevent the spread of the infection to other parts of the body, avoid scratching the blisters or sores. Because impetigo is commonly seen in children, it may be helpful to cut the fingernails and cover the affected areas of the body with bandages or gauze. It also is important to prevent the spread of infection to other individuals in close contact by not sharing things such as blankets, linens, toys, or clothing.

What about MRSA Infections?

MRSA stands for methicillin-resistant Staphylococcus aureus. It is a form of Staphylococcus aureus or "staph" bacteria that is resistant to certain antibiotics. It is transmitted by directly contacting an infected person, touching contaminated surfaces, or sharing personal items that have been in contact with infected skin. MRSA is a large problem in hospitals or health care facilities (like dialysis centers and nursing homes). MRSA also can infect people in the community, however, such as children at day care centers and children who are involved in sports that involve close contact. This is known as community-associated MRSA or CA-MRSA.

MRSA infections can appear like a pimple or boil, with redness, swelling, pain, or pus. Serious infections may spread into the blood and cause blood infections. If you experience a MRSA infection, your doctor may drain the infected area and prescribe antibiotics such as linezolid, clindamycin, or doxycycline. Do not try to drain the wound yourself! This can worsen the infection or spread it to others.

To prevent the spread of MRSA, here are some helpful tips:

Cover your wound with clean, dry bandages until the affected area is completely healed.
Maintain good hand hygiene—you and those in close contact with you should wash hands frequently with soap and water.
Do not share personal items, such as linens and clothing, with others.

General Management of Skin Infections

With antibiotic treatment, signs and symptoms of skin infections begin to improve after approximately 2 to 3 days. If your skin infection does not improve or gets worse (especially if you develop a fever or the infection spreads), notify your doctor right away. If you are prescribed topical or oral antibiotics, be sure to finish the full course of antibiotics unless otherwise directed. Keep in mind that the length of treatment will differ depending on the type and severity of the infection. Lastly, as is true among all skin infections, you should keep the affected area or wound clean with good skin hygiene.

Depression

2009-04-14T12:21:00.000-07:00

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.

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

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.

Nonprescription Products for the Baby

2009-04-12T09:52:00.000-07:00

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

11/18/2008

US Pharm. 2008;33(11):12-15.

The pharmacist is on the front lines of pharmaceutical care when patients need assistance with minor health conditions. Quite often, parents and caregivers request assistance with infants. The pharmacist must have an acute understanding of which products are proven safe and effective for babies and which are not.

Age Limitations
When the FDA began its massive review of nonprescription products in 1972, one of the major tasks it had to accomplish was to determine the safe ages of use for each ingredient.¹ The agency sought data and eventually established the minimal safe ages for which specific ingredients could be given and the appropriate dosages for each age. When medications switched from prescription to nonprescription status, the sponsor and the FDA cooperated to establish the minimum age that would be safe for self-use.

What Is Safe for Babies?
The end result of the FDA's deliberations is that many nonprescription products are prohibited in children under the age of 2 years, while others are labeled against use in patients under the ages of 3, 4, 5, 6, 12, 17, or 18 years.¹ For example, the FDA recommends that OTC cough and cold medications not be used to treat infants and children under 2 years of age, and manufacturers have recently announced voluntary labeling changes for those under age 4.² Products safe for use in babies include the following: teething products, colic products, ibuprofen concentrated infants' drops (except when used for sore throat), ipecac syrup, sunscreens (with age restrictions), and some nonmedicated topical products, such as those used for diaper rash. It must be noted that many nonprescription products have never undergone scientific scrutiny to prove their safety and efficacy, regardless of age-group.¹ This includes most herbals, homeopathics, and dietary supplements. Because of lack of knowledge regarding safety and/or efficacy in babies, these products should be avoided.

Teething Products
The pharmacist can recommend topical products for teething if the child is 4 months or older.¹ As the central incisors usually do not begin to erupt until 6 to 10 months of age, this is an appropriate age limitation. Ingredients proven safe and effective for teething include benzocaine and phenol. Of the two, benzocaine 5% to 20% is more readily available and may be a better choice. It is found in Baby Anbesol (7.5% benzocaine), Baby Orajel (7.5%), and Zilactin Baby Teething Swabs (10%). Parents or caregivers should be cautioned against use of unproven and potentially dangerous teething remedies such as homeopathic teething tablets containing belladonna, coffee, magnets, tea tree oil, anise seed, clove oil, and cantharides.

Some parents may ask for assistance when the baby is experiencing fever, nasal congestion, or diarrhea.^3-5 When the pharmacist recommends a physician visit, the parent may assert that the potentially dangerous symptom is only due to teething. The pharmacist should stress that none of those symptoms are manifestations of teething, and the child's physician should be consulted for proper treatment.

Colic Products
Parents may ask for help with a baby whose violent and prolonged crying is assumed to be due to colic. The etiology of colic is not always clear, but some believe the underlying cause is trapped intestinal gas.^1,6 This has led to widespread acceptance of such simethicone-containing products as Infants' Mylicon Drops and Little Tummys Gas Relief Drops. Simethicone is nontoxic and can be given to infants according to the doses on the label. Pharmacists should be cautious about stocking or recommending various "gripe water" products, such as Little Tummys Gripe Water, Baby's Bliss Gripe Water, Wellements Gripe Water, and Gentle Care Gripe Water.⁷ These unproven products contain sodium bicarbonate, ginger, fennel, and/or chamomile, none of which is known to be safe in babies or effective for colic. Pharmacists should neither stock nor recommend these products.

Ibuprofen Infants' Drops
Ibuprofen concentrated infants' drops (e.g., Motrin) are approved for babies down to 6 months of age who experience minor aches and pains due to the common cold, influenza, headaches, toothaches, teething, and immunizations.¹ (The product is also indicated for sore throat but should not be used if the patient is under the age of 3 years.) Parents should ask a physician before using it if the child has not been drinking fluids, has lost a substantial amount of fluid due to continued vomiting or diarrhea, has stomach pain, or has experienced problems in the past when administered pain relievers or fever reducers. Parents should cease using the product and immediately consult the child's pediatrician or general practitioner if an allergic reaction occurs, as manifested by hives, facial swelling, asthma (wheezing), or shock. They should also seek medical help if pain or fever gets worse or lasts more than three days, if the child does not appear to obtain any relief within the first day (24 hours) of treatment, if stomach pain or upset worsens or persists, if redness or swelling is present in the painful area, or if any new symptoms appear. Before using the drops, the parent should check with the child's physician if the child is under a physician's care for any serious condition or is taking any other medications, including those containing ibuprofen, other pain relievers, or fever reducers.

Ipecac Syrup
For many years, ipecac syrup was considered to be a vital part of the medicine chest for every home with an infant. Given as quickly as possible after ingestion of a potentially toxic substance, it was allegedly useful in forcing the child to vomit. In recent years, however, its use has become the subject of substantial controversy. In 2003, a leading pediatric journal published research demonstrating that use of ipecac did not affect referral to emergency departments or the rate of adverse outcomes.^8-10 Furthermore, ipecac does not completely remove toxins from the stomach, causes adverse effects, is mistakenly given when it should not have been, may cause persistent vomiting, and is subject to abuse by anorexics and bulimics. As a result of ipecac's many problems, the American Academy of Pediatrics Committee on Injury, Violence, and Poison Control recommended against keeping it in the home and also took the unusual step of recommending that any ipecac already present in a household be disposed of safely. An FDA panel voted six to four to make ipecac prescription only, but the FDA has not yet acted as of this writing, and the drug remains available. Stocking and recommending it in light of the current climate is not prudent. Rather, parents should be urged to call the National Poison Hotline (800-222-1222) immediately for proper advice when a poisoning incident occurs.

Sunscreens
It is now general knowledge that sunscreens are highly effective in preventing the consequences of sun exposure when used as directed. Many parents try to place sunscreen on infants when they are about to enter the sun. However, the FDA does not wish to allow labeling on any sunscreen product for babies younger than 6 months.^1,11 There are several reasons for this. The first is that the FDA advises parents to keep babies less than 6 months of age out of the sun entirely. Therefore, having a sunscreen labeled for use under that age would give parents a false sense of security, perhaps conferring the mistaken idea that babies will be protected if the sunscreen is used. Babies cannot voluntarily move to shade when they are uncomfortable. They have underdeveloped sweat glands, which increases the risk of heat prostration. In addition, their ability to metabolize, detoxify, and eliminate the ingredients found in sunscreens is not fully developed. However, for babies above the age of 6 months, parents should choose a sunscreen with the highest sun protection factor (SPF) available (i.e., SPF 50+) to minimize the dangers of sun exposure.

Diaper Rash Products
Diaper rash products are a necessity for parents whose children are not yet toilet trained.¹² If skin is allowed to remain in prolonged contact with urine and feces, the pH becomes favorable for reactivation of skin-destructive enzymes.¹ The obvious method to avoid diaper rash is to change diapers as soon as they are wet or soiled. However, for a variety of reasons, this is not always practical. Therefore, parents often ask for advice concerning an ongoing case of diaper rash. If the skin is already broken, the baby should be referred to the pediatrician to assess the skin for the presence of a bacterial or candidal infection. If the skin is merely inflamed, however, the pharmacist can recommend a variety of diaper rash products.

Some diaper rash products are potentially dangerous and should be avoided.^1,13 They include A+D Original Ointment (contains lanolin, a potential allergen), Balmex (inactive ingredients include aloe vera and balsam of Peru, not known to be safe when applied to babies), Boudreaux's Butt Paste (contains Peruvian balsam, potentially dangerous boric acid, and castor oil [unknown safety/efficacy]), and Hyland's Diaper Ointment (contains calendula [unknown safety/efficacy] and lanolin).

The list of products with which to exercise caution also includes Johnson's Baby Oil.^1,13 This product contains mineral oil, which the FDA discussed as a possible cause of chronic irritation and folliculitis. Johnson's Original Baby Powder and Medicated Baby Powder contain talc and cornstarch, respectively. Using powders around the baby is a practice that can cause inhalation pneumonia. Thus, powdered products should be used very cautiously, if at all. The parent or caregiver who insists on their use should be instructed to place a small amount into the hand while away from the baby's head, then pat it gently on the diaper area without raising a cloud of injurious dust. The safest and most effective diaper rash ingredient may well be simple petrolatum, typified by Vaseline Nursery Jelly. Using this product avoids the potential allergenicity of lanolin, the possible toxicity of boric acid/borates, and the dangers of inhalation posed by powders.

Pediatric Dosing Charts
A final issue is that of pediatric dosing charts. Pharmacists noticed the widespread voluntary recall of various cough and cold medications advertised and promoted for infants while lacking any proof of safety and efficacy in that group. The recall was issued just prior to an FDA meeting that confirmed the need to remove these products from the market. The manufacturers have also engaged in a practice that may cause pediatric dangers. Since the 1980s, many have published pediatric dosing charts purporting to provide pediatric doses of antidiarrheal medications, analgesics, and cough/cold products.¹ These doses were not known to be safe and effective through legitimate research submitted to the FDA. If these charts are still to be found in pharmacies, they should be discarded and never consulted.

Understanding and Managing Lactose Intolerance

2009-04-12T01:17:00.000-07:00

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

2009-04-11T20:26:00.000-07:00

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.

Automated External Defibrillators in the Community Setting

2009-04-11T20:07:00.000-07:00

Rahmat M. Talukder, RPh, PhD
Assistant Professor, Department of Pharmaceutical Sciences
College of Pharmacy, Southwestern Oklahoma State University
Weatherford, Oklahoma

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

2/20/2009
US Pharm. 2009;34(2):12-15.

Sudden cardiac arrest (SCA) is the abrupt loss of heart function leading to sudden cardiac death (SCD). Most cardiac arrests occur when the electrical impulses in the diseased heart become rapid (ventricular tachycardia) or chaotic (ventricular fibrillation [VF]), or both.¹ This irregular heart rhythm (arrhythmia) may cause the heart to suddenly stop beating. As a result, the arterial pressure suddenly drops to critically low levels. Death usually ensues within less than 10 minutes due to the lack of oxygen supply to vital organs. Application of a therapeutic dose of electrical shock to the affected heart with a defibrillator within a few minutes of onset of VF can depolarize the heart muscle, reestablishing normal electrical activity.

SCD is a major health problem worldwide and is the leading cause of death in many developed countries.^2-5 In North America, the annual incidence of out-of-hospital SCA is about 0.55 per 1,000.⁶ In Europe, about 275,000 individuals suffer from cardiac arrest annually, while the reported incidence of SCD in the United States varies from 180,000 to 250,000 annually.^7-9 Approximately 70% to 80% of all cardiac arrests occur at home, often while the victim is alone or asleep.¹⁰ The reported incidence of out-of-hospital pediatric cardiac arrest varies widely from 2.6 to 19.7 annual cases per 100,000.¹¹ The actual number of SCDs that occur in the general population is large, even though the incidence is lower compared to the number of SCDs in the high-risk population.¹² Thus, the cost of SCA and SCD to society is not easily calculable.

Chain of Survival

The 1960 recommendation of closed-chest cardiac massage by Kouwenhoven is generally considered to be the advent of the modern era of cardiopulmonary resuscitation (CPR).¹³ The concept of “chain of survival” was fully described in the 1992 guidelines for CPR and emergency cardiac care of the American Heart Association (AHA).¹⁴ Chain of survival refers to a series of critical interventions that reduce the mortality from SCA. If one of these actions is neglected, it is unlikely the victim will survive. The chain of survival has four interdependent links: 1) early access, 2) early basic CPR, 3) early defibrillation, and 4) early advanced cardiac life support (ACLS). The guidelines were revised in 2005 to create a single international version of evidence-based, scientific resuscitation guidelines. However, the most critical element is that the effectiveness of an emergency cardiac care system does not depend on an individual link; instead the whole system must be taken into consideration, and survival rates will drop when there is any inadequacy in the chain.¹⁵ Nevertheless, recognition of the emergency and initiation of the chain remains the most critical point—if no one recognizes the emergency and no action is taken, the possibility of survival plummets to zero.

Early Access: Early access refers to the actions taken from the time the victim collapses until emergency medical service (EMS) personnel arrive. When someone suffers from SCA, the most important actions a bystander can take are to recognize the critical nature of the situation and call an emergency service number. However, recognition of early warning signs, such as chest pain, shortness of breath, and patient activation of the emergency response system can significantly increase the rate of survival. This is the compelling reason that the AHA stresses education concerning the importance of recognizing the signs and symptoms of cardiac arrest, acute myocardial infarction, and stroke, and initiating the action plan for survival.

Early CPR: Research confirms that the survival rate is higher in victims who receive early CPR than in those who receive delayed CPR.^16-18 CPR helps preserve cerebral and myocardial viability. CPR alone cannot stand as the sole important link to increased survival, as a significant barrier to successful CPR is the complexity of the skills required. However, the primary reason for poor outcomes with CPR is most often due to delays in initiating defibrillation.¹⁹

Early Defibrillation: The survival rate from SCA is poor if the victim does not receive electrical therapy within a few minutes to restore normal electrical cardiac activity. Reports suggest that early defibrillation is critical in improving survival.²⁰ The most critical factor in survival from VF is the time difference between the onset of fibrillation and administration of defibrillation.² Studies find that the probability of survival is reduced by about 50% for each three-minute delay in administration of defibrillation.²¹ Further, survival rates for SCA can rise as high as 90% when immediate defibrillation is administered.¹⁹ Thus, the AHA and other health advocate groups recognize early defibrillation as a critical component in the chain of survival.²²

However, early defibrillation is not the only important aspect of treatment. Defibrillation works best when CPR is provided until the shock is applied, followed by advanced care. In line with this, the AHA stresses that early CPR coupled with rapid defibrillation is critical to survival of adult victims of SCA; delays in the initiation of CPR or defibrillation can reduce survival.²² Moreover, the AHA emphasizes that all personnel must be trained to operate a defibrillator if their job description includes responding to persons in cardiac arrest. Therefore, all ambulances and other emergency vehicles that respond to or transport cardiac patients should be equipped with a defibrillator.

Early ACLS: ACLS is an enhancement of basic life support (BLS). Professional EMS personnel provide this advanced life support, which includes airway and breathing management, medications, and, in some cases, inducing hypothermia, as well as arranging follow-up care when necessary. Establishing a meaningful ACLS program requires extensive medical knowledge and rigorous hands-on training and practice. Arguments have been advanced both for and against ACLS for treating out-of-hospital cardiac arrest in comparison to BLS with a defibrillator. For victims who do not respond to initial CPR or do not have a rapid response to early defibrillation, ACLS may be of limited or no benefit, as it does not improve survival.²³

Automated External Defibrillators

A defibrillator is a device that applies therapeutic electric shocks to the heart in order to restore normal heart rhythms before the malfunctioning heart suffers SCA followed by SCD. Defibrillators can be external, transvenous, or implanted. Some external devices, known as automated external defibrillators (AEDs), are capable of accurately analyzing cardiac rhythms and advising about and delivering therapeutic electric shocks when needed. Practical defibrillators were first developed in the early 1900s and the first AED was introduced in 1979.²⁴ AEDs use internal computer algorithms to analyze cardiac rhythms and detect VF. Unlike earlier devices, modern AEDs deliver biphasic, effective, low-energy waveform shocks of 120 to 200 joules.

The current generation of AEDs is safe, effective, lightweight, easy to use and maintain, and relatively inexpensive (~$1,500 each).²⁵ They require only four simple steps: 1) turning on the device, 2) attaching two electrodes, 3) pressing a button for rhythm analysis, and 4) pressing another button to administer the shocks. If further shocks are required, the device will instruct accordingly. However, the operator must carefully follow all instructions.

Studies report positive outcomes with early defibril lation in public places, as it saves precious minutes and improves survival rates for cardiac arrest victims.²⁶ It is critical to have trained lay rescuers equipped with AEDs in all public places where large numbers of people congregate, such as airports, airplanes, schools, sports arenas, golf courses, hotels, concert halls, high-rise buildings, manufacturing plants, and shopping malls. All can benefit from obtaining AEDs and training employees to use them as part of a public access defibrillation (PAD) program. President Bush signed Public Law 107-188 on June 12, 2002, which authorized $30 million in federal grants to be made available to states and localities for the purchase and placement of AEDs in public places where cardiac arrests are likely to occur.²⁷ Grant funds can be used to train first responders to administer immediate life-saving care, including AED use and CPR. As a result, more cities across the U.S. are becoming involved in PAD programs.

Properly designed AEDs can be used to deliver an effective defibrillation shock in a timely manner by bystanders with only basic knowledge and training. It is expected that a PAD program will target nonmedical or minimally trained personnel. Therefore, AEDs must be accurate in diagnosing arrhythmias, simple to operate, safe to the patient and rescuer, lightweight, portable, and cost-effective.

Program Goals

The primary goal of an AED or PAD program is to sustain the patient’s previous quality of life by preserving normal neurologic functioning. The program enables rescuers to deliver early defibrillation to victims within three to five minutes of collapse, the first critical moments after an SCA. However, the AED program should not replace the care provided by EMS personnel, but rather provide a lifesaving bridge during the first few critical minutes it takes for advanced life support providers to arrive. Care of the patient should be transferred to the EMS personnel upon their arrival. Furthermore, the program must comply with all applicable state regulations.

Role of the Pharmacist

Pharmacists asked to help convince public or private entities to institute a PAD program should press the following points. First, many people die from SCA every year. A well-established program in all public places will serve as a safety net to guard against death or disability. With public awareness and the availability of AEDs in community settings, the number of deaths from SCA is expected to undergo significant reductions by ensuring more timely access to defibrillation. Proven efficacy of AEDs in preventing death and disability from SCA in public places, coupled with the advent of user-friendly devices, has led to the development of the first nonprescription AED for home use (see sidebar).

Sudden cardiac arrest occurs when a person’s heart stops beating effectively for some reason. Unless swift action is taken, the patient may suffer lifelong disability or death. This is the reason that people are taught such lifesaving techniques as cardiopulmonary resuscitation, also known as CPR. Carrying out CPR can help the patient survive until emergency medical personnel arrive. However, CPR alone is not considered the best therapy in all cases.

New Devices Save Lives

Many people are familiar with the fact that patients whose hearts are not beating effectively are often administered electric shocks to correct and normalize the heart’s rhythms. Movies and television shows often illustrate this technique being carried out in the hospital setting. It is less well known that this procedure has become much more widespread and useful now that these devices, known as
automated external defibrillators (AEDs), have become portable and lightweight.

New Public Law

Most people who suffer cardiac arrest do so nowhere near a hospital or medical facility. They may be in a casino, at a sporting event, at a religious gathering, or in a university classroom. Perhaps a bystander tries to administer CPR until medical personnel arrive. Studies show that many patients would also benefit from the use of an AED if it were available. Modern AEDs are lightweight and portable and have an internal program that determines whether a shock is needed before it is administered. For these reasons, a public law was passed in 2002 with the goal of making AEDs widely available. The law authorized funds for states and localities to purchase and place AEDs in public places. The funds were also used to train people to use the devices and to deliver lifesaving cardiac treatment simply and with minimal training.

Should You Participate?

People lose consciousness while in cardiac arrest; thus, they cannot administer shocks to themselves. A life is in jeopardy, and you may actually save someone by learning to use an AED. If an organization you belong to has placed AEDs in its building, learn where the devices are located. At some point, the organization should offer training. Do not hesitate to take part, as the devices are virtually foolproof. Their internal computer program will not allow you to deliver a shock unless it is actually needed. You should also learn how to check the battery for a full charge.

The Home AED

Some readers are already familiar with the concept of AEDs and the benefits they can provide. They may be surprised to learn that the FDA has approved the first nonprescription AED for use at home. It is known as the Philips HeartStart Home Defibrillator. It comes with a training video that can be used to become familiar with the device. Everyone in the home who might conceivably need to use the AED on a loved one should watch the video. The company offers several flexible payment plans. You may go to www.heartstarthome.com to learn more, or you may also contact the company by calling 1-866-333-4246.

Refractory Epilepsy

2009-04-11T20:00:00.000-07:00

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.

FDA Panel Recommends Davon and Darvocet Be Pulled From Market

2009-04-11T19:59:00.000-07:00

3/18/2009

US Pharm. 2009;34(3):8.

Rockville, MD -- In a close decision, the FDA's panel of medical experts recommended that Darvon and Darvocet be pulled from the market based on concerns that the drugs' risks outweigh their benefits. The final decision will ultimately be made by the FDA, but because of the narrow 14-to-12 vote to yank the drugs, it is not clear whether the FDA will actually go through with the final order to take them off pharmacists' shelves. The panel's recommendation was partly the result of a petition from Public Citizen, a public-advocacy organization that challenged the drugs' efficacy versus their risk of causing heart problems.

A Warning About Warning Labels

2009-04-05T00:31:00.000-07:00

Matthew Grissinger, RPh, FISMP, FASCP
Director, Error Reporting Programs
Institute for Safe Medication Practices
Horsham, Pennsylvania

Susan Proulx, PharmD
President, Med-E.R.R.S.
Institute for Safe Medication Practices
Horsham, Pennsylvania

2/20/2009
US Pharm. 2009;34(2):Epub.

Prescription drug warning labels (PWLs) are applied to prescription vials to provide patients with important instructions for the safe use of medications. Unfortunately, pharmacists may rely on these labels as the primary means of communicating crucial warning statements to patients; however, this practice can be unsafe if the patient is unable to understand the warning. A recent study showed that there is a high level of misunderstanding of PWLs among adults with low literacy levels.¹

Label Comprehension: Eight different PWLs were used in this study (see examples). The rate of correct interpretation of these warnings ranged from 0% to 78.7%. With the exception of “Take with food,” less than half of all patients were able to provide adequate interpretations of the warning labels’ messages. Problems associated with text, icons, and color contributed to patients’ confusion. The findings indicated that some PWLs may inadvertently promote a misunderstanding of safety information, which could potentially lead to hazardous administration of the drug and adverse events.

Multiple-Step Instructions: Rates of comprehension were the lowest for PWLs with multiple steps. Respondents frequently were confused and unable to complete each step (e.g., “Refrigerate, shake well, discard after [date]”).

Reading Difficulty: Two PWLs included in the study were written at a high school or higher reading level and subsequently had the lowest comprehension rates (“You should avoid prolonged or excessive exposure to direct and/or artificial sunlight while taking this medication” and “Do not take dairy products, antacids, or iron preparations within one hour of this medication”). “Take with food” was written below a first-grade level and had the highest comprehension.

Message Clarity: Regardless of reading level, text on certain PWLs was not understood by most patients. For example, “For external use only,” which was written at a first-grade level, proved difficult for 90.7% of respondents to understand. For others, it was apparent that only part of the message could be interpreted. “Do not chew or crush, swallow whole” was misinterpreted as “do not swallow whole” or “chew it up so it will dissolve,” suggesting patients had read some, but not all, of the words on the label.

Icons or Symbols: Adults with low literacy may rely more heavily on symbols to interpret the meaning of labels. However, many of the icons used appeared to confuse patients, especially on labels with text that was difficult to comprehend. For example, the icon on “For external use only” was misinterpreted as “radioactive,” “chills or shaking,” or “take anywhere.”

Label Color: Approximately 42% of the patients correlated the label’s color to the severity of the message. Patients reported that a red label meant danger, yellow translated to caution, and blue, white, and green labels were viewed as “recommendations” that were not as critical as the instructions on red labels.

Safe Practice Recommendations: This study illustrates the importance of providing counseling to patients. Relying on the PWLs used on prescription vials is not enough. Other studies have shown that a combination of a verbal description and a visual symbol improves the overall comprehension of the warning.² Evaluate the clarity of the wording and the symbols used before purchasing PWLs, and be selective about which ones you apply to prescription vials. Establish a process to consistently place only relevant PWLs on vials and to provide verbal instructions to patients.

Pediatric Otitis Media: Managing Ear Infections in Children

2009-04-05T00:26:00.000-07:00

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.

Reducing Medication Errors Using Technological Innovations

2009-04-05T00:24:00.000-07:00

Helen L. Figge, PharmD, MBA, CSSBB, CLSSS
Senior Sales Strategy Consultant, AllscriptsMysis
Chairman, Task Force for Education and Publications
Pharmacy Informatics Section, American Society of Health-System Pharmacists
Clifton Park, New York

3/18/2009
US Pharm. 2009;34(3):HS-15-HS-16.

In its landmark report of 2000, the Institute of Medicine pointed out that thousands of patients are harmed by medication errors annually.¹ In the ambulatory setting, for example, between 1.5% and 4.0% of prescriptions are in error with potentially serious risk to patients.^2-4 According to a 2005 FDA report, medication errors result in at least one death per day and 1.3 million injuries per year in the United States.⁵ Inpatients who are given wrong medications average an additional 12 days in length-of-stay.

Technology enablers have the potential to carry out repetitious and routine mechanical processes in both the ambulatory and inpatient pharmacy setting. Automated pharmacy processes feature much higher precision and lower error rates than can be achieved by humans, thereby reducing medication errors, improving quality, and freeing up the pharmacist for more productive clinical interactions with patients. Through the use of innovative technology solutions, pharmacists can increase their oversight of critical processes during prescription preparation and dispensing, while at the same time making more efficient use of their overall professional time.

One major class of technology enablers with the potential to reduce medication errors is health information technology, which was recently reviewed.⁶ Other major classes of technology solutions include robotics, bar coding and radio frequency identification (RFID), automated calculation of doses and dilutions, digital imaging, telepharmacy, and noninvasive verification of capsule contents using spatially offset Raman spectroscopy (SORS). Often, several of these technologies can be employed in combination to provide an optimal solution for a given application.

Efficiency Gains

Robotic solutions have the potential to yield major improvements in efficiency and quality. Robotic devices can perform repetitious mechanical procedures with greater precision and accuracy than a human operator and do not become distracted or fatigued. Commercial applications typically combine a robotic system with computerized algorithms for automated dosing and dilutions. These systems employ bar coding or RFID for positive identification of pharmaceutical agents and diluents. Digital images are taken at critical steps during pharmaceutical preparation and dispensing so that a pharmacist can validate the accuracy of the process from a workstation, including confirmation that the dose was made with the right amounts of the correct products and diluents. The robot then applies a patient-specific label with a bar code that can be used to ensure that the right patient receives the dose.

One potential application for a robotic system is the preparation of chemotherapy doses. With a robotic process, pharmacists and technicians have direct contact only with sealed bags and vials and do not physically have direct contact with the pharmaceutical agents, diluents, or uncapped sharps. This improves safety for staff, who are not directly exposed to the drugs, and for patients, who will receive the right drug at the right dose and right dilution. Due to the efficiency of the process, doses can be made just in time so that they will be freshly prepared when administered. Robotic systems can also prepare and dilute various other intravenous medications including antibiotics. Again, every dose is accurate, verified, individually labeled, and bar-coded. Other robotic systems can fill ambulatory prescriptions for oral medications (capsules and tablets). Some commercial systems can fill up to 150 prescriptions per hour, thereby automating the repetitive dispensing sequences that are commonly subject to human error.

A telepharmacy system has been described at the University of Kansas Hospital in which the chemotherapy preparation process in the pharmacy's sterile room is monitored by bar coding and a camera that documents key steps.⁷ The technician scans the bar code on the chemotherapy drug vial to establish a match in the patient's computerized record. Then, in the sterile prep room, the technician captures an electronic image of the vial label and filled syringe prior to injecting the dose into an IV bag. A clinical pharmacist at a remote location then verifies the identity of the drug, the dose on the pulled-back syringe, the label on the IV bag, and the patient's medication order. This telepharmacy process, an alternative to using a robot, features quality assurance steps that are expected to greatly reduce errors.

A Multifaceted Approach

Crane and Crane at Dartmouth proposed that a systems approach combined with an array of technology solutions would radically reduce medication errors in hospitals.⁸ Their proposed strategy included computerized decision support (including real-time medical informatics), electronic medical records, computerized physician order entry (CPOE), bar coding, automated dispensing machines, and robotics. In theory, this appears to be a comprehensive approach; however, it is necessary to test the concept in actual practice. In this regard, there are some studies in the literature focused on the evaluation of one or more of these technologies. Poon et al tested the efficacy of bar coding in reducing medication errors in the hospital setting.⁹ When the process was configured to scan every dose, the use of bar coding resulted in an 86% to 97% relative reduction in the incidence of potential adverse drug events. Reifsteck et al reported on an end-to-end automated medication management system developed at Presbyterian Healthcare Services in Albuquerque.¹⁰ This implementation featured automated pharmacy operations with bar-coded medication administration, tightly interwoven with CPOE and decision support. The technology solution resulted in a dramatically lowered mortality rate and medication error rate. Oswald and Caldwell studied filling and dispensing rates before and after implementation of an automated pharmacy carousel system at a university hospital.¹¹ The implementation of the automated cabinets decreased medication filling errors. Teagarden et al studied the dispensing error rate in a high-volume highly automated mail-service pharmacy.¹²

Using the automated process, the dispensing error rate was 0.075%. Most errors were related to incomplete or incorrect directions on the final label and were associated with the initial stages of processing, such as order entry. No errors were introduced by the mechanical dispensing system in over 21,000 filled prescriptions. Hence, available data, although limited in scope, suggest that the proposal of Crane and Crane has potential merit.⁸ Further studies of a multicomponent system featuring the integration of software and automation are needed to thoroughly test the model.

A final technology of great future interest is the ability to noninvasively detect the ingredients in a capsule using a form of spectroscopy with a 250-mW laser at 827 nm.¹³ SORS was developed at the Rutherford Appleton Laboratory in the United Kingdom and might have potential in detecting counterfeit or contaminated pharmaceutical products. The technology could also be used in conjunction with a robotic system to definitively confirm the identity of agents that are in the process of being dispensed. It is expected that this technology could contribute greatly to reduction in medication errors.

Error Rates Close to Zero?

Given the magnitude of morbidity caused by adverse drug events, including medication errors, it is imperative that systematic approaches be taken to redesign the medication dispensing process to eliminate the potential for error. It is conceivable that the combined application of powerful computer software and pharmacy system automation, including robotics, can bring dispensing error rates down close to zero. With the introduction of monitoring methods such as telepharmacy and SORS, the potential exists to continuously monitor dispensed products for correct product and dose, which could further detect and eliminate errors. The reduction of error rates to near zero will likely require close integration between the computer software and pharmacy automation, with human interfaces that are designed to error-proof inputs to the system. Further outcomes studies using such systems are required to prove that the potential reduction in medication errors can actually be achieved in both inpatient and ambulatory settings.

Onglyza, Bristol-Myers diabetes drug appears safe

2009-03-30T23:43:00.000-07:00

By MATTHEW PERRONE, AP Business Writer Matthew Perrone, Ap Business Writer – Mon Mar 30, 5:33 pm ET

A potential blockbuster diabetes medication from Bristol-Myers Squibb appears free from heart-related side effects that have plagued similar treatments, federal health officials said Monday.

Despite low rates of heart attacks and related problems in testing, the Food and Drug Administration will still ask an outside panel to scrutinize the company's safety data at a meeting Wednesday.

Bristol-Myers and partner AstraZeneca have asked the FDA to approve Onglyza to reduce blood sugar levels in patients with type 2 diabetes. The drug uses a chemical reaction similar to Merck's Januvia and would compete against the blockbuster medication, which had sales of $1.4 billion last year.

The drug is part of a new wave of medications taking aim at the U.S. diabetes market, which has grown to more than $5 billion as the disease becomes more prevalent.

Analyst estimates of Onglyza's market potential vary, given its similarity to a more established drug. Sales estimates range from $300 million per year to more than $1 billion.

Shares of New York-based Bristol-Myers climbed 36 cents, or 1.7 percent, to close at $21.02 Monday. U.S.-traded shares of London-based AstraZeneca rose $1.87, or 5.8 percent, to $34.25.

Regulators have begun demanding more rigorous safety testing of diabetes drugs since a 2007 analysis suggested GlaxoSmithKline's blockbuster pill Avandia could increase heart risks.

Under guidelines issued last year, FDA requires companies to test diabetes drugs on more high-risk patients, including the elderly, to detect potential heart problems. Detecting heart risks connected with diabetes drugs is challenging because patients with the disease are already at risk of heart problems.

Because Bristol-Myers and AstraZeneca conducted their studies before the guidelines were released, their testing "was not designed to prospectively measure cardiovascular risk," agency reviewers noted. As a result the FDA said there is "insufficient information" to determine if some heart problems were related to the drug, according to briefing documents posted online.

At the agency's request, the companies went back after the fact and tried to analyze reports of heart problems with the drug. Based on that assessment, the level of heart attacks, deaths and other cardiovascular problems appeared well within the new safety limits imposed by the FDA.

The agency will ask its panel of experts on Wednesday whether the company's results are strong enough to make a follow-up safety study unnecessary.

A decision on whether to approve the drug is expected by the end of April. The FDA is not required to follow its panels' advice, though it usually does.

Bristol-Myers and British firm AstraZeneca are just two of the drugmakers looking to capitalize on the U.S. epidemic of Type 2 diabetes, which affects some 23 million adults and teenagers.

People with the disease have trouble breaking down carbohydrates, because their bodies have become resistant to the protein insulin, which is critical to digesting sugars. Over time, diabetics are at higher risk for heart attacks, kidney problems, blindness and other serious complications.

Onglyza, known generically as saxagliptin, belongs to the DPP-4 inhibitor family of the diabetes medications, which also includes Merck's drug Januvia.

The drugs work by blocking the DPP-4 enzyme, which spurs release of insulin-boosting proteins that help control blood sugar levels.

On Thursday FDA's panel will review another proposed diabetes treatment from Novo Nordisk. The Danish drugmakers's liraglutide boosts insulin while restricting the hormone GLP-1 hormone, which drives up blood sugar.

If approved, the once-daily injection would compete with Eli Lilly and Amylin Pharmaceutical's Byetta, a twice-daily injectable drug in the same family of medications. The makers of Byetta are working on their own extended-release version of the drug that would only require one injection per week.

Recommendations for the Use of OTC Cough and Cold Medications in Children

2009-03-30T00:44:00.000-07:00

Antihistamines

Antihistamines are reversible H₁-receptor antagonists that block histamine activity in the respiratory tract, gastrointestinal (GI) tract, and blood vessels. They may help prevent and treat nasal and ocular itching, rhinorrhea, and sneezing associated with the common cold, but they have not been proven to prevent colds, cure them, or shorten the course. Side effects of antihistamines include drowsiness, nervousness, insomnia, dry mouth, and dizziness. OTC cold and allergy formulas for children contain first- or second-generation antihistamines. There is no FDA-approved dosing of antihistamines for colds; however, dosing for allergic rhinitis is given. The two classes differ mainly in their sedative effects, with first-generation antihistamines causing more sedation.^3-6

First-generation antihistamines include chlorpheniramine, diphenhydramine, and brompheniramine. Appropriate dosing of chlorpheniramine in children aged 2 to 6 years is 0.35 mg/kg/day divided every four to six hours, with a maximum daily dose (MDD) of 6 mg. Recommended diphenhydramine dosing in children aged 2 to 6 years is 5 mg/kg/day divided six hours as needed, with an MDD of 300 mg. Diphenhydramine should not be used in neonates owing to possible central nervous system effects. Dosing of brompheniramine in patients aged 2 to 6 years is 1 mg every four to six hours.² Brompheniramine is not available OTC as a single-active-ingredient product, but it is found in combination with other active ingredients in pediatric cough and cold medications.

Second-generation antihistamines available OTC include cetirizine and loratadine. Appropriate cetirizine dosing in children is as follows: age 6 to 12 months, 2.5 mg/day; age 12 to 23 months, initial dosing 2.5 mg/day (may be increased to 2.5 mg twice/day); age 2 to 5 years, initial dosing 2.5 mg/day (may be increased to 5 mg/day in single or divided doses). The usual dose of loratadine for children aged 2 to 5 years is 5 mg once/day.²

Antihistamines should not be used to sedate children, and manufacturers of certain antihistamine products are making voluntary labeling changes that warn parents not to use the product with the intention of making a child sleepy.¹ Parents should avoid using antihistamines in children with glaucoma, breathing disorders, liver disease, or seizure disorders unless directed otherwise by their primary health care provider.^3-6

Decongestants

Nasal decongestants are sympathomimetic amines that exert their vasoconstrictive action by affecting sympathetic tone in the nasal mucosa. Decongestants decrease enlarged blood vessels and alleviate mucosal edema by acting on adrenergic receptors.^5,7,8 Phenylephrine stimulates alpha-1 receptors, whereas oxymetazoline, xylometazoline, and naphazoline stimulate alpha-2 receptors.⁸

Pseudoephedrine exerts its action by having both a direct and an indirect effect on adrenergic activity. Like phenylephrine and the imidazoline derivatives, pseudoephedrine stimulates alpha receptors but also indirectly causes the release of norepinephrine from its storage sites.^7,8

Systemic and nasal decongestants are available OTC. Systemic nasal decongestants are indicated for temporary relief of nasal congestion, to promote nasal or sinus drainage, and for cough caused by postnasal drip. Topical nasal decongestants are indicated for the symptomatic relief of both nasal and nasopharyngeal mucosal congestion.^5,7

Side effects from decongestants are more likely to occur in children than in adults. Effects include elevated blood pressure, tachycardia, palpitations, arrhythmia, restlessness, insomnia, anxiety, tremors, psychological disturbances, and hypersensitivity reactions. Because they are minimally absorbed, topical decongestants have systemic side effects that are milder and occur less frequently compared with systemic dosage forms. Topical use may cause burning, stinging, sneezing, or local irritation. The use of topical decongestants should be limited to three days, since prolonged use has been associated with tachyphylaxis, rebound nasal mucosa edema, and rebound nasal congestion.^5,7,8

The recommended dosing for phenylephrine nasal drops is 1 to 2 drops of 0.16% solution in each nostril every three hours as needed in infants older than 6 months; in children aged under 6 years, the dosing is 2 to 3 drops of 0.125% solution in each nostril every four hours as needed.² Appropriate dosing of oral phenylephrine in children aged 2 to 6 years is 2.5 mg every four hours or 3.75 mg every six hours, with an MDD of 15 mg.^2,9 Pseudoephedrine in children aged under 12 years is dosed at 4 mg/kg/day divided every six hours as needed with an MDD of 60 mg.^2,9

Expectorants

Guaifenesin is the only nonprescription expectorant available for use in children. It is an oral mucolytic that helps loosen phlegm and bronchial secretions by increasing respiratory-tract secretions, which leads to a more productive cough and better airway clearance.⁶ If the cough lasts for more than one week, recurs, or is accompanied by a fever, rash, or persistent headache, consultation with a primary health care provider is recommended. Adverse effects associated with guaifenesin include nausea, vomiting, dizziness, drowsiness, headache, and rash.

Guaifenesin should be taken with a full glass of water, and adequate hydration during use should be maintained. The extended-release tablets should not be chewed or crushed; therefore, if the patient cannot swallow the tablet, a different dosage form--such as syrup, solution, liquid, or minimelt (oral granule)--should be used. The most effective way to administer the oral granules is to place them on the tongue and swallow them without chewing; they may have an unpleasant taste if chewed. Appropriate dosing for children aged up to 6 years is as follows: age under 2 years, individualized dose (common dosing = 25-50 mg every four hours, with an MDD of 300 mg); age 2 to 6 years, 50 to 100 mg every four hours, with an MDD of 600 mg.^4-6

Antitussives

Codeine, although not available OTC in all states, is the gold-standard antitussive. Nonprescription antitussives that are available OTC to treat cough are dextromethorphan and diphenhydramine.¹⁰ Codeine produces cough suppression by acting centrally on the cough center located in the medulla portion of the brainstem. When used at antitussive doses, codeine should not exhibit addictive properties.¹⁰ Dextromethorphan, the d-isomer of codeine, exerts its pharmacologic action in the same way as codeine; however, it lacks analgesic and addictive properties when used at recommended doses.^4,5 In children, the recommended dose of both dextromethorphan and codeine is 1 mg/kg/day divided into four doses, with an MDD of 30 mg for children aged 2 to 5 years.^2,11 Recommended dosing for diphenhydramine, a first-generation antihistamine, in children aged less than 6 years is 5 mg/kg/day divided every six hours, with an MDD of 300 mg.²

Side effects of codeine include lightheadedness, dizziness, sedation, GI effects, and sweating. The most common effects resulting from an overdose are respiratory depression and a decreased level of alertness or consciousness. It has been reported that codeine is unlikely to produce significant side effects in children given less than 2 mg/kg; however, somnolence, ataxia, miosis, vomiting, rash, facial swelling, and itching have been reported in children receiving codeine doses of 3 to 5 mg/kg/day. Side effects of dextromethorphan include drowsiness, dizziness, nausea, GI upset, and abdominal discomfort.⁴ Dextromethorphan may cause behavioral disturbances and respiratory depression when overdosage occurs.

Insufficient evidence exists to support the use of codeine or dextromethorphan for antitussive purposes in the pediatric population.¹¹ Pharmacists should counsel parents about the lack of data supporting the use of these drugs for antitussive purposes as well as the potential risks associated with their use. Additionally, evidence suggests that second-generation nonsedating antihistamines such as loratadine are ineffective for lessening cough associated with the common cold, and therefore should not be used.¹²

Combination Products

Many nonprescription cough and cold formulations contain more than one active ingredient to treat two or more simultaneous symptoms. It is important to remember that combination cough and cold medications should be used only if the corresponding symptom is present and that combination products should not be given in addition to a different nonprescription product with the same active ingredient.

Nonprescription cough and cold formulations are available in the following combinations: antihistamine/decongestant, antihistamine/antitussive, antitussive/expectorant, decongestant/expectorant, antihistamine/antitussive/decongestant, and antitussive/decongestant/expectorant.⁵ In addition, some multisymptom products contain antipyretics and analgesics such as acetaminophen and ibuprofen. Weight-based dosing of oral acetaminophen in children is recommended at 10 to 15 mg/kg/dose every four to six hours as needed; daily dosing should not exceed 90 mg. Nonprescription ibuprofen dosing for children is 5 to 10 mg/kg/dose every six to eight hours, with an MDD of 40 mg/kg.²

Voluntary and Regulatory Changes

The safety of OTC cough and cold preparations in the pediatric population is of great concern owing to reports of severe adverse reactions and deaths in infants and children. In October 2007, the FDA's advisory committees on Nonprescription Drugs and Pediatrics met to discuss the safety and efficacy of nonprescription cough and cold medications in children. Ten days prior to the meeting, a voluntary withdrawal of 14 nonprescription infant cough and cold medications was announced by the Consumer Healthcare Products Association (CHPA) on behalf of the products' manufacturers. Manufacturers recalled these products even though they believed that they were safe. Cases of misuse leading to overdose of infants less than 2 years of age had been reported. The advisory committees concluded that evidence from pediatric studies was insufficient to prove the efficacy of cold and cough medications in children; they voted 13 to 9 to recommend that cough and cold products no longer be used in children under 6 years of age.^13,14

The FDA issued a public health advisory in January 2008 recommending that OTC cough and cold medications not be used in children under 2 years of age because of the risk of serious, life-threatening adverse events. Additionally, the FDA agreed to the manufacturers' request to change the product labeling to warn parents not to use antihistamine products to sedate children.^13,14

In 2008, the FDA held two public meetings to gather more information about the regulatory process for pediatric cough and cold medicines and about scientific testing in children. On October 8, 2008, the FDA issued a statement supporting the CHPA's announcement that manufacturers of nonprescription OTC cough and cold medicines for children were voluntarily modifying package labeling to state, "Do not use in children under 4 years of age."¹⁵

In addition to product-labeling changes, new child-resistant packaging and measuring devices for the products are being introduced. The manufacturers have been transitioning this new labeling and packaging throughout the 2008-2009 cough and cold season.¹

Complementary and Alternative Therapies

Alternative cough and cold therapies such as increased fluid intake, room humidifiers, nasal dilator strips, nasal aspiration or irrigation, and vitamin C can be used alone or in combination with an OTC cough and cold medication. Increased fluid intake helps prevent dehydration in a child suffering from a cough or cold. Room humidifiers provide relief from congestion by moistening the air.¹⁶ Warm-mist humidifiers work by boiling water in a reservoir, thereby posing a potential burn risk; for that reason, cool-mist humidifiers are generally recommended. Because bacteria thrive in moist settings, parents should be encouraged to empty water from the humidifier and wipe all surfaces dry on a daily basis.¹⁷

Nasal dilator strips are adhesive bands placed on the nose that dilate the nasal air passages or stiffen the nasal wall, leading to increased airflow and thus relieving nasal congestion.^18,19 Nasal dilator strips with or without added menthol are FDA-approved for use in children aged 5 years or older. Latex allergy is a potential concern with this product.¹⁸

Cleansing of the nasal passages with a bulb syringe and nasal irrigation with saline drops are two options for treating small children with congestion. Aspiration with a bulb syringe clears mucus from the nasal passages; 0.65% sodium chloride drops and sprays soothe irritated mucus membranes and rehydrate dried secretions for easier removal from the nasal passages.^7,18

Supplementation with vitamin C may decrease the duration of the common cold in children. A 2004 Cochrane systematic review suggests that, in children, doses of 0.2 g to 2 g vitamin C are beneficial for reducing a cold's duration. Studies have shown that children have a greater decrease in cold duration than adults, and that higher doses confer a greater benefit than lower doses. Studies evaluating 0.2 to 0.75 g/day vitamin C reported a 7% reduction in cold duration compared with an 18% reduction in studies evaluating 1 g/day.²⁰ Children given 2 g/day demonstrated a median decrease in cold duration of 26%, versus a 6% median decrease in adults receiving 1 g/day.²¹ At doses greater than 1 g, side effects including nausea, vomiting, increased iron absorption, and diarrhea may occur.⁵

Conclusion

Pharmacists are accessible members of the health care team and are often consulted by parents or guardians regarding selection of appropriate nonprescription cough and cold products for their children. The parent or guardian should be counseled to carefully follow certain guidelines for usage (see sidebar) when an OTC cough and cold medication is being considered for use in children.^22,23

3/18/2009

US Pharm. 2009;34(3):33-35.

Pharmacists (career in US)

2009-03-21T20:34:00.000-07:00

Significant Points

Excellent job opportunities are expected.
Earnings are high, but some pharmacists are required to work nights, weekends, and holidays.
Pharmacists are becoming more involved in counseling patients and planning drug therapy programs.
A license is required; the prospective pharmacist must graduate from an accredited college of pharmacy and pass a series of examinations.

Nature of the Work

Pharmacists distribute prescription drugs to individuals. They also advise their patients, as well as physicians and other health practitioners, on the selection, dosages, interactions, and side effects of medications. Pharmacists monitor the health and progress of patients to ensure the safe and effective use of medication. Compounding—the actual mixing of ingredients to form medications—is a small part of a pharmacist’s practice, because most medicines are produced by pharmaceutical companies in a standard dosage and drug delivery form. Most pharmacists work in a community setting, such as a retail drugstore, or in a health care facility, such as a hospital, nursing home, mental health institution, or neighborhood health clinic.

Pharmacists in community pharmacies dispense medications, counsel patients on the use of prescription and over-the-counter medications, and advise physicians about patients’ medication therapy. They also advise patients about general health topics such as diet, exercise, and stress management, and provide information on products such as durable medical equipment or home health care supplies. In addition, they may complete third-party insurance forms and other paperwork. Those who own or manage community pharmacies may sell non-health-related merchandise, hire and supervise personnel, and oversee the general operation of the pharmacy. Some community pharmacists provide specialized services to help patients with conditions such as diabetes, asthma, smoking cessation, or high blood pressure; others also are trained to administer vaccinations.

Pharmacists in health care facilities dispense medications and advise the medical staff on the selection and effects of drugs. They may make sterile solutions to be administered intravenously. They also plan, monitor and evaluate drug programs or regimens. They may counsel hospitalized patients on the use of drugs before the patients are discharged.

Pharmacists who work in home health care monitor drug therapy and prepare infusions—solutions that are injected into patients—and other medications for use in the home.

Some pharmacists specialize in specific drug therapy areas, such as intravenous nutrition support, oncology (cancer), nuclear pharmacy (used for chemotherapy), geriatric pharmacy, and psychiatric pharmacy (the use of drugs to treat mental disorders).

Most pharmacists keep confidential computerized records of patients’ drug therapies to prevent harmful drug interactions. Pharmacists are responsible for the accuracy of every prescription that is filled, but they often rely upon Pharmacy technicians and pharmacy aides to assist them in the dispensing process. Thus, the pharmacist may delegate prescription-filling and administrative tasks and supervise their completion. Pharmacists also frequently oversee pharmacy students serving as interns.

Increasingly, pharmacists are pursuing nontraditional pharmacy work. Some are involved in research for pharmaceutical manufacturers, developing new drugs and testing their effects. Others work in marketing or sales, providing clients with expertise on the use, effectiveness, and possible side effects of drugs. Some pharmacists work for health insurance companies, developing pharmacy benefit packages and carrying out cost-benefit analyses on certain drugs. Other pharmacists work for the government, managed care organizations, public health care services, the armed services, or pharmacy associations. Finally, some pharmacists are employed full time or part time as college faculty, teaching classes and performing research in a wide range of areas.

Work environment. Pharmacists work in clean, well-lighted, and well-ventilated areas. Many pharmacists spend most of their workday on their feet. When working with sterile or dangerous pharmaceutical products, pharmacists wear gloves, masks, and other protective equipment.

Most full-time salaried pharmacists work approximately 40 hours a week, and about 10 percent work more than 50 hours. Many community and hospital pharmacies are open for extended hours or around the clock, so pharmacists may be required to work nights, weekends, and holidays. Consultant pharmacists may travel to nursing homes or other facilities to monitor patients’ drug therapy. About 16 percent of pharmacists worked part time in 2006.

Training, Other Qualifications, and Advancement

A license is required in all States, the District of Columbia, and all U.S. territories. In order to obtain a license, pharmacists must earn a Doctor of Pharmacy (Pharm.D.) degree from a college of pharmacy and pass several examinations.

Education and training. Pharmacists must earn a Pharm.D. degree from an accredited college or school of pharmacy. The Pharm.D. degree has replaced the Bachelor of Pharmacy degree, which is no longer being awarded. To be admitted to a Pharm.D. program, an applicant must have completed at least 2 years of postsecondary study, although most applicants have completed 3 or more years. Other entry requirements usually include courses in mathematics and natural sciences, such as chemistry, biology, and physics, as well as courses in the humanities and social sciences. In 2007, 92 colleges and schools of pharmacy were accredited to confer degrees by the Accreditation Council for Pharmacy Education (ACPE). About 70 percent of Pharm.D. programs require applicants to take the Pharmacy College Admissions Test (PCAT).

Courses offered at colleges of pharmacy are designed to teach students about all aspects of drug therapy. In addition, students learn how to communicate with patients and other health care providers about drug information and patient care. Students also learn professional ethics, concepts of public health, and medication distribution systems management. In addition to receiving classroom instruction, students in Pharm.D. programs spend about one-forth of their time in a variety of pharmacy practice settings under the supervision of licensed pharmacists.

In the 2006–07 academic year, 70 colleges of pharmacy also awarded the master-of-science degree or the Ph.D. degree. Both degrees are awarded after the completion of a Pharm.D. degree and are designed for those who want additional clinical, laboratory, and research experience. Areas of graduate study include pharmaceutics and pharmaceutical chemistry (physical and chemical properties of drugs and dosage forms), pharmacology (effects of drugs on the body), and pharmacy administration. Many master’s and Ph.D. degree holders go on to do research for a drug company or teach at a university.

Other options for pharmacy graduates who are interested in further training include 1-year or 2-year residency programs or fellowships. Pharmacy residencies are postgraduate training programs in pharmacy practice and usually require the completion of a research project. These programs are often mandatory for pharmacists who wish to work in hospitals. Pharmacy fellowships are highly individualized programs that are designed to prepare participants to work in a specialized area of pharmacy, such clinical practice or research laboratories. Some pharmacists who own their own pharmacy obtain a master’s degree in business administration (MBA). Others may obtain a degree in public administration or public health.

Licensure. A license to practice pharmacy is required in all States, the District of Columbia, and all U.S. territories. To obtain a license, a prospective pharmacist must graduate from a college of pharmacy that is accredited by the ACPE and pass a series of examinations. All States, U.S. territories, and the District of Columbia require the North American Pharmacist Licensure Exam (NAPLEX), which tests pharmacy skills and knowledge. Forty-four States and the District of Columbia also require the Multistate Pharmacy Jurisprudence Exam (MPJE), which tests pharmacy law. Both exams are administered by the National Association of Boards of Pharmacy (NABP). Each of the eight States and territories that do not require the MJPE has its own pharmacy law exam. In addition to the NAPLEX and MPJE, some States and territories require additional exams that are unique to their jurisdiction.

All jurisdictions except California currently grant license transfers to qualified pharmacists who already are licensed by another jurisdiction. Many pharmacists are licensed to practice in more than one jurisdiction. Most jurisdictions require continuing education for license renewal. Persons interested in a career as a pharmacist should check with individual jurisdiction boards of pharmacy for details on license renewal requirements and license transfer procedures.

Graduates of foreign pharmacy schools may also qualify for licensure in some U.S. States and territories. These individuals must apply for certification from the Foreign Pharmacy Graduate Examination Committee (FPGEC). Once certified, they must pass the Foreign Pharmacy Graduate Equivalency Examination (FPGEE), Test of English as a Foreign Language (TOEFL) exam, and Test of Spoken English (TSE) exam. They then must pass all of the exams required by the licensing jurisdiction, such as the NAPLEX and MJPE. Applicants who graduated from programs accredited by the Canadian Council for Accreditation of Pharmacy Programs (CCAPP) between 1993 and 2004 are exempt from FPGEC certification and examination requirements.

Other qualifications. Prospective pharmacists should have scientific aptitude, good interpersonal skills, and a desire to help others. They also must be conscientious and pay close attention to detail, because the decisions they make affect human lives.

Advancement. In community pharmacies, pharmacists usually begin at the staff level. Pharmacists in chain drugstores may be promoted to pharmacy supervisor or manager at the store level, then to manager at the district or regional level, and later to an executive position within the chain’s headquarters. Hospital pharmacists may advance to supervisory or administrative positions. After they gain experience and secure the necessary capital, some pharmacists become owners or part owners of independent pharmacies. Pharmacists in the pharmaceutical industry may advance in marketing, sales, research, quality control, production, or other areas.

Employment

Pharmacists held about 243,000 jobs in 2006. About 62 percent worked in community pharmacies that were either independently owned or part of a drugstore chain, grocery store, department store, or mass merchandiser. Most community pharmacists were salaried employees, but some were self-employed owners. About 23 percent of pharmacists worked in hospitals. A small proportion worked in mail-order and Internet pharmacies, pharmaceutical wholesalers, offices of physicians, and the Federal Government.

Job Outlook

Employment is expected to increase much faster than the average through 2016. As a result of rapid growth and the need to replace workers who leave the occupation, job prospects should be excellent.

Employment change. Employment of pharmacists is expected to grow by 22 percent between 2006 and 2016, which is much faster than the average for all occupations. The increasing numbers of middle-aged and elderly people—who use more prescription drugs than younger people—will continue to spur demand for pharmacists throughout the projection period. Other factors likely to increase the demand for pharmacists include scientific advances that will make more drug products available and the coverage of prescription drugs by a greater number of health insurance plans and Medicare.

As the use of prescription drugs increases, demand for pharmacists will grow in most practice settings, such as community pharmacies, hospital pharmacies, and mail-order pharmacies. As the population ages, assisted living facilities and home care organizations should see particularly rapid growth. Demand will also increase as cost conscious insurers, in an attempt to improve preventative care, use pharmacists in areas such as patient education and vaccination administration.

Demand is also increasing in managed care organizations where pharmacists analyze trends and patterns in medication use, and in pharmacoeconomics—the cost and benefit analysis of different drug therapies. New jobs also are being created in disease management—the development of new methods for curing and controlling diseases—and in sales and marketing. Rapid growth is also expected in pharmacy informatics—the use of information technology to improve patient care.

Job prospects. Excellent opportunities are expected for pharmacists over the 2006 to 2016 period. Job openings will result from rapid employment growth, and from the need to replace workers who retire or leave the occupation for other reasons.

Projections Data

Projections data from the National Employment Matrix
Occupational title	SOC Code	Employment, 2006	Projected employment, 2016	Change, 2006-16		Detailed statistics
Occupational title	SOC Code	Employment, 2006	Projected employment, 2016	Number	Percent	Detailed statistics
Pharmacists	29-1051	243,000	296,000	53,000	22	PDF	zipped XLS
NOTE: Data in this table are rounded. See the discussion of the employment projections table in the Handbook introductory chapter on Occupational Information Included in the Handbook.

Earnings

Median annual of wage-and-salary pharmacists in May 2006 were $94,520. The middle 50 percent earned between $83,180 and $108,140 a year. The lowest 10 percent earned less than $67,860, and the highest 10 percent earned more than $119,480 a year. Median annual earnings in the industries employing the largest numbers of pharmacists in May 2006 were:

Department stores	$99,050
Grocery stores	95,600
Pharmacies and drug stores	94,640
General medical and surgical hospitals	93,640

According to a 2006 survey by Drug Topics Magazine, pharmacists in retail settings earned an average of $92,291 per year, while pharmacists in institutional settings earned an average of $97,545. Full-time pharmacists earned an average of $102,336, while part-time pharmacists earned an average of $55,589.

For the latest wage information:

The above wage data are from the Occupational Employment Statistics (OES) survey program, unless otherwise noted. For the latest National, State, and local earnings data, visit the following pages:

Pharmacists

Related Occupations

Pharmacy technicians and pharmacy aides also work in pharmacies. Persons in other professions who may work with pharmaceutical compounds include biological scientists, medical scientists, and chemists and materials scientists. Increasingly, pharmacists are involved in patient care and therapy, work that they have in common with physicians and surgeons.

Sources of Additional Information

Disclaimer:

Links to non-BLS Internet sites are provided for your convenience and do not constitute an endorsement.

For information on pharmacy as a career, preprofessional and professional requirements, programs offered by colleges of pharmacy, and student financial aid, contact:

American Association of Colleges of Pharmacy, 1426 Prince St., Alexandria, VA 22314. Internet: http://www.aacp.org

General information on careers in pharmacy is available from:

American Society of Health-System Pharmacists, 7272 Wisconsin Ave., Bethesda, MD 20814. Internet: http://www.ashp.org
National Association of Chain Drug Stores, 413 N. Lee St., P.O. Box 1417-D49, Alexandria, VA 22313-1480. Internet: http://www.nacds.org
Academy of Managed Care Pharmacy, 100 North Pitt St., Suite 400, Alexandria, VA 22314. Internet: http://www.amcp.org
American Pharmacists Association, 1100 15th Street, N.W. Suite 400., Washington, DC 20005. Internet: http://www.aphanet.org

Information on the North American Pharmacist Licensure Exam (NAPLEX) and the Multistate Pharmacy Jurisprudence Exam (MPJE) is available from:

National Association of Boards of Pharmacy, 1600 Feehanville Dr., Mount Prospect, IL 60056. Internet: http://www.nabp.net

State licensure requirements are available from each State’s board of pharmacy. Information on specific college entrance requirements, curriculums, and financial aid is available from any college of pharmacy.

Suggested citation: Bureau of Labor Statistics, U.S. Department of Labor, Occupational Outlook Handbook, 2008-09 Edition, Pharmacists, on the Internet at http://www.bls.gov/oco/ocos079.htm (visited March 21, 2009).

Last Modified Date: December 18, 2007

Pharmacists resource on healthsensei

Optimizing Individualized Management of OSTEOARTHRITIS

FACULTY:

Diagnosis and Management of Osteoarthritis

Assessing the Impact of OA

Important Pathophysiologic and Clinical Aspects of OA

Pathophysiology of OA

Pharmacotherapy for Pain Management in the Patient With OA

Oral Agents

Opioids, Including Tramadol

Topical Agents

Adjuvant Therapies

Emerging Treatments and Concepts for Pain Treatment

Nonpharmacologic Interventions in OA Addressing Risk Factors

Educational and Physical Interventions

Nutraceuticals

Current OA Treatment Guidelines

New Opportunities and Perspectives in OA Management

Pharmacoeconomic Considerations

Conclusions

An Update on the Current Treatment of HIV

FACULTY:

GOAL:

Nucleoside Reverse Transcriptase Inhibitors

Nonnucleoside Reverse Transcriptase Inhibitors

Protease Inhibitors

Other Therapies

Guarding Against Opportunistic Infections

Role of the Pharmacist

Herpes Zoster (Shingles) and Postherpetic Neuralgia Management

FACULTY:

FACULTY DISCLOSURE STATEMENTS:

PATHOPHYSIOLOGY AND PRESENTATION

Early Stage

Active Stage

Complications

Postherpetic Neuralgia

MANAGEMENT OF SHINGLES

Antiviral Therapy

Corticosteroids

Pain Management of PHN

Topical Analgesics

Oral Agents

Other Interventions

The Use of OTC Medications in Older Adults

Allergy

The Common Cold

Osteoarthritis

Heartburn

Constipation

Insomnia

Urinalysis: A Guide for Pharmacists

FACULTY DISCLOSURE STATEMENTS:

COLLECTING URINE FOR TESTING

VISUAL EXAMINATION (MACROSCOPIC ANALYSIS)

DIP-AND-READ TESTING How to Use the Test Strips

Storage of Test Strips

Uses of Dip-and-Read Testing

MICROSCOPIC ANALYSIS

CONCLUSION

pressure ulcer

PREVALENCE

RISK FACTORS

Intrinsic Factors

Extrinsic Factors

SCREENING

PATHOPHYSIOLOGY

STAGES OF PRESSURE ULCER

THERAPEUTIC TREATMENT OPTIONS

PHARMACOLOGIC TREATMENT OPTIONS

Wound Care

Nutrition

Topical Growth Factors

Pain Control

THE PHARMACIST'S ROLE

Contemporary Options for the Management of Scars

Yvette C. Terrie , BSPharm, RPhJeffrey R. Marcus , MD, FAAP, FACS

Pathophysiology of Wound Healing and Scar Formation

Factors That Affect Wound Healing

Scarring

Nonpharmacologic Interventions in OA
Addressing Risk Factors

DIP-AND-READ TESTING
How to Use the Test Strips

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