Optimizing Individualized Management of OSTEOARTHRITIS

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

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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.¹ There 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.² Pharmacists 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.² Such 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.² In their nondispensing (ie, advisory) role, pharmacists have the potential to improve patient outcomes related to medication use.^3,4 Clinical 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.⁵ The 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.⁶ The most common site of OA is the knee; knee OA affects 16% of the population [.greaterequal]45 years of age.⁶ However, 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 1.⁷ Obesity 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).⁵ This 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.⁹ In 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.¹⁰ A 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.⁶ Patients 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.¹³ Sleep 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.¹⁴ Fear of these risks is frequently cited as a reason for undertreatment with these agents.¹⁵ The 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.¹⁶ Results 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.¹⁹ Inheritable 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.¹⁹ Plain film radiographs are useful in differential diagnosis and for monitoring the progression of the disease.²² However, plain radiographs may not reveal significant abnormalities in patients with early-stage disease.²¹ Magnetic 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.²¹ Erythrocyte 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).²³ Synovial 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.²⁴ The 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.^25,27 These 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.^28,29 A 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.³⁰ It is modestly effective for relieving pain and decreasing stiffness, but it often fails to control severe pain.^21,31 Meta-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.³² Hepatotoxicity 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).²¹ Selective 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.^21,31 A 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.³⁴ Product 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.³⁷ The 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.³⁴ Opioid 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.^38,39 Approaches that have been taken to decrease these risks include the development of extended-release formulations and other abuse-resistant formulations.⁴⁰ Extended-release opioid formulations may also increase convenience for patients as well as provide better round-the-clock pain control.⁴¹ Programs 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.³¹ Intra-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.^21,31 Further 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.^43,44 Topical analgesics are thus particularly suited for use in elderly patients because they decrease the risk for systemic adverse effects.⁴⁴ Topical NSAIDs, lidocaine, capsaicin, and salicylate/menthol have all been shown to be effective for the treatment of peripheral pain.⁴⁵ Topical 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.⁴⁶ Longer-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.²¹ Two published studies, each of 2 weeks’ duration, have demonstrated the efficacy of lidocaine patches in reducing the pain of OA.^47,48 A third study showed similar efficacy between lidocaine patches and oral celecoxib for up to 12 weeks.²¹ Capsaicin 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.^49,50 Medications suitable for the treatment of sleep disorders in OA patients include nonbenzodiazepine agonists (zolpidem, zopiclone, zapelon) and benzodiazepines (lorazepam, temazepam).⁴⁹ Various 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.⁴⁰ An 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-B₂ receptor antagonist has been found to be effective for the treatment of OA of the knee following intra-articular injection.²⁷ Novel 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.⁵² OA 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).³⁰ These 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.⁵⁷ Dimethyl sulfoxide and methylsulfonylmethane have also been employed to treat OA, but available data cannot support a positive recommendation for the use of either agent.⁵⁸ Foods 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.^30,35,36,60 The 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.⁶¹ Generally, a combination of nonpharmacologic and pharmacologic treatments will be required to achieve optimal outcomes in most patients.³⁵ Combinations 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.⁶² The 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.¹³ Unfortunately, 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.⁶³ Thus, 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.⁵⁷ In one study, an increase in copayments for OA medications resulted in a significant increase in the number of patients who simply discontinued treatment.⁶⁴ This 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

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.

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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.¹ Though 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/mm³.² Originally 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.⁴ Following 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.⁵ Being 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.^6,7 Because 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 dailya 300 mg with 100 mg RTV daily	Hyperbilirubinemia, nephrolithiasis
Darunavir (Prezista)	800 mg with 100 mg RTV dailya 600 mg with 100 mg RTV bid	Rash, headache, nausea, diarrhea
Fosamprenavir (Lexiva)	1,400 mg bida 1,400 mg with 100-200 mg RTV dailya 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 dailya 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.⁸ The 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.¹ Efavirenz 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.¹ Nelfinavir 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 PDE₅ inhibitor 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 Fluticasonea

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.¹ Atazanavir 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.⁹ Indinavir 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.¹² Raltegravir 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.¹³ It 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/mm³ receive prophylaxis to decrease their risk.¹ First-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/mm³ and 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

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.

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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.¹ The 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).² The 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.³ The 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.⁶ In 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.⁷ TABLE 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.^8,9 Clinical 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.^10,11 Clinical 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.¹² The 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.¹³ TCAs 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_A or GABA_B receptors. 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_A or GABA_B receptors. 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.¹⁶ Specifically, 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.¹⁷ TENS 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.¹⁸ Biofeedback 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.¹⁹ Nerve 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.²⁰ The 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).²¹ Further 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.