The pharmacist's role can be integral to adequate cancer pain relief and a return of quality of life.

	Despite the availability of many classes of analgesic medications intended to alleviate pain, ranging in intensity from mild to severe, pain remains one of the most frequent and troubling issues encountered by patients with cancer. It is estimated that 30% to 90% of all patients will experience pain at some point during their course of disease, with advanced stages of cancer more commonly associated with pain-related syndromes than early-stage disease.

 More importantly, undertreatment of pain in this patient population is commonplace and can result in significant issues related to quality of life including sleep disruptions, depression, loss of appetite, impairment of activities of daily living, etc.

 Therefore, it should be a priority for health care providers to routinely evaluate and appropriately manage patients for cancer-related pain syndromes.

	Most commonly, pain is assessed by allowing the patient to rate the intensity of their pain using a 0 to 10 numerical scale, a visual analog scale, or a highly simplified Faces Pain scale that has been validated in pediatric patients and other populations incapable of accurately verbalizing their condition. Where possible, in addition to identifying their pain intensity, patients should also be queried to describe the character of their pain, ie, burning, shooting, stabbing, tingling, etc. Combining the pain score with the patient’s description of the pain allows the practitioner to determine the best approach to appropriately manage the patient’s complaints.

	Historically, pain management in cancer patients has been guided by the World Health Organization (WHO) algorithm for initiation of nonopioid and opioid therapy (Figure). This 3-tiered approach relies on the level of patient-reported pain intensity and matches medication therapy accordingly.

 Although this algorithm continues to represent an intuitive approach to management of pain in the cancer patient, it should not replace a provider’s clinical acumen in addressing both acute and chronic aspects of pain management.

	Prior to initiating therapy, it is essential that providers first determine the underlying nature of the patient’s pain syndrome. The majority of cancerrelated pain can be attributed to the location and pattern of tissue and/or organ invasion of the primary tumor(s) or the presence of metastatic disease.

 Mechanistically, this nociceptive-type pain is due to the direct injury of somatic or visceral structures with resulting nociceptor activation. In contrast to nociceptive pain, many cancer patients experience neuropathic pain secondary to their underlying malignancy or as a consequence of their chemotherapy. This neuropathic pain results from spontaneous activation of nerve tissue and frequently responds to therapy with anticonvulsant medications such as gabapentin or pregabalin.

 Once the type of pain, nociceptive or neuropathic, has been determined, the practitioner should continue their assessment by classifying the degree of pain intensity using a scale ranging from mild (pain score of 1-4) to moderate (5-6) or severe (7-10), combined with an assessment of whether the pain is acute or chronic in nature.

	For opioid-naïve patients (ie, those not receiving chronic daily opioid therapy), mild acute pain should initially be managed with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) at appropriate doses. These nonopioid analgesics are commonly administered orally and patients should be cautioned that daily doses not exceed 4 g per day of acetaminophen or 3.2 g per day of ibuprofen. Additionally, patients should be counseled about the risk of liver toxicity with acetaminophen and risk of gastrointestinal side effects with NSAIDs. Given the antipyretic properties of these drugs, additional warning may be necessary for patients concurrently receiving myelosuppressive chemotherapy due to the concern of masking fevers, which may otherwise be one of the only indicators of active infection in a neutropenic host.

	For patients with moderate to severe pain, opioids represent the treatment of choice with drug selection and route of administration dependent on the level of pain intensity. Where possible, every attempt should be made to start opioids orally at the lowest possible dose that results in pain relief. For patients not having been treated previously with opioids, 5 to 10 mg of oral morphine in an immediate-release form is frequently a suitable starting point for moderate pain. In contrast, severe pain requires a more aggressive approach, with parenteral bolus administration of opioids. Here, an IV dose of morphine 2 to 5 mg should be considered for initial therapy.

 Morphine and the other short-acting opioids (hydromorphone, fentanyl, and oxycodone) may be used interchangeably in equianalgesic doses and are preferred in this setting compared with longer-acting opioids (methadone and levorphanol) due to their ease of titration and time to pain relief (Table).

	For cancer patients who are opioid- tolerant and complaining of acute or breakthrough pain, consideration should first be given to dose escalation of the current opioid therapy. If the patient is unable to tolerate an increase in dose, an alternate opioid should be considered. When rotating opioids does become necessary, consideration must be given to the equianalgesic doses of the opioids and the total daily dose of the new drug should be reduced by 30% to 50% to account for incomplete cross-tolerance of opioids. Otherwise, the patient may experience increased transient opioid side effects that could have been avoided if careful consideration had been given to the patient’s opioid tolerance and overall pain management. Addition of an adjuvant analgesic (eg, NSAIDs, antidepressants) to the patient’s pain regimen may also yield enhanced analgesia for specific pain syndromes (eg, bone pain, neuropathic pain), help to manage opioid adverse events, or in some cases allow the dose of opioid to be reduced.

	It should be noted that adequate pain relief and defining the individual patient’s goal for comfort is important. Rather than achieving a pain score of zero, the identified goal may be a pain score of less than 4 or could involve the identification of a patient’s real world goal of returning to an activity or hobby that their current level of pain is preventing them from enjoying. Once this level of pain relief is achieved, it is essential to convert the patient from short-acting opioids to a manageable oral regimen composed of extendedrelease short-acting opioids, extendedrelease fentanyl transdermal patches, or long-acting opioids.

	Regardless of which analgesic medication is chosen to alleviate the patient’s acute or chronic pain, it is important to recognize that pain management is not a “one size fits all” approach to treatment and practitioners should attempt to tailor therapy to the individual patient.

	Additionally, health care providers should consider some recommendations applicable to all cancer patients with pain.

		Multiple studies have reported that practitioners tend to underestimate the level of pain a patient is experiencing while family members tend to overestimate the patient’s level of pain.

 Therefore, the patient’s report of pain intensity is considered the gold standard for pain assessment and should be believed by the health care provider for purposes of initiating therapy.

		Mixed agonist-antagonists (eg, pentazocine, butorphanol, nalbuphine, etc) should not be recommended due to a ceiling effect limiting their efficacy while also potentially reversing analgesia leading to withdrawal symptoms.

		Patients should be reassessed frequently for response to therapy. For patients complaining of severe pain, reassessment should occur every 60 minutes for oral opioids and every 15 minutes following intravenous administration of opioids.

 Practitioners should not fear increasing the opioid dose or hesitate to consider an alternative therapy in patients with unresolved pain.

		Patients should be prescribed an adequate dose of breakthrough pain medication, often with the immediaterelease form of their long-acting opioid. The rescue dosing may be equivalent to 10% to 20% of the total daily dose divided as frequently as each hour as needed. For patients requiring multiple doses of rescue medication, practitioners should consider revising the daily dose of long-acting opioid to reflect the increasing dependency on opioids to ensure patients receive adequate analgesia.

		Patients may benefit from nonpharmacologic treatment of cancer pain to supplement their pain regimen. These interventions may include hot or cold therapy, massage, music therapy, hypnosis, relaxation strategies, etc.

 Through the addition of these nonpharmacologic treatment modalities, it is possible to reduce the patient’s reliance on opioids and ultimately to improve quality of life.

		Practitioners should be aware of and anticipate adverse events associated with opioid therapy.

	As a class, opioids have common and predictable side effects that include constipation, nausea, sedation, respiratory depression, cognitive dulling, etc. With time, patients will become tolerant to all of these adverse events with the exception of constipation. When initiating opioid therapy, practitioners should ensure patients understand and prophylactically manage bowel issues. This can be accomplished with hydration and the addition of bowel regimens containing stool softeners (eg, docusate) and laxatives (eg, sennosides, polyethylene glycol, etc) titrated to ensure patients continue having regular bowel movements.

	Naloxone, an opioid antagonist, can be used to reverse more serious acute adverse events including respiratory depression. If naloxone is administered, patients should be very closely monitored for obvious signs of opioid withdrawal including agitation, anxiety, tachycardia, sweating, hypertension, etc.

	Cancer pain management is a complex and often arduous task. As a result, pharmacists are frequently called upon in cancer centers to manage these patients. Depending on the institution, pharmacists may be expected to provide medication recommendations for initial pain management, addition of adjuvant analgesics, dosage adjustments based upon organ function, conversion of opioids based on equianalgesic dosing, or monitoring of side effects associated with pain management. Overall, the pharmacist’s role in cancer pain management can be integral to the patient receiving adequate pain relief and a return of the patient’s quality of life.

	1. Hewitt D. The management of pain in the oncology patient. 

	2. Zhukovsky D, Gorowski E, Hausdorff J, et al. Unmet analgesic needs in cancer patients. 

	3. Cohen M, Easley M, Ellis C, et al. Cancer pain management and the JCAHO’s pain standards: an institutional challenge. 

	4. Stjernsward J, Colleau S, Ventafridda V. The World Health Organization Cancer Pain and Palliative Care Program: past, present, and future. 

	7. The NCCN Clinical Practice Guidelines in Oncology Adult Cancer Pain (Version 2.2011). 2011 National Comprehensive Cancer Network, Inc. NCCN.org. Accessed February 14, 2012.

	8. Foley K, Abernathy A. Supportive care and quality of life. In: DeVita VT, Hellman S, Rosenberg S, Markoe AM. 

Cancer: Principles and Practice of Oncology. 

8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:2757-2790.

	9. Lussier D, Huskey A, Portenoy R. Adjuvant analgesics in cancer pain management. 

	10. Curtis J, Engelberg R. Measuring success of interventions to improve the quality of end-of-life care in the intensive care unit. 

	11. Puntillo K, Neighbor M, O’Neil N, Nixon R. Accuracy of emergency nurses in assessment of patients’ pain. 

	12. Desbiens N, Mueller-Rizner N. How well do surrogates assess the pain of seriously ill patients? 

	13. Portenoy R, Lesage P. Management of cancer pain. 

	14. Hanks G, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. 

	15. Stoelb B, Molton R, Jensen M, Patterson D. The efficacy of hypnotic analgesia in adults: a review of the literature. 

	16. Huang S, Good M, Zauszniewski J. The effectiveness of music in relieving pain in cancer patients: a randomized controlled trial. 

Steve Stricker, PharmD, MS, BCOP, is assistant professor of pharmacy practice at Samford University’s McWhorter School of Pharmacy in Birmingham, Alabama.

Articles

Clinical Care Focus

Managing Cancer Pain: Therapy Should Be Tailored to Each Patient

	RT is a 44-year-old woman with a history of right lower extremity deep vein thrombosis (DVT) 1 month after surgery for right tibia fracture repair, morbid obesity (weight = 177 kg), and tobacco dependence. She was initiated on warfarin therapy and enoxaparin 170 mg subcutaneously BID for DVT treatment, but could not tolerate warfarin due to extreme malaise. The patient was subsequently transitioned to fondaparinux 10 mg subcutaneously daily as monotherapy and anti-Xa monitoring was recommended by the hematology clinic. The primary care provider ordered an anti-Xa level for 3 to 4 hours post-dose, which resul-ted as 1.04 anti-Xa IU/mL. The clinical pharmacist was consulted to assist with interpretation of the level.

	Fondaparinux is a parenterally administered selective factor Xa inhibitor that is FDA approved for treatment of venous thomboembolism (VTE). Currently, the safety and efficacy of fondaparinux use in patients with morbid obesity is not well established due to the scarcity of literature in this population. The recommended treatment dosage for VTE in patients weighing more than 100 kg is 10 mg subcutaneously daily, but for patients in significant excess of 100 kg, as in this patient’s case, the ability of the 10-mg daily dose to provide adequate anticoagulation is uncertain.

	Fondaparinux use for short-term treatment of DVT in obesity was evaluated in the MATISSE-DVT trial, which was published in the 

 in 2004. In the MATISSE-DVT study, 119 study subjects weighed >100 kg and received fondaparinux 10 mg daily. There was no significant difference in the primary outcomes of VTE or major bleeding in the overall study population, but separate p values for the subgroup of patients >100 kg and the range of patient weights were not reported. Thus, the greatest weight in which fondaparinux 10 mg daily has demonstrated safety and efficacy is unknown.

	Anti-Xa levels can be used to assess low molecular weight heparin’s (LMWH’s) antithrombotic activity in obese patients. However, because fondaparinux is a direct Factor Xa inhibitor and not an LMWH, the LMWH anti-Xa assay that was ordered for this patient cannot be interpreted. A fondaparainux-specific anti-Xa assay would be required instead. The utility of a fondaparinux-specific anti-Xa assay for this patient is also limited by the absence of a definitive correlation between fondaparinux anti-Xa levels and safety and efficacy outcomes. Additionally, fondaparinux doses of greater than 12 mg were associated with increased risk of puncture site bleeding in acute coronary syndrome patients in the PENTUA study, so the utility of fondaparinux monitoring in obesity is limited by the inability to safely recommend higher doses. The pharmacist’s role in this patient’s case was to describe limitations of the current clinical evidence and prevent interpretation of a lab test that was ordered incorrectly.

Dr. Maxwell is clinical assistant professor in the department of clinical pharmacy and outcomes sciences at South Carolina College of Pharmacy in Columbia, South Carolina.

Pharmacist Rounds

Ambulatory Care: Anticoagulation

Neelu P. Patil, PharmD, BCPS               Rochelle Vargas, BS

Best strategies to help the pharmacy department get ready for a survey and stay ready.

	Regulatory compliance is one of the most important aspects of hospital pharmacy, but it can be underappreciated. The hospital system and pharmacy are surrounded by regulations, and it is essential for all members of the pharmacy team to be familiar with these regulations and medication management standards to ensure compliance with all functions associated with medication use. The purpose of these standards is to ensure safe and consistent care of patients. Here are some of the “must know” points regarding hospital pharmacy accreditation—who is involved, what they are looking for, and how you can be prepared.

	The regulatory compliance of a hospital pharmacy is assessed through accreditation. Accreditation means that you are certified as meeting a standard or certain performance level. Currently, there are 3 hospital accreditation organizations in the United States: The Joint Commission (TJC), the American Osteopathic Association’s Healthcare Facilities Accreditation Program (HFAP), and the DNV Healthcare program National Integrated Accreditation for Healthcare Organizations (NIAHO). These organizations have very specific overall standards. When these organizations survey the institution, you must not only meet their standards but also any applicable federal or state regulations. While the goals of the 3 accreditation organizations are similar, each one is a little bit different. Make sure that you know the standards of the organization that you work with.

	What are the benefits of being an accredited hospital? The accrediting agency provides peer-reviewed standards to help the organization identify performance measures. Also, being an accredited hospital shows that there is a commitment to quality and patient safety. Studies have shown that hospitals that adhere to set procedures are able to provide better patient care than those that do not. Another important benefit is the financial implication. Reimbursement is tied to receipt of federal funds for services provided. In order to receive federal payments, an institution must be certified by the Centers for Medicare & Medicaid Services (CMS). The 3 accreditation organizations have “deemed status” in which their standards are at least equivalent to CMS standards.

	Surveyors provide a rigorous evaluation of the hospital’s processes and helpful expert advice on how to improve them. For the hospital pharmacy setting, they are concerned with how the pharmacy functions to provide the best quality of service for the hospital system. Some of the specific items looked at include practices relating to medication management, departmental policies, quality assurance initiatives, and performance improvement data.

	Knowing frequently scored standards in other organizations can help your institution pay special attention to these topics when undergoing preparation efforts. Start early to work with organizational leaders in addressing these before your accreditation visit. For example, a top Joint Commission medication standard scored as noncompliant in 2011 related to medication storage issues and medication security. In this standard, it is required that hospitals store all medications in a secure area to prevent diversion and be locked when necessary. To comply with this, hospitals should ensure that mobile medication carts are stored in a locked room or are under constant surveillance, medications are not lying on counters accessible to the public, and areas that should be locked remain locked.

	Accreditation surveys are undoubtedly challenging to prepare for and can be a major source of consternation for pharmacy staff. Preparing for a survey is now a continuous process in health care organizations. Preparation for a future survey can be time-consuming and resource intensive, but an organized approach is the best way of being prepared. Here are some strategies you can employ to help the department get ready—and stay ready.

	Efforts should begin well in advance of the upcoming survey. One way to start is to perform an overall self-assessment of how both the department and hospital policies and procedures align with each of the accrediting organization’s standards. A detailed action plan can be developed from this information to help identify gaps, resulting in quality assurance initiatives and audit planning. Having started early, you can have time to correct deficiencies and educate staff. It is also important to stay knowledgeable about the standards, interpretations, and standards changes to ensure continuous compliance. An organization is never really finished—it takes due diligence at all times because expectations are always changing.

	Conduct compliance “readiness rounds” with hospital leadership to all pharmacy areas. The purpose of the rounds is to ensure overall compliance and correct non-compliance issues, as well as provide additional staff education. These rounds will allow staff members the opportunity to ask critical questions and obtain valuable responses from leadership. Rounding frequency should increase as the date of the survey approaches. Also, there has been increased interest by accrediting organizations on areas outside of the pharmacy department which are utilizing and preparing medications, such as outpatient ambulatory areas or physician practices. These areas should also be part of the unannounced rounds to ensure compliance with medication standards since the pharmacy department is ultimately responsible for medication use in the organization. Also, educational handouts can be very helpful to increase staff awareness. This could be through the creation of pocket guide resource books on accreditation standards and pharmacy procedures, posting of Joint Commission National Patient Safety Goal fliers throughout the department, departmental policy review and updates, attendance at staff meetings for question and answer sessions, creation of checklists to assist staff in preparing their area for survey, and frequent departmental newsletter updates.

	A variety of approaches should be used for staff education. One example we used at our institution was to place red balloons near fire extinguishers and pull stations to highlight fire safety, as well as perform fire drills. This was well received by staff and it made employees remember what to do in the event of a fire emergency.

	There is a way to prepare so the survey journey becomes a familiar path. The best preparation is to follow your hospital’s policies in everyday work, because they should be based on practices that promote quality of care and patient safety, and meet regulatory standards. Continuous readiness should become a part of departmental culture, and embedding standard compliance into daily operations is the key to a successful survey. With thorough preparation, you can start your next accreditation survey with confidence and be prepared to demonstrate compliance.

Neelu P. Patil, PharmD, BCPS, currently serves as the compliance and policy specialist for the UNC Health Care Pharmacy Department. She earned her bachelor’s from the University of Tennessee in Knoxville and doctor of pharmacy degree from the University of Tennessee Health Science Center. She completed a pharmacy practice residency at the Memphis Veterans Affairs Medical Center.

Rochelle Vargas, BS, earned her bachelor’s of science in business administration from the University of Phoenix. Over her 16-year tenure at UNC Health Care, she has held various positions within the department of pharmacy from Medicaid specialist to billing supervisor to her current role as a quality assurance (QA) specialist for nearly 5 years. As a QA specialist, her responsibilities include hospital and pharmacy compliance with regulatory standards.

Viewpoints

Pharmacy Accreditation 101

	JM is a 46-year-old man with a history of actively abusing cocaine intravenously who presented with methicillin-resistant 

 (MRSA) endocarditis (vegetation on tricuspid valve per TEE). After 7 days of IV vancomycin therapy (with troughs in the 15 to 20 mcg/mL range), JM’s blood cultures remain positive for MRSA, and the microbiology laboratory reports a vancomycin minimum inhibitory concentration (MIC) of 2 mcg/mL. What treatment options are available for this patient?

	Vancomycin has been the mainstay of therapy for MRSA bacteremia and endocarditis. Vancomycin is recommended for the treatment of MRSA endocarditis by both the Infectious Diseases Society of America (IDSA) guidelines for the treatment of MRSA infections and the American Heart Association Infective Endocarditis guidelines.

 The IDSA guideline also recommends daptomycin as an alternative to vancomycin on the basis of a randomized controlled trial where daptomycin was noninferior to low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin in the treatment of 

	The Clinical and Laboratory Standards Institute (CLSI) decreased the vancomycin MIC breakpoint for 

 from ≤4 mcg/mL to ≤2 mcg/mL in 2006. However, data from several studies have noted an association between vancomycin MICs >1 mcg/mL and vancomycin treatment failure.

 The association between higher vancomycin MICs and clinical failures has even been noted in patients with methicillin-susceptible 

 who received treatment with beta-lactam therapy.

 The IDSA MRSA treatment guidelines state that “if the patient has not had a clinical or microbiologic response to vancomycin despite adequate debridement and removal of other foci of infection, an alternative to vancomycin is recommended regardless of MIC.”

 Although there is controversy regarding the utility of vancomycin when the MIC is >1 mcg/mL, in a case such as this one, regardless of MIC an alternative treatment is indicated given JM’s treatment failure evidenced by persistently positive blood cultures.

	There is a scarcity of robust data available to guide treatment choices at this point. Daptomycin is FDA approved for 

 bacteremia and right-sided endocarditis. Other agents that can be used for MRSA when the MIC for vancomycin is >2 mcg/ mL include ceftaroline, linezolid, quinupristin/ dalfopristin, tigecycline, and telavancin; however, none of these agents are FDA approved for these indications, and consideration must be given to the site of infection and patient-specific factors.

	In the case of vancomycin failure, it is important to obtain an MIC for daptomycin before initiating therapy, as daptomycin resistance has been seen in MRSA isolates with elevated vancomycin MICs.

 In this case, the daptomycin MIC was reported as 0.5 mcg/mL, and the patient was successfully treated with a 6-week course of daptomycin. This case highlights the importance of the relationship between pharmacy and the microbiology laboratory to utilize available information such as MIC data to guide treatment choices.

	1. Liu C, Bayer A, Cosgrove S, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant 

	2. Baddour L, Wilson W, Bayer A, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications. 

	3. Fowler VG, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by 

	4. Lodise TP, Graves J, Evans A, et al. Relationship between vancomycin MIC and failure among patients with methicillin-resistant 

	5. Soriano A, Marco F, Martinez JA, et al. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant 

	6. Sakoulas G, Moise-Broder PA, Schentag J, et al. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant 

	7. Holmes N, Turnidge J, Munckhof W, et al. Antibiotic choice may not explain poor outcomes in patients with high vancomycin MIC 

	8. Patel JB, Jevitt LA, Hageman J, McDonald LC, Tenover FC. An association between reduced susceptibility to daptomycin and reduced susceptibility to vancomycin in 

Dr. Heil is infectious diseases clinical pharmacy specialist at the University of Maryland Medical Center in Baltimore, Maryland.

MRSA Endocarditis

	ST is a 54-year-old woman with chronic neck pain related to severe cervical stenosis. Over the past several months, she has undergone unsuccessful trials with various long-acting opioids. Her pain clinic physician is now interested in pursuing a trial of methadone. What information should be ascertained prior to starting methadone? What education can the clinic-based pharmacist provide the patient regarding methadone use?

	Methadone is an opioid agonist indicated for the treatment of moderate-to-severe pain as well as detoxification or maintenance treatment of opioid addiction. It is not uncommon for chronic pain patients to initially have a negative connotation of methadone, as it is often thought of only for its role in opioid addiction. An important aspect of patient education in the setting of pain management is providing reassurance that methadone is indeed indicated for the treatment of chronic pain.

	In addition to the typical adverse effects associated with opioid therapy, including sedation, respiratory depression, and constipation, methadone poses risk of QTc interval prolongation which may result in torsade de pointes. A 2009 guideline, published by an independent physician panel, recommends that all patients being considered for methadone be warned of the potential for arrhythmias and questioned regarding history of structural heart disease, syncope, or arrhythmias. It is recommended to measure the QTc interval by electrocardiogram prior to starting methadone, within 30 days of methadone initiation, and annually thereafter. A QTc interval greater than 500 milliseconds is justification for considering methadone discontinuation, dose decrease, or elimination of factors that predispose to arrhythmias, such as electrolyte abnormalities. A QTc interval of 450 to 500 milliseconds warrants a thorough discussion of the risks and benefits of methadone therapy and more frequent electrocardiogram monitoring. 1 More frequent electrocardiogram monitoring for a QTc interval of 450 to 500 milliseconds was not defined by the guideline; however, a reasonable approach is to monitor every 6 months or following dose increases.

	Patients should be warned regarding the potential for serious drug interactions with methadone, which may increase the risk of respiratory depression or QTc prolongation. Since methadone is a CYP3A4 substrate, CYP3A4 inhibitors may increase plasma methadone concentrations and increase the risk of respiratory depression. Agents that prolong the QTc interval, such as tricyclic antidepressants, levofloxacin, and atypical antipsychotics, may further increase the risk of serious QTc interval prolongation. Patients should notify all health care providers considering new prescription or over-the-counter medications so appropriate evaluation for interactions is performed.

	Because of the variable and long elimination half-life of methadone, patients should be instructed not to exceed their prescribed dose, as significant drug accumulation may cause fatal respiratory depression.

	1. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone treatment. 

Dr. McKnight is a clinical pharmacist at the University of North Carolina Hospitals Pain Management Center in Chapel Hill, North Carolina.

Chronic Pain Management With Methadone

	Ceftaroline (Teflaro), manufactured by Forest Pharmaceuticals, is FDA approved for the treatment of community-acquired pneumonia (CAP) and acute bacterial skin and skin structure infections (ABSSSIs) caused by susceptible isolates of Gram-negative and Gram-positive bacteria, including methicillin-resistant 

(MRSA). Ceftaroline is the first “5th-generation cephalosporin” and has a broader Gram-positive spectrum of activity than all other cephalosporins due to its activity against MRSA.

	Ceftaroline fosamil is a beta-lactam antibiotic and the prodrug of ceftaroline. Similar to all other beta-lactam antibiotics, ceftaroline inhibits bacterial cell wall synthesis through binding to penicillin-binding proteins (PBPs). Ceftaroline’s affinity for PBP2a and PBP2x results in its bactericidal activity against MRSA and 

, respectively. Ceftaroline does not exhibit activity against 

 species and possesses minimal activity against 

. Ceftaroline is also not effective against Gram-negative bacteria that produce extended-spectrum beta-lactamases (ESBLs), including carbapenemases, class B metallo-beta-lactamases, and AmpC cephalosporinases. According to the package insert, ceftaroline possesses in vitro antimicrobial activity (as detailed in Table 1).

	The pharmacokinetics of ceftaroline following single and multiple infusions of 600 mg every 12 hours for 14 days in healthy adults with normal renal function are summarized in Table 2.

 The median volume of distribution of ceftaroline at steady state is 20.3 L or 0.37 L/kg; plasma protein binding of ceftaroline is approximately 20%. Ceftaroline fosamil is rapidly converted in the plasma by phosphatases to the active form, ceftaroline; ceftaroline is not a substrate for CYP450 enzymes.

 Ceftaroline is primarily renally eliminated, with 88% of an administered dose recovered from urine and 6% from feces. The elimination half-life of ceftaroline is 2.6 hours.

	The dose of ceftaroline is 600 mg administered intravenously every 12 hours and infused over 60 minutes in patients ≥18 years of age. The recommended duration of therapy of ceftaroline in ABSSSIs is 5 to 14 days while that for CAP is 5 to 7 days. Although not an approved route of administration, there are data to support administration of ceftaroline via the intramuscular route in patients without IV access. Dosing regimens have not been established for pediatric patients. Dose adjustments of ceftaroline in elderly patients should be based upon renal function.

	Dosage adjustment of ceftaroline is required for patients with a creatinine clearance of <50 mL/ min. Ceftaroline is hemodialyzable; 21.6% of a single 400-mg ceftaroline dose is removed by a 4-hour dialysis session. Ceftaroline should be administered following hemodialysis on dialysis days. Ceftaroline dose adjustments based on renal function are described in Table 3.

	Ceftaroline has been studied in humans for the treatment of CAP and ABSSSIs. There have been 4 Phase 3 studies; 2 studies evaluated the safety and efficacy of ceftaroline versus vancomycin in skin and skin-structure infections (CANVAS 1 and 2), and 2 studies evaluated the safety and efficacy of ceftaroline versus ceftriaxone in community-acquired pneumonia (FOCUS 1 and 2). The studies demonstrated noninferiority of ceftaroline compared with vancomycin in the treatment of acute bacterial skin and skin structure infections (CANVAS) as well as noninferiority when compared with ceftriaxone in the treatment of community-acquired bacterial pneumonia (FOCUS).

	Ceftaroline is well tolerated and has an adverse effect profile similar to that of other cephalosporins. The most common adverse events reported in clinical trials include diarrhea, nausea, and headache; however, ceftaroline has also rarely caused 

—associated diarrhea, direct Coombs test seroconversion, and QTc interval prolongation. Although there are no controlled trials of ceftaroline in pregnant women, the FDA has given ceftaroline a category B designation due to the lack of toxicity seen in animal studies. Compatibility studies of ceftaroline with other drugs are limited; therefore, ceftaroline should not be mixed with or physically added to solutions containing other drugs before reviewing compatibilities.

Product Availability and Cost Considerations

	The prodrug, ceftaroline fosamil, is available as 400- and 600-mg vials of powder for reconstitution. Vials must be kept refrigerated. Each vial must be reconstituted with 20 mL of Sterile Water for Injection, USP, resulting in 20 mg/mL and 30 mg/mL concentrations using the 400- and 600-mg vials, respectively.

 The final ceftaroline solution for infusion should be administered within 6 hours of preparation when stored at room temperature and within 24 hours when refrigerated at 2°C to 8°C (36°F to 46°F).

 The Average Wholesale Price (AWP) of ceftaroline (Teflaro) is $49 per vial (both 400 and 600 mg). Health care professionals can access more information about ceftaroline, including complete prescribing information, at 

	1.       Teflaro [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc; February 2011.

	2.       Ceftaroline (Drug Evaluation). In: DrugDex editorial staff: DRUGDEX System. Thompson Micromedex, Greenwood Village, Colorado.

	3.       Steed M, Rybak M. Ceftaroline: a new cephalosporin with activity against resistant gram-positive pathogens. 

	4.       Saravolatz L, Stein G, Johnson L. Ceftaroline: a novel cephalosporin with activity against methicillin-resistant 

	5.       Laudano J. Ceftaroline fosamil: a new broad-spectrum cephalosporin. 

Ashley N. Lewis, PharmD, BCPS, is a drug information specialist at University of North Carolina Hospitals (UNCH). She completed her pharmacy training at Virginia Commonwealth University and went on to complete a general pharmacy practice residency followed by a drug information specialty residency at the Medical University of South Carolina. She is currently the pharmacy and therapeutics secretary at UNCH, and manages the day-to-day operations of the Drug Information Center and serves as a clinical assistant professor at the UNC Eshelman School of Pharmacy.

Formulary Drug Review

FDA approved for the treatment of community-acquired pneumonia, ceftaroline is the first 5th-generation cephalosporin.

Ceftaroline (Teflaro)

Understanding the drug interactions associated with antiepileptic drugs can avoid complications.

	Epilepsy is one of the most common chronic neurologic disorders, with a prevalence rate between 0.5% and 1% in the Western population.

 It is characterized by recurrent and unprovoked seizures, a consequence of abnormal discharge of neurons in the brain. Seizure types are further subclassified based on both the patient’s symptoms and electroencephalography (EEG) characteristics.

	While other treatment options exist, pharmacotherapy remains the standard of care in patients with epilepsy. Extensive drug therapies are available today due to the high demand, research, and approval of antiepileptic drugs (AEDs) in the last 2 decades.

	AEDs work through a multitude of mechanisms of action. As a result, one can observe a myriad of different responses from different patients. Due to this variety of properties, AEDs must not be assumed to be appropriate for every epilepsy syndrome. Drugs such as valproic acid, lamotrigine, and topiramate are considered 

, and are effective for most seizure types and useful in patients with refractory seizures. 

 antiepileptic drugs such as carbamazepine, phenytoin, and gabapentin treat partial seizures or secondary generalized tonicclonic seizures, but may worsen certain seizure types.

	Most notably, carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, and vigabatrin have been associated with exacerbating absence and myoclonic seizures. For these reasons, AEDs must be carefully selected for each individual patient and specific seizure disorder.

	AED therapy is effective for most patients; however, when to initiate therapy is a complex decision. The First Seizure Trial Group (FIRST) study indicates that waiting to initiate therapy until a second epileptic seizure has occurred has no long-term consequences, particularly with lowrisk patients.

 Regardless of when treatment is initiated, however, therapy with a single agent is the ideal treatment goal. Monotherapy has been shown to achieve seizure control in more than 70% of epileptic patients.

	When patients do not demonstrate satisfactory outcomes on monotherapy, physicians often prescribe additional AEDs. In these cases, polytherapy is employed in an attempt to reduce the number or severity of seizures. Optimal polytherapy involves combining drugs that differ in mechanism. This strategy aims to overlap mechanisms of action and allow for synergistic effects between drugs.

	Unfortunately, polytherapy usually results in improvement for only a minority of patients. Only an additional 10% will respond significantly to 2 medications, and even less will respond to 3.

 Marginal reductions in the number of seizures may increase quality of life. However, these benefits with polytherapy must always be weighed against the pitfalls of multiple medications including additional costs, adverse effects, drug interactions, and complicated regimens that hinder compliance.

	The treatment of status epilepticus is complex, but pharmacists should be aware that newer AEDs with IV formulations, such as levetiracetam and lacosamide, are being studied and may replace older medications, such as phenytoin, for this indication.

	AEDs are notorious for drug—drug interactions due to liver enzyme induction and inhibition, as well as complications in protein binding. Potent CYP450 enzymatic inducers include carbamazepine, phenytoin, and phenobarbital. A potent enzyme inhibitor is valproic acid. Interactions with these drugs can occur with other medications that heavily rely on hepatic metabolism. Concomitant administration of oral contraceptives with the inducers previously mentioned along with lamotrigine, oxcarbazepine, and topiramate may decrease their efficacy. 

 Some of the AEDs are also highly protein-bound, and thus compete with other protein-bound agents for binding sites (Table). This can lead to an unexpected increase in free concentrations of 1 or both drugs.

	While it is common to utilize generic medications in many conditions, this practice is much more controversial in epilepsy. The requirements for generics to prove bioequivalence are stringent; however, many epileptologists believe that even minute disturbances may lead to devastating effects in epileptic patients. This belief is held despite data from a 2002 FDA study showing generics differed on average only 3.5% in bioavailability and a 2010 study noting no association between generics and poorer seizure control. It is thought that even small changes in plasma concentration can result in an increase in dose-dependent adverse reactions or a loss of seizure control. This concept is important because 1 additional seizure can lead to an injury or accident.

	For this reason, the American Academy of Neurology has issued strong statements against generic substitution unless the ordering physician consents.

 It is important for pharmacists to recognize that patients with epilepsy admitted to a hospital may receive either a generic substitution for a brand drug that they’ve been controlled on or a different manufacturer’s generic product— and that these substitutions may result in clinical sequelae.

	Pharmacists are likely to encounter the use of AEDs in patients with both epilepsy and another condition such as stroke, asthma, hypertension, cancer, and mental health disorders.

 Pharmacists must review the use of these drugs with consideration that some may be problematic in certain chronic conditions or changes may be needed following exacerbations of these conditions.

	For patients presenting with cardiovascular disease, the risk of phenytoininduced hypotension and arrhythmias is higher, particularly when using intravenous formulations (IV) of this drug. Additionally, the IV use of phenytoin’s prodrug, fosphenytoin, is contraindicated in patients with severe heart disease and second- or third-degree AV block. Valproic acid appears to be a safer alternative formulation in these instances, as there are fewer concerns of hemodynamic instability, particulary when infused at moderate rates, and it is available in an IV formulation. Levetiracetam is also available through this route, but less data exist for its use in emergent situations.

	Epilepsy patients with varying degrees of renal dysfunction also pose a challenge to practitioners. AEDs that are mainly eliminated hepatically, such as carbamazepine, phenytoin, lamotrigine, and valproic acid, are recommended over medications primarily eliminated through the kidney, such as levetiracetam, gabapentin, and pregabalin. Additionally, if there is concern for nephrolithiasis, topiramate and zonisamide should be avoided. In the case of hemodialysis, each AED is likely to be affected to a different degree, as properties such as protein binding and volume of distribution influence changes in concentrations during this process. For this reason, the pharmacist must be prepared to provide revised dosing regimens to patients undergoing hemodialysis.

	Pharmacists must also be aware of the potential complications of AED therapy in the presence of hepatic dysfunction. Besides decreasing the clearance of medications, hepatic insufficiency may also lead to hypoalbuminemia. This becomes problematic with highly protein-bound drugs such as phenytoin which can become toxic due to an increase in the free fraction of the drug. In severe liver disease, drugs with minimal hepatic metabolism and low protein binding, such as gabapentin, levetiracetam, oxcarbazepine, pregabalin, and topiramate, are more appropriate.

 Valproic acid is usually avoided in the presence of liver injury as it is known to be hepatotoxic.

	Women of child bearing age should be provided counseling on the potential risks associated with antiepileptic drugs before conception, as these drugs may pose harm in the early phases of pregnancy. Due to its high rate of teratogenicity, valproate is avoided in this population. It is recommended to give the lowest effective dose and as few medications as possible to maintain seizure control. Pregnant women taking AEDs should be given information about and enrolled in the Antiepileptic Drug Pregnancy Registry. Additionally, like the general population, women of reproductive age with epilepsy should aim for sufficient intake of folic acid.

	Pharmacists must also be prepared for fluctuations in plasma concentrations of AEDs for pregnant patients. Pregnancy may increase the clearance and decrease concentrations significantly for lamotrigine, phenytoin, and carbamazepine. Concentrations of these drugs should be monitored and dose adjustments made during pregnancy and after delivery.

	Recently, concerns about bone health have risen with the use of AEDs. Although the association and specific mechanism of this risk of antiepileptic drugs is not fully clear, it is suspected that long-term use of some of these drugs may predispose patients to low bone mineral density. Changes in the metabolism of vitamin D is only 1 of the suspected pathways of this irregularity. The older enzyme-inducing drugs are the agents most associated with a risk for mineral bone disease. The consensus on many of the newer medications is not clear. Therefore, pharmacists should counsel all patients on proper bone health including DXA screenings, adequate exercise, smoking cessation, and a sufficient intake of calcium and vitamin D.

	Antiepileptic medications often pose significant clinical dilemmas and complexities. It is crucial that pharmacists understand the drug interactions associated with AEDs to anticipate and avoid complications. Additionally, formulary issues such as generic substitution are magnified in the epileptic population. Counseling patients on pregnancy risks with these drugs as well as proper maintenance of healthy bone density can lead to improved quality of care.

	AEDs have a strong place in therapy in both epilepsy and many other chronic conditions. Pharmacists should be involved in patient care to decrease adverse effects and drug interactions as well as to aid in dose adjustments. This ensures safe and effective drug therapy.

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	2.      Chong DJ, Bazil CW. Update on anticonvulsant drugs. 

	3.      Perucca E, Gram L, Avanzini G, et al. Antiepileptic drugs as a cause of worsening seizures. 

	4.      Musicco M, Beghi E, Solari A, Viani F; First Seizure Trial Group (FIRST Group). Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy. 

	5.      National Institute for Health and Clinical Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. http://guidance.nice.org.uk/CG20. Updated January 11, 2012.

	6.      Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. 

	7.      Brodie MJ, Covanis A, Gil-Nagel A. Antiepileptic drug therapy: does mechanism of action matter? 

	8.      RogersSJ, Cavazos JE. Epilepsy. In: Dipiro JT, Talbert RL, Yee GC, et al. 

Pharmacotherapy: A Pathophysiologic Approach.

 7thed. New York, NY: McGraw-Hill; 2008:930.

	9.      Bialer M, Midha KK. Generic products of antiepileptic drugs: a perspective on bioequivalence and interchangeability. 

	10.  Tellez-Zenteno JF, Matijevic S, Wiebe S. Somatic comorbidity of epilepsy in the general population in Canada. 

	11.  Gimenez JR, Sanchez-Alvarez JC, Canadillas-Hidalgo F, et al. Antiepileptic treatment in patients with epilepsy and other comorbidities. 

	12.  Harden Cl, Pennell PB, Koppel BS. Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III: vitamin K, folic acid, blood levels, and breast-feeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. 

	13.  Noe KH. Seizures: diagnosis and management in the outpatient setting. 

Dr. Smith is a neuropsychiatry pharmacy resident, Ernest Mario School of Pharmacy, Rutgers University.

Chronic Care Focus

Effective Drug Therapy for Epilepsy

	There is an old adage that says if you put "skin in the game," you will be more willing to participate in an activity or take responsibility for an outcome.

	This idiom is commonly ascribed to Warren Buffett, who requires the executives of the companies he manages to have a financial investment in their own organization.

 If you personally have something at stake, you will be more motivated to achieve results. The same is true for airline pilots. If they make an error when flying an aircraft, their outcome will be no different from that of the passengers on that plane. If, however, a surgeon makes a mistake when operating, only the patient suffers the poor outcome.

	In pharmacy, there are many applications for this adage. If a patient receives medications at a reduced cost or for free, will they be less likely to have lower adherence as opposed to those who had to pay a portion of the cost of the medication? Some might argue that if a patient has complete knowledge about their disease state, understanding and recognition about the benefit of drug therapy, and they can comfortably afford it, the “skin in the game” concept should be nullified. This means that whether a patient has paid for their medication or received it for free, adherence should not differ.

	Noncompliance is a major issue in health care today. Studies have shown that patients with chronic disease states are noncompliant half the time and one-third of prescriptions are never filled.

 It is recognized that there are many factors that influence adherence, including cost of medications, patient understanding of their disease state and how medications can improve their health, and daily pill burden.

	Studies have evaluated this concept of whether reduced copays lead to improved adherence. A study tested adherence rates when 1 group received 50% price reductions for brand name copays.

 In patients with diabetes, adherence improved by 7% to 14% in the lower copay group, demonstrating that a reduction in the amount that patients pay out of pocket can be a factor in improving their adherence rate.

	Another study eliminated copays for statin drugs for patients with diabetes or vascular disease and found that adherence to statins improved by 2.8% compared with a control group.

 Interestingly, they also studied a group that was on clopidogrel who received copay reduction (not elimination). This cohort had an increase in adherence of 4%. While this study was not focused on evaluating whether paying a modest amount or none at all is better, it is interesting to note that both were deemed effective.

	This leads to a study released in late 2011 that evaluated patients who had had a prior myocardial infarction.

 They were randomized to either copayments for statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or beta-blockers of $13 to $25 or no copayment at all. The primary outcome was determining whether no copayments would lead to a reduction in the first major vascular event or revascularization (presumably because adherence would improve). Even though adherence improved 4% to 6%, overall costs were no different between the groups and there was no difference in overall outcomes.

	What do these studies mean for health-system pharmacy? They suggest that adherence is impacted by factors other than money and knowledge of disease state. In the most recent study, every enrolled patient had had a cardiovascular event in the previous year. If any patient would have a first-hand understanding about the need to take their medications, these would. When you couple that recent experience with free medications, adherence should soar and patient outcomes should improve. Unfortunately, this was not found.

	Health-system pharmacists interact with patients throughout the course of their event and have a unique opportunity to educate them about the need for medications and the value of adherence. How can we blame the rest of the health care system if we are unwilling to do our part?

	If we had some “skin in the game” as it relates to the outcomes of the patients we serve, we would be more motivated to work with patients to improve their health. The tide is starting to turn and health care is starting to incentivize us more. But there is a lot that can still be done—and we are better positioned than anyone else to take advantage of it. Let’s begin thinking like an airline pilot and start taking these outcomes personally.

	1. Language: Who’s got a skin in the game? International Herald Tribune. Editorials & Commentary. The New York Times website. 

http://www.nytimes.com/2006/09/17/opinion/17iht-edsafire.2839605.html

	2. O’Reilly KB. Tactics to improve drug compliance. American Medical Association website. 

www.ama-assn.org/amednews/2011/10/03/prsa1003.htm

http://content.healthaffairs.org/content/27/1/103.full

	4. Health Affairs. 2010;29(11);1995-2001. 