Chronic pain has been defined by the International Association for the Study of Pain (IASP) as pain that persists beyond the normal tissue healing time of 3 months, and it may be classified into 3 distinct categories: nociceptive, neuropathic, and a mixture of the two.

 Neuropathic pain is somatosensory system disease or damage, which can be caused by a wide variety of nerve-damaging diseases or medications affecting the peripheral or central nervous system.

 There are many FDA-approved and off-label therapies for the treatment of neuropathic pain that provide effectiveness through a variety of mechanisms and differ vastly in their pharmacokinetic and pharmacodynamic profiles.

Definitions and Pathophysiology of Neuropathic Pain

Neuropathic pain has been described as “pain initiated or caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system.”

 Several mechanisms have been identified in the pathogenesis of neuropathic pain, but it is a lesion to afferent pathways that must be present for the syndrome to even develop.

 These lesions may lead to spontaneous ectopic nerve impulse generation within damaged and neighboring nociceptive fibers (C-fibers and Alpha-delta-fibers); upregulation of voltage-gated sodium channels, which contributes to changes in membrane excitability; central sensitization development as a consequence of ectopic activity; or constant release of excitatory amino acids and neuropeptides throughout the peripheral afferent fibers that leads to excitation of several receptors, such as N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic.

These varying mechanisms contribute to the development of several different types of neuropathy and result in diverse signs and symptoms.

 These varying mechanisms can be used to our advantage when selecting monotherapy or rational polypharmacy. Symptoms may manifest in patients as burning, pins and needles, electrical-type pain that radiates from a central locus, paresthesias, numbness, tingling, or hypersensitivity to temperature or touch.

 Potential causes of such neuropathies include, but are not limited to, diabetes, traumatic nerve injuries, autoimmune disorders, genetic disorders, and medications.

 A multitude of treatments, differing vastly in mechanisms, have been identified and proven to provide relief from these kinds of neuropathies.

Antidepressants: Pharmacology in Neuropathic Pain and Differences

The mechanism by which antidepressants relieve neuropathic pain has been identified as their ability to inhibit the reuptake of serotonin and norepinephrine (NE), with the primary mediator being NE.

 There are 2 classes of antidepressants whose pharmacologies involve the aforementioned mechanism: tricyclic antidepressants (TCAs) and selective serotonin-NE reuptake inhibitors (SNRIs).

 Specific serotonin inhibitors lack quality evidence for efficacy to treat neuropathic pain.

Common TCAs used in the treatment of neuropathic pain include amitriptyline, desipramine, doxepin, imipramine, nortriptyline, and trimipramine.

 Despite none having FDA-approved neuropathic pain management indications, this class of agents is among those preferred as first-line treatment by the IASP evidence-based guidelines for pharmacological management of neuropathic pain.

 Their history is quite extensive, and their role in the treatment of neuropathic pain has been highlighted by an assortment of randomized controlled trials.

 A meta-analysis published by Finnerup et al in 2015 found that the number needed to treat for TCAs was 3.6 (95% CI, 03.0-04.4) and the number needed to harm was 13.4 (95% CI, 9.3-24.4).

 A major limitation, however, is associated with the relative “sloppiness” of these medications: their tricyclic structure allows them to bind to and inhibit histaminergic-1, alpha-adrenergic, and muscarinic receptors.

 This haphazard capability of inhibiting numerous receptors can lead to a profusion of adverse effects (AEs) including cardiac conduction abnormalities, orthostatic hypotension, fatigue, dry mouth, constipation, sweating, or dizziness.

 These AEs greatly diminish the use of TCAs, making them poor choices for a vast majority of patient populations.

Although they primarily inhibit the reuptake of serotonin and NE, SNRIs have nontricyclic structures.

 These agents include venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran. The relative selectiveness of these therapies allows them to bind only to serotonin and NE reuptake transporters, while avoiding the other somatosensory receptors.

 This selectiveness remarkably reduces the risk of AEs compared with TCAs; nevertheless, SNRI are still susceptible to their own degree of adverse reactions.

 Common AEs include nausea, vomiting, headache, dry mouth, sweating, and an increased risk of serotonin syndrome and cardiovascular effects, such as hypertension, with minimal influence on cardiac conduction.

The differences within this class of medications lie in the fact that not all are FDA-approved for pain management due to their notable varied pharmacokinetic profiles. Currently, only duloxetine and milnacipran carry this indication; however, duloxetine and venlafaxine are recommended as first-line treatment for neuropathic pain by the IASP.

, the many pharmacokinetic differences exhibited between these agents may play a role in selection. Duloxetine and venlafaxine are almost entirely metabolized through CYP2D6, whereas milnacipran is almost equally eliminated through renal excretion and hepatic metabolism.

82% hepatically metabolized into active (nortriptyline) and inactive metabolites

Weakly inhibits CYP1A2, 2C19, 2C9, and 2E1

Articles

Chronic Care Focus

Chronic pain has been defined by the International Association for the Study of Pain as pain that persists beyond the normal tissue healing time of 3 months, and it may be classified into 3 distinct categories: nociceptive, neuropathic, and a mixture of the two.

Treatment of Neuropathic Pain

DIR FEES: THE LATEST IN A LONG LINE OF SPREAD STRATEGIES 

Pharmacy benefit managers (PBMs) play an important and necessary role within our private health care system. Because there is no central authority to set prices for drugs, PBMs step in to create a marketplace (of sorts) for buyers and sellers. They also provide administrative functions, such as adjudicating claims and writing checks on behalf of payers. PBMs handle billions of transactions a year, ostensibly to generate operating revenue. However, these transactions are largely a commodity. So to supplement that revenue, spread strategies need to be employed. Spread occurs when a portion of the buy—sell difference can be retained by a PBM. This is akin to the house’s take in a casino (except without knowing the percentage “take”). Direct and indirect remuneration (DIR) fees are the latest in a long line of reimbursement strategies that rely on spread and generate margin for PBMs.

TRANSPARENCY IS THE KRYPTONITE OF ANY SPREAD BUSINESS

Squeezing one end of the proverbial margin balloon results in the other end getting bigger. In the case of DIR fees, the federal government wanted a clearer view into the spread and to receive a bigger part of that spread. Thus, the payer side of the balloon got squeezed. As a result, community pharmacies, by and large, ended up rebalancing the air in the balloon on the other side through DIR fees, which are simply a way to package the PBM margin in another way and place the burden of that spread on the pharmacy. The package may include network access fees, performance tiering, and other attributions of apportionment. It can be anything that is assigned to the total dollar amount. This strategy is only possible (politically or otherwise) through lack of transparency in the clawback provisions. Although good at generating profit, lack of transparency is an anathema to properly functioning marketplaces. Remember collateralized debt obligations and the financial crisis? Nobody had any idea what was in those packaged debt vehicles; not the buyers or sellers, just the people who created them.

NO LONGER INSIDE BASEBALL: THE TRANSPARENCY DISCUSSION GOES MAINSTREAM 

Advocating for transparency in pharmacy reimbursement can be challenging since conversation typically comes across as esoteric, with discussions involving highly technical rebate structures and multiple layers of interested parties. There is general lack of fanfare surrounding the issue despite the best efforts of pharmacies, as the average individual finds it difficult to understand or to attach to emotionally. However, several catalyzers are now in play that are rapidly changing that dynamic and widening the aperture of the discussion to include mainstream policymakers and media channels.

CATALYZER #1: DIR FEES WERE BORN OUT OF REGULATION TO CREATE TRANSPARENCY FOR THE FEDERAL GOVERNMENT 

Anytime a program that involves government is implemented, it is ultimately subject to public scrutiny, open forums, and disclosure. Avenues to engage, if you are a patient advocate or a provider advocate, are much more plentiful. DIR fees (and ultimately, spread itself) will likely be the issue that pierces the transparency veil of all mechanisms that create spread because the rules and procedures around government make the discussion hard to hide.

CATALYZER #2: DIR FEES REQUIRE OPACITY TO GENERATE MARGIN 

Spread margin is an animal of opacity. In a transparent environment, margin is generated as a fee (not spread). DIR fees require opacity to exist. The country’s mood is currently not favorable toward the person behind the curtain pulling the strings but not willing to come out and show his cards.

CATALYZER #3: DIR FEES AFFECT THE CONSUMER 

Recent reporting has uncovered ways in which DIR fees may affect consumers and their out-of-pocket spend. That is a significant shift in tact that will broaden the audience of the interested.

CATALYZER #4: PRESIDENT TRUMP’S POPULIST STANCE ON DRUG COSTS 

This one is the kicker. For years, pharmacies and Pharmaceutical Research and Manufacturers of America (PhRMA) have been at odds during budget season because both contribute to the total cost of drugs, fighting between therapeutic interchange and pharmacy reimbursement reductions as competing ways to accommodate drug budget cuts. However, as PhRMA and pharmacies have been squeezed over time, the portion of available margin going to these 2 stakeholders has come more in line per transaction with PBM spread. This has had the effect of bringing otherwise warring parties closer together to spotlight the PBM industry’s role as part of the drug cost driver equation (which is the opposite of its intended market purpose). The fact that a Republican is proposing price controls will shine a $300 billion-watt bulb on how drugs are purchased and reimbursed through the entire value chain.

CATALYZER #5: LEGISLATION (REGARDLESS OF OUTCOMES) 

No proposed or introduced legislation is worth a darn unless it has broad political momentum behind it. Legislators can introduce legislation all session long that gets referred to committee, with no hearings or momentum. However, because of catalyzers 1 through 4 above, House Resolution 1038 and Senate Bill 413, which speak to transparency, now have legs. And even if they never reach a vote, they will no doubt have a much wider audience, and that is a game changer.

TROY TRYGSTAD, PHARMD, PHD, MBA, is vice president of Pharmacy Programs for Community Care of North Carolina, which works collaboratively with more than 1800 medical practices to serve more than 1.6 million Medicaid, Medicare, commercially insured, and uninsured patients. He received his PharmD and MBA degrees from Drake University and a PhD in pharmaceutical outcomes and policy from the University of North Carolina. He also serves on the board of directors for the American Pharmacists Association Foundation.

Editor’s Note

Pharmacy benefit managers (PBMs) play an important and necessary role within our private health care system.

The One that Broke the Camel's Back: DIR Fees Set to Catalyze Transparency Discussion With a Wider Audience

The American Brain Tumor Association reports that American clinicians will diagnose more than 79,000 diverse primary brain tumors in 2017.

 Approximately one-third will be malignant.

The most common primary tumors—originating in the meninges&mdash;account for 37% of cases.

 Meningiomas are usually benign, grow slowly, and rarely recur after removal. Neoplasms that originate from connective tissue are referred to collectively as “gliomas” and represent 25% of total lesions but 75% of malignancies.

 Other brain lesions include primary central nervous system lymphomas, nerve sheath tumors, pituitary tumors, and metastases. This article focuses on malignant tumors that require pharmacotherapy in addition to surgery.

Tumor headaches are most common with posterior fossa tumors and in pediatric patients.

 They are unaffected by time of day, Valsalva maneuvers, or posture changes. When increased intracranial pressure causes pain that resembles tension-type headache, its location may suggest the side involved.

Although headache is the most common presenting symptom for meningiomas, malignant tumors usually start with other symptoms.

 Gliomas typically create generalized symptoms that develop slowly as the tumor grows, although ventricular obstruction or bleeding may cause an acute onset. TABLE 1

 highlights nonspecific symptoms as opposed to symptoms that may indicate progressed or localized disease.

Physical findings alone cannot confirm a brain mass.

 Magnetic resonance imaging (MRI) with contrast is the gold standard for identifying and monitoring lesions2; however, computed tomography (CT) scans are appropriate during preliminary diagnosis, or when MRI is contraindicated (eg, patient has implanted devices or is claustrophobic). Clinicians must consider the patient’s renal status and allergy history before administering contrast media (TABLE 2

The multidisciplinary team—a neurosurgeon, an oncologist, a radiologist, a radiation therapy expert, and a pharmacist&mdash;will consider the tumor origin, location, and comorbid conditions.

 Once a neoplasm is confirmed, corticosteroids address cerebral edema. Dexamethasone’s high potency and low association with salt retention make it the drug of choice.

• 10 mg intravenous as soon as possible

• 4 mg intramuscularly every 6 hours until cerebral edema subsides

Dexamethasone may be discontinued once acute control is achieved, but some patients will require oral maintenance doses every 8 to 12 hours while they start definitive therapy.

Seizures are common in glioma patients, but studies discourage prophylactic use of anti-epileptic drugs (AEDs) in patients lacking seizure histories or in patients undergoing neurosurgery.

 When AEDs are necessary, clinicians should select noninducers (eg, levetiracetam, topiramate, valproic acid) to avoid possible drug interactions with chemotherapy.

Patients may receive surgery, radiation, or chemotherapies. Surgical treatments include biopsy, debulking, or total removal; ventricular shunt placement; or drug-impregnated wafers.

 Targeted radiation therapy (RT) decreases healthy cells’ exposure, but diffuse disease often requires whole brain radiation.

When treating malignant gliomas, cellular origin and level of disease progression dictate treatment. Gliomas are classified as astrocytoma or oligodendroglioma, which are typically low-grade tumors and can become anaplastic when cells lose their normal differentiation.

 Highly vascular and necrotic, glioblastoma is the highest grade malignancy.

 A biopsy confirms diagnosis in low-grade glioma, and surgeons will resect the tumor, if possible, to delay or prevent progression.

 After surgery, patients may receive RT immediately or wait until disease progression. Study results suggest that immediate RT increases time to disease progression with no significant effect on overall survival. TABLE 3

 lists factors that clinicians consider to categorize risk and determine how aggressively to manage the disease.

 Although chemotherapy is not a mainstay for gliomas, low-grade gliomas can behave aggressively in high-risk patients, who will then require adjuvant RT or chemotherapy. ONLINE TABLE 4

 highlights chemotherapy used to treat gliomas.

Chemotherapy usually reserved for high-risk patients or recurrent disease

			Tumors with 1p/19q respond well to preferred agents

Oncology Focus

Brain Neoplasms and Malignancies

Antimicrobial stewardship is a hot topic in pharmacy right now, with more overseeing bodies requiring it lately. The Obama administration first called for the establishment of antimicrobial stewardship programs (ASPs) in all acute care hospitals by 2020 as part of its National Action Plan for Combating Antibiotic-Resistant Bacteria.

 A similar mandate has been in place in all Veterans Affairs’ hospitals since July 2014.

 Currently the CMS mandate is on hold due to the change in presendential administration. The Joint Commission went into effect on January 1, 2017.

It makes sense that institutions enforce the appropriate selection and use of antimicrobials, as the use or misuse of these medications in one individual can directly impact their efficacy in another individual. The same is not true for cholesterol or pain medications.

The CDC and the Infectious Diseases Society of America/ Society for Healthcare Epidemiology of America each has guidelines outlining key principles of ASPs.

 Each set of guidelines advocates for the use of advancing technology to aid in the identification of infection and de-escalation of antimicrobials. Strategies such as computerized clinical decision support at the time of ordering and rapid diagnostic technologies (RDTs) are gaining in literature support for their impact and utility in aiding ASPs. Study results have shown that the time to appropriate antimicrobial selection, duration of antimicrobial therapy, length of stay, and mortality rates can all decrease. However, these are costly endeavors for institutions to implement, often with up-front costs upwards of tens or hundreds of thousands of dollars.

Most of these studies simultaneously implemented RDTs with dedicated ASP intervention. Therefore, it is difficult to accurately assess whether all the benefits seen from implementing RDT are due to the technology itself, the ASP, or a combination of the 2. If you build it, will they come? If the technology itself is available, will the house staff be able to intervene and realize the same touted benefits without the input of a dedicated stewardship team? Several studies have recently reviewed these concepts.

Holtzman and colleagues performed a retrospective review of peptide nucleic acid fluorescence in situ hybridization (PNA FISH) implemented in their institution without any active notification or ASP intervention.

 The PNA FISH was batched, performed on the overnight shift, and updated in computerized microbiology reports by 5 AM. A total of 199 patients (100 pre-PNA FISH and 99 post-PNA FISH) with blood cultures positive for coagulase-negative staphylococci (CoNS) were evaluated. There were no differences in terms of hospital length of stay and vancomycin use. The authors concluded that the implementation of technology alone, without real-time notification and/or ASP support and intervention, may not translate into clinical advantages.

Another study looked at PNA FISH, this time for streptococcal and enterococcal bacteremia, also without ASP involvement. Cosgrove et al prospectively randomized 220 patients growing gram-positive cocci in their blood to either standard microbiologic methods or standard methods plus PNA FISH.

 They did not see differences in time to effective or optimal therapy, length of stay, or in-hospital mortality. They concluded that lack of ASP intervention may reduce the benefits of RDT.

Continuing with the gram-positive organisms, Frye and colleagues retrospectively reviewed their experience with a twice-daily (once daily on weekends) batched polymerase chain reaction (PCR) test to identify 

 and detect methicillin-resistant strains.

 Similar to the previous studies, no change in alerts or computerized decision support was provided. Overall, 126 patients with 

 bacteremia (68 pre-PCR and 58 post-PCR) and 118 patients with CoNS (66 pre-PCR and 52 post-PCR) were evaluated. The time to organism identification significantly decreased post PCR; however, the time to optimal antibiotic therapy did not. These authors also concluded that the implementation of RDT alone is not enough to improve antibiotic use.

Banerjee and colleagues took these notions 1 step further. They performed a prospective, randomized, controlled trial of patients with positive blood cultures in 3 distinct arms: standard blood culture processing methods, rapid multiplex PCR (rmPCR) identification, and rmPCR with real-time ASP intervention (rmPCR/AS).

 For all patients receiving rmPCR, computerized reports contained templated comments guiding treatment, empiric antibiogram-led therapy, and institutional protocols, thus building on the idea that the technology must be coupled with real-time guidance.

The rmPCR detected and immediately identified a number of gram-positive, gram-negative, and 

 organisms. Susceptibility reports were not integrated into the assay, but performed by another system as soon as a culture flagged positive. In the rmPCR/AS group, an ASP pharmacist or physician was paged with positive results on a 24/7 basis; however, active interventions may have been delayed until the morning shift if they were not deemed critical.

A total of 617 patients were included in the study. Overall, patients in both rmPCR groups had a quicker time to organism identification, quicker appropriate up-escalation of therapy (eg, switched from ceftriaxone to cefepime if 

 identified), quicker appropriate de-escalation of therapy (eg, vancomycin to cefazolin if methicillin-susceptible 

 identified), and less treatment of contaminated blood cultures compared with the control groups. In regard to the impact of ASP on the rmPCR implementation, the rmPCR/AS group had more de-escalation of any antimicrobial following Gram stain or PCR identification and a faster time to de-escalation from Gram stain report. There were no differences seen in terms of clinical or microbiologic outcomes among the groups. The authors were able to prove that the availability of the technology combined with templated computerized comments reduced the treatment of contaminates and decreased the use of broad spectrum antimicrobials. However, the addition of ASP enhanced antimicrobial de-escalation.

Last, MacVane and Nolte performed a pre-post quasiexperimental study with 3 groups of patients presenting with bloodstream infections: standard organism identification (control), standard identification plus ASP intervention (AS), and rmPCR plus ASP intervention (BCID). The overall study cohort included 364 patients. The AS and the BCID groups had higher rates of de-escalation compared with the control group. Additionally, the BCID arm had significantly faster organism identification time, shorter time to effective therapy, and faster de-escalation time compared with the other two groups. No differences were seen in mortality, 30-day readmission rates, lengths of stay, or costs.

These study results highlight the importance of a dedicated, knowledgeable team integrated with the implementation of RDT. Employing RDT alone will not result in tangible clinical benefits. A recent survey of infectious diseases (ID)-interested pharmacists

 indicated that most institutions employ some form of RDT, although the type varied greatly from one institution to another. Pharmacists were the most likely healthcare professional to receive alerts of positive RDT results. Familiarity with different types of RDT changed depending on the technology in question. However, pharmacists with ID training (residency, fellowship, or stewardship certificate training) self-reported an increased rate of familiarity with any RDT compared with non-ID-trained pharmacists (P ≤ .05).

Where does this leave us? Technology is a vital component of delivering rapid, cutting-edge medicine to our patients. If institutions are to follow recommendations to implement ASP and utilize RDT, they should optimally employ ID-trained pharmacists. As the need would far exceed the supply, educational programs should focus on the instruction of non- ID—trained pharmacists in the utility of RDT. General clinical pharmacy meetings and on-demand/home study continuing education programs would be a perfect venue for disseminating this information to a wide-reaching audience. Together, the combination of RDT and an antimicrobial stewardship pharmacist can have immediate, positive benefits on the management of bloodstream infections.

MONICA V. MAHONEY, PHARMD, BCPS AQ-ID, graduated from MCPHS-University (Boston) and completed PGY1 and PGY2 specialty training at Tufts Medical Center. She is the Clinical Pharmacy Coordinator in Infectious Diseases at Beth Israel Deaconess Medical Center in Boston, MA.

National Action Plan for Combating Antibiotic-Resistant Bacteria. March 2015. White House website. whitehouse.gov/sites/default/files/docs/national_ action_plan_for_combating_antibotic-resistant_bacteria.pdf. Accessed September 28, 2016.

Department of Veterans Affairs. VHA Directive 1031. Veterans Affairs website. va.gov/vhapublications/ViewPublication.asp?pub_ID=2964. Published January 22, 2014. Accessed September 28, 2016.

Approved: new antimicrobial stewardship standard. Joint Commission website. jointcommission.org/assets/1/6/New_Antimicrobial_Stewardship_ Standard.pdf. Published July 2016. Accessed September 30, 2016.

Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the infectious diseases society of America and the society for healthcare epidemiology of America. 

. 2016;62(10):e51-e77. doi: 10.1093/cid/ciw118.

Holtzman C, Whitney D, Barlam T, Miller NS. Assessment of impact of peptide nucleic acid fluorescence in situ hybridization for rapid identification of coagulase-negative staphylococci in the absence of antimicrobial stewardship intervention. 

. 2011;49(4):1581-1582. doi: 10.1128/ JCM.02461-10.

Cosgrove SE, Li DX, Tamma PD, et al. Use of PNA FISH for blood cultures growing Gram-positive cocci in chains without a concomitant antibiotic stewardship intervention does not improve time to appropriate antibiotic therapy. 

. 2016;86(1):86-92. doi: 10.1016/j.diagmicrobio. 2016.06.016.

Frye AM, Baker CA, Rustvold DL, et al. Clinical impact of a real-time PCR assay for rapid identification of a staphylococcal bacteremia. 

. 2012;50(1):127-133. doi: 10.1128/JCM.06169-11.

Banarjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. 

. 2015;61(7):1071-1080. doi: 10.1093/cid/civ447.

MacVane SH, Nolte FS. Benefits of adding a rapid PCR-based blood culture identification panel to an established antimicrobial stewardship program. 

. 2016;54(10):2455-2463. doi:10.1128/JCM.00996-16.

Mahoney MV, Bland CM, Kuper K, Bookstaver PB. Familiarity and utilization of rapid diagnostic technologies for antimicrobial stewardship. Presented at: 2016 IDWeek; October 26-30, 2016. New Orleans, LA. Abstract 1883.

Viewpoints

Antimicrobial stewardship is a hot topic in pharmacy right now, with more overseeing bodies requiring it lately.

A Perfect Trifecta: The Pharmacist, Antimicrobial Stewardship, and Rapid Diagnostic Technologies

As we emerge from peak flu season, this year’s challenges highlight the importance of vaccination and pharmacists’ contribution. The CDC estimates this season’s flu vaccine reduced the risk of getting sick by about half (48%) for vaccinated individuals.

Although we haven’t had a major flu pandemic in quite some time, the Ebola and Zika outbreaks serve as examples of what can happen when a dangerous pathogen becomes easily transmissible. This is why many epidemiologists are watching out for the next “big one”—on the scale of the 1918 flu pandemic&mdash;that could be brewing right now in a rainforest or a makeshift laboratory. Bill Gates recently sounded an alarm to this effect: “Whether it occurs by a quirk of nature or at the hand of a terrorist, epidemiologists say a fast-moving airborne pathogen could kill more than 30 million people in less than a year,” wrote Gates, who, through his foundation, is well connected with top epidemiologists. “And they say there is a reasonable probability the world will experience such an outbreak in the next 10 to 15 years.”

Are public health agencies and pharmacies as ready as they should be? When it comes to pandemics, we can’t be overprepared. In a 2016 interview, Sonia Shah, author of 

Pandemic: Tracking Contagions from Cholera to Ebola and Beyond

, cited a survey that revealed “the majority of ... pandemic experts of all kinds felt that a pandemic that would sicken a billion people, kill 165 million people, and cost the global economy about $3 trillion would occur sometime in the next 2 generations.”

Advances in biotechnology, vaccines, and drugs appear to be our best defenses, and pharmacists are perfectly positioned to employ them. According to the CDC, 1 in 4 Americans is vaccinated in a pharmacy. Because pharmacists are the most widespread and accessible immunizers, public health agencies should be ready to collaborate with them in a pandemic. Pharmacists could immunize patients efficiently, thereby allowing other health care providers the time to treat sick patients. However, for pharmacies to be fully leveraged, significant planning and coordination is needed, and more work is necessary to ensure pharmacists are incorporated early.

Sam Graitcer, MD, of the CDC Pandemic Influenza Vaccine Task Force, spoke of this collaboration at the 2016 National Adult and Influenza Immunization Summit. In his presentation, “Being Ready for the Next Pandemic: Coordination Between Public Health and Pharmacies for Expanded Access to Pandemic Vaccines,” Graitcer noted how, in 2009, pharmacists, although they provided H1N1 vaccinations, were underutilized because the vaccine was not widely available in pharmacies until after the peak of the disease. During a severe pandemic, beginning widespread vaccination at the peak of disease would have little impact, according to Graitcer. Early and expanded use of pharmacists is critical. 

® will continue to do all it can to help educate and prepare pharmacists with content, such as in last month’s Infectious Disease issue. This month’s Central Nervous System issue features carefully prepared articles on headaches, multiple sclerosis, and epilepsy to help you provide the highest quality of care to your affected patients.

From the Chairman

The Next Pandemic: Ready or Not?

TE is a 67-year-old man presenting to his primary care provider for concerns over forgetfulness and difficulty completing routine tasks. Past medical history includes transient ischemic attack, second-degree atrioventricular (AV) block type 2, Lyme disease (1999), and benign prostate hyperplasia. The physician becomes concerned that TE is exhibiting symptoms of dementia and performs a work-up as follows:

Mini-mental status exam (MMSE) score: 23/30

The physician diagnoses TE with mild Alzheimer’s dementia and wishes to initiate pharmacotherapy to improve his quality of life. She would prescribe an acetylcholinesterase inhibitor (AChEI), but is concerned about TE’s history of second-degree AV block type 2.

Alzheimer’s disease affects an estimated 5.4 million Americans, with nearly 5.2 million of that patient population being age 65 or older.

 It is the most common form of dementia and is typically characterized by progressive memory loss and declining cognitive functioning. There are no medical treatments that significantly alter progression of the disease, but several agents are available to improve cognitive functioning in its different stages.

AChEIs are considered first-line agents for mild to moderate Alzheimer’s disease due to a belief that patients with Alzheimer’s have an impaired acetylcholine synthesis process.

 These medications bind to acetylcholinesterase (AChE) and inactivate the enzyme, thereby increasing the amount of acetylcholine available at the synaptic cleft. This inhibition of AChE affects the acetylcholine not only in the central nervous system but also in peripheral tissue, such as the heart, where it can have an effect on cardiac conduction. Second-generation ChEIs, which include all of the currently available medications, act more selectively to inhibit AChE in the central nervous system and are associated with a lesser incidence of severe cardiovascular events. The most well-known first-generation ChEI is tacrine, which was discontinued in the United States due to concerns over hepatotoxicity.

 reviews the various agents that the FDA has approved for Alzheimer’s disease.

The role of cardiac monitoring in the management of patients on ChEIs was discussed in detail in an article in 

 The authors determined that although syncope occurs with relatively common frequency among patients on ChEIs, the incidence of significant cardiovascular events, such as symptomatic bradycardia and heart block, is rare, and frequent monitoring, such as with an electrocardiography or a Holter monitor, was resource-intensive and not justified.

 However, sick-sinus syndrome, bradycardia, and conduction abnormalities are considered relative contraindications to ChEI treatment due to the increased risk of significant bradycardia, which can lead to syncopal episodes, new onset seizures, and heart failure if untreated. Rowland and colleagues proposed a protocol to assist in managing cardiac patients requiring ChEI treatment, and while each clinic may manage patients differently, the protocol is consistent with the reviewed evidence.

TE would be an appropriate candidate to initiate ChEI pharmacotherapy as long as his current bradycardia is asymptomatic. The provider would want to monitor TE’s pulse after 1 week of therapy and assess for symptomatic improvement of his dementia. Titration should be done carefully after 4 weeks of treatment, noting that the maximum recommended dose for mild Alzheimer’s disease is 10 mg once daily. TE and his family should be aware that any syncopal episodes or suspected seizures are cause for concern and should be reported to his physician. Given his second-degree AV block type 2 history, he has a low threshold for requiring a pacemaker and his cardiologist should be made aware of the new ChEI medication. Pulse checks should be done at baseline, every month while the dose is being titrated, and biannually thereafter. TE would likely benefit from the addition of memantine when his disease progresses to moderate Alzheimer’s disease, but clinical trials currently do not support the use of memantine in mild Alzheimer’s disease and the FDA has not approved it for this indication.

CHRISTOPHER TANSKI, PHARMD, is a clinical staff pharmacist at Pinnacle Health in Harrisburg, Pennsylvania.

Alzheimer’s disease facts and figures. Alzheimer’s Association website. alz.org/mglc/in_my_community_60862.asp. Accessed September 23, 2016.

Winslow BT, Onysko MK, Stob CM, Hazlewood KA. Treatment of Alzheimer disease. 

Drug record: tacrine. LiverTox website. www.livertox.nih.gov/Tacrine.htm. Accessed September 23, 2016.

Rowland JP, Rigby J, Harper AC, Rowland R. Cardiovascular monitoring with acetylcholinesterase inhibitors: a clinical protocol. 

. 2007;13(3):178-184. doi: 10.1192/apt.bp.106.002725.

Aricept [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2015.

Exelon [package insert]. East Hanover, NJ: Novartis; 2013.

Razadyne [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc; 2013.

Namenda [package insert]. St. Louis, MO: Forest Pharmaceuticals Inc; 2005.

Namzaric [package insert]. Irvine, CA: Allergan USA; 2016.

Case Report

Forgetfulness and Cognitive Issues in an Older Man

Multiple myeloma (MM) is a cancer caused by uncontrolled proliferation of plasma cells in the bone marrow. Over the past decade, MM survival time has increased substantially due to the development of novel treatments, such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and autologous stem-cell transplantation (ASCT). Although these advances have increased survival time, most patients die from refractory disease, propagating the need for effective treatments with longer remissions.

In November 2015, the FDA approved 2 monoclonal antibodies (mAbs) for the treatment of MM: daratumumab (Darzalex, Janssen) and elotuzumab (Empliciti, Bristol-Meyers Squibb). In April 2015, recruitment began for a phase 1 clinical trial evaluating the safety and efficacy of atezolizumab (Tecentriq), an anti-programmed death ligand-1 antibody, for use in MM.

Therapeutic Use, Dosing, and Administration

Daratumumab is FDA-approved in patients who have received at least 3 prior lines of chemotherapy or who are refractory to both a PI and an IMiD, whereas elotuzumab is indicated in patients who have received 1 to 3 prior chemotherapies. Both mAbs are dosed according to body weight and administered by intravenous infusion once weekly initially, with subsequent reduced frequency. For the first 8 weeks, daratumumab 16 mg/kg IV is administered weekly; after this time, dosage switches to every 2 weeks for the next 16 weeks and then every 4 weeks until disease progression.

In combination with lenalidomide and dexamethasone, elotuzumab 10 mg/kg IV is administered weekly for the first 2 cycles (28 days each), then every 2 weeks thereafter until disease progression. Due to the high risk for infusion reactions, patients should receive an IV corticosteroid, acetaminophen, and an oral antihistamine prior to therapy. If a reaction of grade 2 or greater occurs, the infusion should be interrupted and symptoms managed appropriately.

Hematopoietic cells, including MM cells, express CD38, a glycoprotein involved in cellular adhesion and signaling. Daratumumab is a humanized recombinant immunoglobulin G1 kappa (IgG1k) mAb that targets CD38 cells and inhibits the growth of tumor cells that express CD38 by inducing apoptosis. Hematopoietic cells also express high levels of a surface receptor known as SLAMF7, or CD319. As a human IgG1k immunostimulatory mAb, elotuzumab tags the SLAMF7 receptor on MM cells and activates natural killer cells to destroy the MM cells.

Daratumumab monotherapy in patients with treatment-refractory MM (SIRIUS) was an open-label, multicenter, phase 2 trial that evaluated the use of daratumumab 16 mg/kg in heavily pretreated patients with MM (n = 106). Patients 18 years or older were enrolled if they had received at least 3 prior lines of treatment with evidence of disease progression or had disease refractory to both a PI and an IMiD. Patients were excluded if they received anti-MM treatment within 2 weeks or ASCT within 12 weeks of day 1 of therapy. The primary endpoint was overall response rate (ORR [partial response (PR) + very good PR + complete response (CR) + stringent CR]). Progression-free survival (PFS) was included as a secondary endpoint. Notably, 87% of patients had received more than 3 previous lines of therapy (median = 5) and 95% were considered double refractory to a PI and an IMiD. An ORR of 29.2% was observed (95% CI, 20.8%-38.9%), and the median PFS was 3.7 months (95% CI, 2.8-4.6 months). No patients discontinued treatment due to drug-related adverse events (AEs).

Elotuzumab Therapy for Relapsed or Refreactory MM (ELOQUENT-2) is an open-label, multicenter, randomized phase 3 trial evaluating the efficacy of elotuzumab in patients with MM. The trial is ongoing and will continue until 427 deaths, the predetermined overall survival end point. It includes patients 18 years or older who have failed 1 to 3 prior treatments with documented disease progression (median = 2) and who are receiving lenalidomide and dexamethasone with elotuzumab (n = 321) or without elotuzumab (control group; n = 325). Co-primary endpoints include PFS and ORR (PR or better). At the time of interim analysis, 35% of the elotuzumab group and 20% of the control group were still receiving study treatment.

The 1-year and 2-year rates of PFS in the elotuzumab group were 68% (95% CI, 63%-73%) and 41% (95% CI, 35%-47%), respectively, compared with 57% (95% CI 51%-62%) and 27% (95% CI, 22%-33%) in the control group. The median PFS was 19.4 months (95% CI 16.6-22.2 months) in the elotuzumab group versus 14.9 months (95% CI, 12.1-17.2 months) in the control group (HR, 0.7; 

 <.001). The ORR was 79% in the elotuzumab group and 66% in the control group (OR, 1.9; 

 <.001). Notably, 65% of the elotuzumab group and 57% of the control group reported serious AEs.

Clinical trials evaluating the safety and efficacy of these mAbs in combination with other anti-MM agents are ongoing.

Although well tolerated in clinical trials, daratumumab and elotuzumab are associated with a few notable adverse reactions: infusion-related reactions (48% and 10%, respectively), fatigue (39% and 62%), pyrexia (21% and 20%), cough (21% and 34%), diarrhea (16% and 47%), constipation (15% and 36%), and upper respiratory tract infections (20% and 23%).

Daratumumab and elotuzumab have not been found to induce or inhibit any transporters or enzymes, so drug interactions are not expected.

Based on similar naming, daratumumab may be confused with denosumab or dinutuximab. Elotuzumab may be confused with daratumumab, eculizumab, or evolocumab.

Monoclonal antibodies may be a viable option for patients with refractory MM. Unfortunately, these agents have not been directly compared in clinical trials. Daratumumab may be used as monotherapy, and elotuzumab may be used in combination with lenalidomide and dexamethasone. Although effective, mAbs are expensive: the average wholesale prices are $540.00 for daratumumab 100 mg/5 mL, $2160.00 for daratumumab 400 mg/20 mL, $2131.20 for elotuzumab 300 mg/vial, and $2841.60 for elotuzumab 400 mg/vial. Future studies evaluating the use of these agents in varying combinations with other anti-MM agents may expand their current place in therapy.

, is an assistant professor of clinical education at UNC Eshelman School of Pharmacy.

 is a PharmD candidate at UNC Eshelman School of Pharmacy.

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Formulary Drug Review

Multiple myeloma (MM) is a cancer caused by uncontrolled proliferation of plasma cells in the bone marrow.

March 2017