Pharmacy and wellness review vol 6 iss 3 summer 2015 rev date 8 17 2015 by ONU Communications & Marketing

Volume 6, Issue 3 Summer 2015

ISSN 2168-7382

Current Trials and Therapies for the Treatment of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia CE Included

Adam Smith, fifth-year pharmacy student from Dublin, Ohio; Angela Chu, fourth-year pharmacy student from Shawnee, Kan.; Lucy Wagala, fourth-year pharmacy student from Glenview, Ill.; Hannah Stewart, fifth-year pharmacy student from Brazil, Ind.; Lindsey Peters, PharmD, visiting assistant professor of pharmacy practice 10

The Effects of Long-Term Benzodiazepine Use and Withdrawal in the Elderly CE Included

Lydia Suchecki, fifth-year pharmacy student from Beavercreek, Ohio; Hannah Granger, fourth-year pharmacy student from Sardinia, Ohio; Jamie Kellner, fifth-year pharmacy student from New Waterford, Ohio; Mary Ellen Hethcox, BSPh, PharmD, director of drug information services, assistant professor of pharmacy practice 19

Pain Management in Dementia Patients in Nursing Homes

Tiffany Kneuss, fifth-year pharmacy student from Dennison, Ohio; Kelsey Weisenburger, fifth-year pharmacy student from Perrysburg, Ohio; Hannah Stewart, fifth-year pharmacy student from Brazil, Ind.; Kelly Reilly Kroustos, PharmD, CGP, CDP, associate professor of pharmacy practice

Combating Antibiotic Resistance in the 21st Century

Kevin Krivanek, fifth-year pharmacy student from Brecksville, Ohio; Brian Heilbronner, fourth-year pharmacy student from Lorton, Va.; Brendan Rasor, fourth-year pharmacy student from Kettering, Ohio; Kelsey Lindsley, fifth-year pharmacy student from Port Clinton, Ohio; Andrew Roecker, PharmD ’00, BCPS, chair of the department of pharmacy practice, professor of pharmacy practice

Editorial Board:

Editor-in-Chief Brooke Marlowe Managing Editor Joy Hoffman Emily Limberg Lead Editors Jamie Kellner Kelsey Lindsley Kimberly Loughlin Rachel Muhlenkamp Hannah Stewart Formatting Editor Katherine Liu Website Editor Kayti Kinter Faculty Advisors: Mary Ellen Hethcox, BSPh, PharmD Karen L. Kier, BSPh ’82, Ph.D., BCPS, BCACP Natalie DiPietro Mager, PharmD ’01, MPH Layout Darlene Bowers

What is the SmartPill®?

Christina Ciccone, fourth-year pharmacy student from Pickerington, Ohio; Pul Lee, fourth-year pharmacy student from Seoul, South Korea; Kimberly Loughlin, fifth-year pharmacy student from Mishawaka, Ind.; David Koh, PharmD, assistant professor of pharmacology

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Current Trials and Therapies for the Treatment of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Adam Smith, fifth-year pharmacy student from Dublin, Ohio; Angela Chu, fourth-year pharmacy student from Shawnee, Kan.; Lucy Wagala, fourth-year pharmacy student from Glenview, Ill.; Hannah Stewart, fifth-year pharmacy student from Brazil, Ind.; Lindsey Peters, PharmD, visiting assistant professor of pharmacy practice This knowledge-based activity is targeted for all pharmacists and is acceptable for 1.0 hour (0.1 CEU) of continuing education credit. This course requires completion of the program evaluation and at least a 70 percent grade on the program assessment questions.

ACPE Universal Activity Number (UAN): 0048-0000-15-207-H01-P Objectives After completion of this program, the reader should be able to: 1. Identify the symptoms of ALS and FTD. 2. Classify FTD subtypes based on patient presentation. 3. Recognize the most prominent gene mutations in ALS and FTD. 4. Describe various targets of ASO therapy. 5. List common and serious adverse effects of ISIS 333611. 6. Define the role of the pharmacist in the management of ALS and FTD. Abstract An area of health care that provides many more questions than answers includes neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, and frontotemporal dementia (FTD) are both diseases about which we know very little. However, ALS and FTD affect nearly 30,000 and 60,000 Americans respectively. Currently, there is not a cure for ALS or FTD and treatment options are aimed toward symptom management. Much of the pathophysiology of these diseases is unknown, but we do know there are genetic implications, specifically in SOD1, TARDBP and c9ORF72. These mutations lead to cognitive deficits, muscle weakness and, eventually, paralysis. The only U.S. Food and Drug Administration (FDA) approved treatment for ALS is riluzole (Rilutek®) which helps to slow the disease progression but still lacks a curative effect. An area of interest in the treatment of ALS and FTD is antisense oligonucleotide (ASO) therapy. Current trials examining ASOs as targets for SOD1 and c9ORF72 have shown promise. With these therapies still in preliminary trials, care for these patients is largely palliative. Pharmacists, as part of a multidisciplinary team, can play an integral role in the management of disease sequelae to improve the patient’s quality of life. Key Terms Amyotrophic Lateral Sclerosis; Antisense Oligonucleotides; Frontotemporal Dementia; Riluzole

Introduction Understanding neurodegenerative disorders, their prevalence and their current treatment options is critical for health care professionals. Most underlying pathologies of these disorders remain unknown. Therefore, these conditions often have high mortality rates. Amyotrophic lateral sclerosis (ALS) is one such disease that affects the motor neurons in the brain and spinal cord, leading to muscle weakness, atrophy and, eventually, paralysis in patients.1 Frontotemporal dementia (FTD) describes a group of neurodegenerative diseases sharing physical manifestations in the loss of cerebral tissue in the frontal and temporal lobes. Frontotemporal dementia is classified into three major groups depending on patient presentation including behavioral, aphasic or motor disorder.2 Amyotrophic lateral sclerosis affects about 30,000 Americans, primarily between 40 and 70 years of age, with approximately 5,600 new diagnoses each year.3 Frontotemporal dementia associated disorders affect about 60,000 Americans, primarily men between 50 and 60 years of age, and comprise an average of 15 percent of all dementia cases.4,5 Both disorders, ALS and FTD, may be inherited together.6 Neither ALS nor FTD have cures, and treatment options are limited. Current treatment options focus on slowing disease progression and improving the patient’s quality of life, rather than curing the disease. Recent research has revealed that familial ALS, which accounts for roughly 10 percent of all ALS cases,3 and familial FTD have genetic mutations on the same chromosome. These findings suggest that antisense oligonucleotide (ASO) therapy may be a realistic treatment option by targeting these genetic markers. Still, further research in neurodegenerative disorders is necessary in order to find a cure for these devastating diseases.

Disease Background Amyotrophic Lateral Sclerosis (ALS) Neither ALS nor FTD have defined diagnostic tests and the clinical presentation may be similar between the two. Amyotrophic lateral sclerosis symptoms usually do not show until later stages in life and may include muscle weakness in the arms and legs, twitching, slurred speech and difficulty chewing, swallowing or breathing.1,3 Amyotrophic lateral sclerosis is a diagnosis of exclusion, but may be supported by abnormal electromyography and nerve conduction study results. Sensory nerve conduction is still intact in ALS patients, so nerve conduction studies will yield normal results. However, electromyography of muscles associated with the cervical, thoracic and lumbar nerve regions will be abnormal because of chronic denervation from ALS. These results will show

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Current Trials and Therapies for the Treatment of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

repeating, multispiked electrographs common to all muscular atrophy diseases.7 Magnetic resonance imaging (MRI) is not very helpful in these patients because results are often normal, however MRI can aid in the exclusion of other cerebral diseases.1 The only FDA approved drug for treating ALS is riluzole (Rilutek®) dosed 50 mg twice daily. Riluzole inhibits the release of glutamate and inactivates voltage gated sodium channels.8 In a double-blind, placebo-controlled trial of riluzole, ALS patients receiving riluzole had better survival and safety outcomes with decreased muscle deterioration compared to placebo. Of 155 patients (77 treated with riluzole and 78 treated with placebo), 74 percent of riluzole patients were still living at 12 months compared to only 58 percent of placebo patients. Muscle deterioration, measured by muscle strength tests, was also statistically significantly lower in riluzole patients with a 33.4 percent decline in muscle deterioration rate versus a 22.9 percent decline with placebo. The most common side effects reported with riluzole were asthenia, spasticity, nausea and mild alanine transaminase (ALT) increase, but these effects are common to the

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ALS patient population in general.9 Riluzole is the only medication that slows ALS progression. Other medications prescribed only ease symptoms and do not stop or slow the disease progression. Nonpharmacologic treatment options include physical, occupational and speech therapy for motor skill rehabilitation and nutritional support for hypoproteinemia. Mechanical ventilation can also be used for patients with decreased respiratory function due to weakened respiratory muscles and has been shown to improve patients’ quality of life and prolong survival.1,10 Frontotemporal dementia (FTD) Frontotemporal dementia is divided into three major classes with further subclasses based on clinical presentation, as shown in Table 1.5,11 Like ALS, FTD has no definitive diagnostic test and is also a diagnosis of exclusion. Frontotemporal dementia often is confused with Alzheimer’s disease because of similar symptoms and brain region effects. Testing is done to distinguish between the two disease states. An MRI may reveal frontal and temporal lobe atrophy in late stage FTD while positron emission tomography and single photon emission computed tomography scans can measure decreased

Table 1. Frontotemporal Dementia Subclasses.5,11 Class

Major Effect

Symptoms

Behavioral Variant FTD (bvFTD)

Demeanor

· · · ·

Primary Progressive Aphasia (PPA)

Speech and language

See subclass

Nonfluent Variant

Speech

· · · ·

Semantic Variant

Recognition and understanding

· Difficulty recalling familiar words · Inability to understand familiar words · Difficulty recognizing objects and people

Recall

· · · · ·

Movement and cognition

See subclass

Movement with some cognition

· · · ·

Bradykinesia, rigidity and tremor Limb dystonia Visual-space impairment Inability to control hand or arm movement

Movement

· · · ·

Gait problem and loss of balance Facial and upper body muscle stiffness Shifting eye movements Prolonged laughter or crying

Logopenic Variant

FTD Movement Disorder Corticobasal Degeneration (CBD)

Progressive Supranuclear Palsy (PSP)

Lack of empathy Inability to emotionally adapt to social cues Abrupt mood changes Hyperactivity and impulsive behavior

Hesitant speech Difficulty speaking Progressive reading and writing decline Difficulty swallowing and late stage muteness

Slow recall of words Short term memory loss Inability to understand long phrases Progressive reading and writing decline Difficulty swallowing and late stage muteness

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Current Trials and Therapies for the Treatment of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

brain activity. Unlike Alzheimer’s, FTD does not cause significant memory decline but is associated with significant motor dysfunction. A neurological exam can confirm symptoms of FTD and categorize the specific subtype.2 Unlike ALS, there are no FDA approved medications to treat any form of FTD, but symptomatic management is similiar.5 Pathophysiology Despite the rise in awareness of ALS due to the social media “ice bucket challenge,” there is still much to learn about ALS and FTD. We do know that ALS is a neurodegenerative disease that has both genetic and environmental factors that influence diagnosis and prognosis of the disease.12 The area of ALS that is most well-studied is genetically-oriented ALS. The most prevalent genes implicated in the diagnosis of ALS include: Cu/Zn superoxide dismutase-1 (SOD1), transactive response DNA-binding protein of 43kD (TARDBP), fused in sarcoma (FUS), c9ORF72 genes and (vesicle-associated membrane protein)-associated type B (VAPB). The c9ORF72 gene has been identified as the most common genetic cause of ALS. There are other genes that may implicate ALS but have not been proven. The genes that have implications in both ALS and FTD are c9ORF72 and TARDBP. It should also be noted that one or many of these gene-mutations can cause ALS. Regardless of the mutations similar pathophysiologic effects are observed. Each mutation leads to motor neuron death; however they do so via different mechanisms.

Superoxide dismutase-1, located on chromosome 21, was the first gene identified with mutations. Superoxide dismutase-1 functions as an enzyme commonly found in the body that breaks down toxins and free radicals.12 These toxins and free radicals can damage neurons that play a role in muscle movement. Inappropriate regulation of glutamate can exacerbate neuronal damage caused by SOD1 mutations. These defects can cause a breakdown of lower motor neurons at a young age. Due to the prevalence of the SOD1 mutation, it is a target of interest in ASO treatment in clinical trials. Another gene of interest is c9ORF72 which codes for a protein localized in the brain.12 Its exact mechanism is unknown, but a mutation in the gene causes interruption of RNA machinery. This gene mutation can contribute to the classic ALS pathology of muscle wasting but can also lead to degeneration in the brain leading to changes in mental status. Amyotrophic lateral sclerosis and FTD are commonly diagnosed together in patients due to the dual pathology of this mutation. Regardless of which gene mutations are present in ALS patients, the symptomatology always presents similarly. Mutations lead to motor neuronal death whether it be through oxidative stress, misfolded protein accumulation, mitochondrial abnormalities or neuronal excitotoxicity.18 The excess of glutamic acid produced and released in ALS patients leads to excitotoxicity, causing neuronal death. Riluzole (Rilutek®)

Table 2. Genes Involved in the Development of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. 13-17 Disease Implications

Gene

Mechanism of Action

Pathophysiologic Effect of Mutation

Cu/Zn superoxide dismutase (SOD1)

Binding of toxins and free radicals to prevent harm to nerve cells

Oxidative stress leading to motor neuron death

ALS

Transactive response DNAbinding protein of 43kD (TARDBP)

Binds to RNA

Interruption of RNA machinery leading to motor neuron death

ALS and FTD

Fused in sarcoma (FUS)

Unknown

Interruption of RNA machinery leading to motor neuron death

ALS and FTD

c9ORF72

Unknown

Interruption of RNA machinery leading to motor neuron death

ALS and FTD

VAMP-associated type B (VAPB)

Recognizes and regulates unfolded protein buildup in the endoplasmic reticulum

Affects endosomal vesicle trafficking leading to motor neuron death

ALS

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is proposed to inhibit glutamate and, therefore, to exert a beneficial effect in ALS patients. Antisense oligonucleotide therapy is targeted at preventing the protein translation of specific mRNA strands by binding to them, which is another target in ALS therapy. Treatment/Trials/Research Oligonucleotides are relatively short unmodified or chemically modified single-stranded DNA thought to hybridize into unique sequences that are each targets in cells.19 Various types of oligonucleotides have been classified based on their chemistry (e.g., methylphosphonates, phosphorothioates). Theoretically, oligonucleotides were designed to specifically modulate the transfer of genetic information to proteins. The mechanism by which they produce their effect is subtle and complex. Some mechanisms have been defined, but there is still insufficient proof for other mechanisms known to exist. Despite limited knowledge on the mechanism of oligonucleotides, two classes of ASOs have been determined and include RNase H (an enzyme that hydrolyzes the RNA strands of RNA and DNA hybrid helices) dependent oligonucleotides, which induce degradation of messenger RNA, and steric-blocker oligonucleotides, which inhibit the progression of RNA splicing or translation. Antisense oligonucleotides must penetrate targeted cells in order to downregulate gene expression. Uptake by cells is believed to occur by adsorptive endocytosis and fluid phase pinocytosis. The relatively low cost, possibility of sound design and simple concept of oligonucleotides, along with developments in human genome sequencing, have led to the use of oligonucleotides as therapeutic tools and as subjects of various clinical trials and therapeutic studies. Studies using ASOs as treatments for ALS have been conducted to target various mutations that may contribute to ALS. One study found potentially dangerous upregulations of GluR3, an a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit in SOD1G93A (a SOD1 subtype gene) transgenic mouse model of familial ALS. 20 An antisense peptide nucleic acid against GluR3 was created and injected into SOD1 G93A mice, producing significant delay in onset of locomotor impairment. Another study focused on the use of antisense short singlestranded oligonucleotides that were designed to selectively reduce the accumulation of specific portions of the c9ORF72 gene, the most common genetic cause of ALS.21 The accumulation of c9ORF72 in peripheral, neuronal and glial cells contributes to the development of ALS. In this study, ASOs were demonstrated to be an effective and tolerable therapy by selectively reducing the accumulation of expanded c9ORF72 RNA foci without affecting the overall amount of c9ORF72 encoding mRNAs. Both of these studies have contributed to the continuously increasing number of in vitro ASO experiments that allow for characterization of new targets and potential therapeutic agents, such as ISIS 333611.19 ISIS 333611 is an ASO designed in the first-in-human study on the use of antisense oligonucleotides as an ALS therapy. 22 The objective of the study conducted by Miller and colleagues was to assess the safety, tolerability and pharmacoki-

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netics of ISIS 333611. ISIS 333611 was designed to inhibit SOD1 expression through intrathecal administration in patients with familial ALS related to human SOD1. In this randomized, placebo controlled phase 1 trial, 21 patients were administered ISIS 333611 over 11.5 hours. Four cohorts, each with eight SOD1 positive ALS subjects, were given increasing doses of ISIS 333611 (0.15mg, 0.5 mg, 1.5 mg or 3 mg). Subjects within each cohort were randomized (six drug and two placebo). Additionally, participants were allowed to re-enroll in subsequent cohorts; therefore, seven patients enrolled two times and two patients enrolled three times. All dosed participants completed the study and had a variety of SOD1 mutations. Patients varied in age, disease onset and time since diagnosis. Safety was assessed by adverse event collections, physical and neurological examinations, vital signs, clinical laboratory tests, electrocardiograms, ALS functional rating scale-revised assessments, forced vital capacity and recording of use of accompanying medications. When SOD1 protein concentrations were measured in the cervical and lumbar spinal cord of trial subjects and nontrial subjects, there were no significant differences between the two groups.22 No significant changes in cerebral spinal fluid (CSF) SOD1 concentrations were found in re-enrolled participants dosed in more than one cohort. As predicted by Miller and colleagues, the single doses given in the study did not provide drug levels that would be high enough to reduce CSF SOD1 concentration; however, because CSF SOD1 levels were found in all participants and those who re-enrolled, they concluded that CSF SOD1 protein concentration could be a pharmacodynamic biomarker for ISIS 333611 for future studies. Of the participants, 84 percent reported adverse events; however, the most commonly reported adverse events, post lumbar puncture syndrome and back pain, were considered to be associated with the intrathecal infusion procedure and not the drug.22 There was no difference in frequency between drug and placebo treated groups, and the number of adverse events did not increase as the dose of ISIS 333611 increased. There were two severe side effects (lacunar infarction and pneumonia) that were reported and required hospitalization; however, these were seen in the same placebo treated patient. Re-enrollment did not increase the type and frequency of reported adverse events. Adverse events were found to decrease with re-enrollment. No dose limiting toxicities were identified at doses up to 3.0 mg. Dose-dependent CSF and plasma concentrations were observed when ISIS 333611 levels were measured in the plasma at 13 time points from preinfusion to 12 hours postinfusion and in CSF preinfusion and right after postinfusion. This trial demonstrates that ASOs may be promising agents for ALS.22 Although ASOs directed against the SOD1 mutation may be successful, human studies on other ASO targets, such as specific portions of c9ORF72 RNA, may also show the same promising results for potential ALS treatments.20-22 Also, safety and tolerability assessments for any ASO would need to be tested in future studies to make sure treatments do not produce significant neurological and behavioral deficits in humans. In addition to safety, succeeding phase trials

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Current Trials and Therapies for the Treatment of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Table 3. ALS Sequelae Management.12 Medication

Role in Management

Riluzole

ALS

Amitriptyline, Selective serotonin reuptake inhibitors (SSRIs), mirtazapine, buspirone, diazepam, lorazepam

Anxiety

Diazepam, phenytoin, vitamin E

Cramps

Mirtazapine, SSRIs, tricyclic antidepressants (TCAs), venlafaxine

Depression

Amantadine, bupropion SR, fluoxetine, pyridostigmine, venlafaxine

Fatigue

Amitriptyline, atropine, diphenhydramine, hyoscyamine, scopolamine

Sialorrhea

Baclofen, benzodiazepines, dantrolene, tizanidine

Spasticity

Dextromethorphan/quinidine

Pseudobulbar affect

Amitriptyline, oxybutynin, tolterodine

Urinary urgency

Adapted from: Gordon PH. Amyotrophic Lateral Sclerosis: An Update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Goals. Aging and Disease. 2013 Nov; 4(5): 295-310. Available from: www.ncbi.nlm.nih.gov/pmc/articles/PMC3794725/pdf/ ad-04-05-295.pdf

on ASOs directed against SOD1 would need to focus on the efficacy of ISIS 333611, perhaps by using the biomarker SOD1 protein concentration as concluded by Miller et al.22

Role of a Pharmacist With ALS and FTD currently lacking a cure, the management of these diseases is largely palliative. The only FDA approved medication is riluzole (Rilutek®) which has been shown to slow disease progression in ALS patients.8 Pharmacists must collaborate in the management and coordination of these patients’ medications. With many of these patients experiencing sequelae such as anxiety, cramps, depression, fatigue, sialorrhea, spasticity and urinary urgency, pharmacists are essential to manage the pharmacologic therapy associated with each sequela. Another role that the pharmacist may play is in managing the adverse effects from riluzole and the effects of the disease, which in certain instances can be additive. For example, both riluzole and benzodiazepines used for anxiety can cause respiratory depression, and ALS patients can suffer from respiratory failure due to disease progression. Since ALS patients may also have altered pharmacokinetics, dosing must be managed very closely. Medication adherence is important for ALS patients because symptom management greatly influences quality of life in these patients. With many ALS multidisciplinary teams lacking pharmacists, it is vital that pharmacists engage in the management of these patients whose well-being depends greatly on pharmacologic management of sequelae. Eventually, if ASOs are found to be successful agents for ALS, it may become the responsibility of the pharmacist to be able to identify which mutations patients have and which treatments would be best for them.

Conclusion Amyotrophic lateral sclerosis and FTD are diseases that are becoming more prevalent, and there is an increasing awareness of these devastating diseases within the United States due to efforts such as social media’s “ice bucket challenge.” These diseases are debilitating and lead to a drastically decreased quality of life and a much shorter life expectancy. Currently, there are various theories as to what causes the diseases, but there is still not enough evidence to find a cure. With the only FDA approved medication being riluzole (Rilutek®), palliative care and sequelae management by health care providers are central to the care of a patient with a neurodegenerative disease. As depicted in Table 3, pharmacists have a variety of roles in the management of patients with these diseases, with the most important being proper and safe management of the sequelae associated with the pathology of ALS and FTD. Titrating doses, properly treating sequelae and managing drug interactions can not only help increase the patients’ quality of life but also lengthen their lifespan. Although there are many unknowns in these diseases, research and drug trials are leading us closer to better managing the diseases and also closer to a cure. References 1. National Institute of Neurological Disorders and Stroke [Internet]. Bethesda (MD): National Institutes of Health; 2011 Dec 19. Amyotrophic Lateral Sclerosis (ALS) Fact Sheet; 2013 Jun [updated 2014 Sep 19; cited 2015 Feb 15]. Available from: www.ninds.nih.gov/disorders/ amyotrophiclateralsclerosis/detail_ALS.htm. 2. National Institute on Aging [Internet]. Bethesda (MD): National Institutes of Health. Frontotemporal Disorders: Information for Patients, Families, and Caregivers; 2014 Jun [updated 2015 Jan 22; cited 2015 Feb 15]. Available from: www.nia.nih.gov/alzheimers/publication/ frontotemporal-disorders/basics-frontotemporal-disorders. 3. The ALS Association. ALS Association [Internet]. Washington DC: The ALS Association; 2010 [cited 2015 Feb 15]. Available from: www.alsa. org.

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8. 9. 10.

11.

12.

13. 14. 15. 16. 17. 18.

19. 20.

21. 22.

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The Association for Frontotemporal Degeneration. Radnor (PA): The Association for Frontotemporal Degeneration. Fast Facts about Frontotemporal Degeneration; 2011. The Association for Frontotemporal Degeneration [Internet]. Radnor (PA): The Association for Frontotemporal Degeneration; c2007-2015 [cited 2015 Feb 15]. Available from: www.theaftd.org. DeJesus-Hernandez M, Mackenzie I, Boeve B, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20; 72:245-56. Medscape [Internet]. New York (NY): WebMD; 1994. Amyotrophic Lateral Sclerosis Workup; [updated 2 May 2014; cited 28 Mar 2015]; [about 3 screens]. Available from: emedicine.medscape.com/ article/1170097-workup#aw2aab6b5b2. Lexicomp [Internet]. Hudson (OH): Lexicomp. 1978-2015. Riluzole; [updated 2015 Feb 6; cited 2015 Feb 15]. Available from: online.lexi. com/lco/action/doc/retrieve/docid/patch_f/7628. Bensimon G, Lacomblez l, Meininger V, ALS/Riluzole Study Group. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med. 3 Mar 1994;330(9):585-591. Amyotrophic Lateral Sclerosis Society of Canada [Internet]. Ontario (CA): Amyotrophic Lateral Sclerosis Society of Canada; c2007. Ventilation: options and decision making; [cited 28 Mar 2015]. Available from: www.als.ca/en/publications/als-fact-sheets. Alzheimer’s Association [Internet]. Chicago (IL): Alzheimer’s Association; c2015. Frontotemporal Dementia (FTD); 2012 [cited 2015 Feb 15]. Available from: www.alz.org/dementia/fronto-temporal-dementia -ftd-symptoms.asp. Gordon PH. Amyotrophic lateral sclerosis: an update for 2013 clinical features, pathophysiology, management and therapeutic goals. Aging and Disease. 2013 Nov;4(5): 295-310. Available from: www.ncbi.nlm.nih. gov/pmc/articles/PMC3794725/pdf/ad-04-05-295.pdf. Genetics Home Reference [Internet]. U.S. National Library of Medicine. 2012 Aug [13 April 2015; 15 April 2015]. Available from: ghr.nlm.nih. gov/gene/C9orf72. Genetics Home Reference. [Internet]. U.S. National Library of Medicine. 2012 Aug [13 April 2015; 15 April 2015] Available from: ghr.nlm.nih. gov/gene/SOD1. Genetics Home Reference [Internet]. U.S. National Library of Medicine. 2012 Aug [13 April 2015; 15 April 2015]. Available from: ghr.nlm.nih. gov/gene/TARDBP. Genetics Home Reference. [Internet]. U.S. National Library of Medicine. 2012 Aug [13 April 2015; 15 April 2015]. Available from: ghr. nlm.nih.gov/gene/FUS. Genetics Home Reference [Internet]. U.S. National Library of Medicine. 2012 Aug [13 April 2015; 15 April 2015]. Available from: ghr.nlm.nih. gov/gene/VAPB. Rossi FH, Franco MC, Estevez AG. Pathophysiology of amyotrophic lateral sclerosis. Intech. 2013:1-33. Available from: cdn.intechopen. com/pdfs/45326/intech-pathophysiology_of_amyotrophic_lateral_scle rosis.pdf. Dias N, Stein CA. Antisense oligonucleotides: basic concepts and mechanisms. Mol Can Ther. 2002 Mar;1(5):347-55. Rembach A, Turner BJ, Bruce S, et al. Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS. J Neurosci Res. 2004 Aug 15;774 (4):573-82. Lagier-Tourenne C, Baughn M, Rigo F, et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. PNAS. 2013 Nov 19;110(47): 4520-E4539. Miller T, Pestronk A, David W, et al. A phase I, randomised, first-inhuman study of an antisense oligonucleotide directed against SOD1 delivered intrathecally in SOD1-Familial ALS Patients. Lancet Neurol. 2013 May;12(5):435–42. The authors have no conflict of interest or funding support to disclose.

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Assessment Questions 1.

Which of the following is not a symptom of ALS? A. Muscle weakness in the arms and legs B. Slurred speech C. Severe headache D. Difficulty breathing

True or False: FTD has no significant motor dysfunction, but does present with significant memory decline. A. True B. False

While in a medication therapy management (MTM) session with your patient, you note that she has difficulty recalling simple words when speaking. When you ask her about her daily diet, she cannot even remember what she had for breakfast and it is only 10:00 a.m. Her chart notes that the patient has been diagnosed with FTD recently. What specific class of FTD does your patient most likely have? A. Primary progressive aphasia: Logopenic variant B. Behavioral variant C. Primary progressive aphasia: Nonfluent variant D. Movement disorder: Corticobasal degeneration Which class of FTD presents with a lack of empathy and an inability to emotionally adapt to social cues? A. Behavioral Variant FTD (bvFTD) B. Corticobasal Degeneration (CBD) C. Semantic Variant D. Primary Progressive Aphasia (PPA) Which gene mutation is the most common genetic cause of ALS? A. FUS B. c9ORF72 C. TARDBP D. SOD1

Which of the following genes is not implicated in both ALS and FTD? A. FUS B. C9ORF72 C. VAPB D. TARDBP

Which geneâ&#x20AC;&#x2122;s mutations does the agent ISIS 333611 primarily target? A. SOD1 B. VAPB C. FUS D. TARDBP

Which of the following side effects of ISIS 333611 were most commonly reported, but considered to be administration-related in the human phase 1 trial? A. Lacunar infarction and pneumonia B. Neurological deficits and cognitive decline C. Post lumbar puncture syndrome and back pain D. Xerostomia and angioedema

Which of the following is/are a function(s) of a pharmacist in the management of ALS and FTD? A. Management of sequelae B. Patient and family education on the disease C. Dosing adjustments based on altered pharmacokinetics D. All of the above

10. Which of the following ALS pharmacologic therapies can lead to respiratory depression? A. Riluzole B. Benzodiazepines C. Venlafaxine D. Two of the above

Ohio Northern University is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is eligible for credit until 5/7/2018.

To receive continuing education credit for this program, you must answer the above questions and fill out the evaluation form. Please visit www.raabecollegeofpharmacy.org/PAW to enter the required information. Please allow two to three weeks for electronic distribution of your continuing education certificate, which will be sent to your valid email address in PDF format.

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To receive continuing education credit for this program, visit www.raabecollegeofpharmacy.org/PAW OR fill out the form below including your indicated answers to the assessment questions and return to: Office of Continuing Education at The Raabe College of Pharmacy Ohio Northern University 525 South Main Street Ada, Ohio 45810 Continuing Education Registration & Evaluation Form Program Title: Current Trials and Therapies for the Treatment of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia UAN: 0048-0000-15-207-H01-P CEUs: 0.1 All information must be printed CLEARLY to ensure accurate record keeping for attendance and the awarding of continuing education credit. You MUST provide your CPE Monitor# and Month and Day of birth to receive credit.

Name: Address: City:

State:

Phone:

Email:

Check one: Pharmacist

Technician

CPE Monitor #: Program Content:

Zip:

License #:

State:

Birthday (MM/DD): Strongly Disa gree

The program objectives were clear. The program met the stated goals and objectives: 1. Identify the symptoms of ALS and FTD. 2. Classify FTD subtypes based on patient presentation. 3. Recognize the most prominent gene mutations in ALS and FTD. 4. Describe various targets of ASO therapy. 5. List common and serious adverse effects of ISIS 333611. 6. Define the role of the pharmacist in the management of ALS and FTD. The program met your educational needs. Content of the program was interesting. Material presented was relevant to my practice. Audio/visual and/or printed materials aided the learning process. The program used effective teaching/learning methods. The learning assessment activities were appropriate. The program showed good objectivity and no commercial bias. Would you recommend this program to a colleague? What was the most valuable part of this program?

Strongly Agree

1 1 1 1 1 1 1 1 1 1 1 1 1 1

2 2 2 2 2 2 2 2 2 2 2 2 2 2

3 3 3 3 3 3 3 3 3 3 3 3 3 3

4 4 4 4 4 4 4 4 4 4 4 4 4 4

5 5 5 5 5 5 5 5 5 5 5 5 5 5

Based on what you have learned what one change do you plan to make in your practice? Speaker Content: The speaker was well prepared and knowledgeable about the topic. The quality of the speaker was excellent. The speaker provided adequate time for questions. Comments:

Strongly Di sagree

1 1 1

2 2 2

Strongly Agree

3 3 3

4 4 4

5 5 5

Suggestion for future programs you would like to see: Answers to Assessment Questions â&#x20AC;&#x201D;Please Circle Your Answer 1.

A B C D

5. A B C D

7. A B C D

9. A B C D

A B

A B C D

6. A B C D

8. A B C D

10. A B C D

Any questions/comments regarding this continuing education program can be directed to Lauren Hamman, Advanced Administrative Assistant for the Office of Continuing Education (email: l-hamman@onu.edu, phone 419-772-2280).

Ohio Northern University is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is eligible for credit until 5/7/2018. 9

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Geriatrics

The Effects of Long-Term Benzodiazepine Use and Withdrawal in the Elderly Lydia Suchecki, fifth-year pharmacy student from Beavercreek, Ohio; Hannah Granger, fourth-year pharmacy student from Sardinia, Ohio; Jamie Kellner, fifth-year pharmacy student from New Waterford, Ohio; Mary Ellen Hethcox, BSPh, PharmD, director of drug information services, assistant professor of pharmacy practice

This knowledge-based activity is targeted for all pharmacists and is acceptable for 1.0 hour (0.1 CEU) of continuing education credit. This course requires completion of the program evaluation and at least a 70 percent grade on the program assessment questions.

and withdrawal concerns to reduce the negative effects elderly patients may experience with long-term use. Key Terms Accidental Falls; Aged; Benzodiazepines; Cognition; Hypnotics and Sedatives; Pharmacists; Quality of Life

ACPE Universal Activity Number (UAN): 0048-0000-15-209-H01-P Objectives After completion of this program, the reader should be able to: 1. Explain how benzodiazepines differentially affect the elderly population in terms of pharmacokinetics and pharmacodynamics. 2. Discuss specific adverse effects of benzodiazepines in the elderly population and how these adverse effects impact quality of life. 3. Identify patients who are at highest risk of adverse effects with benzodiazepine use. 4. Describe symptoms of and possible treatments for patients experiencing withdrawal from benzodiazepines. 5. Identify ways a pharmacist can improve medication management in the elderly population. Abstract Benzodiazepines remain a commonly prescribed medication in the United States, and the high usage of this drug class is especially a concern in the elderly population for several reasons. First, elderly patients metabolize drugs differently, leading to varying responses. Age-related changes also have a significant impact on the effects of benzodiazepines. Second, elderly patients are more likely to be taking multiple centrally-acting drugs, which can further exacerbate negative effects. In regard to long-term benzodiazepine use, elderly patients experience an increased risk of cognitive impairment, motor vehicle accidents, decline in physical performance, falls and subsequent fractures, and sleep disturbances. Withdrawal is also a significant concern with long-term benzodiazepine treatment, which can lead to rebound symptoms in addition to mood swings, tremor, headache and loss of appetite. A taper of less than six months is recommended when discontinuing benzodiazepines after use longer than the recommended three month duration of treatment. Pharmacists can have a substantial impact in reducing the detrimental effects of long-term use of benzodiazepines by aiding in the tapering process, as well as identifying inappropriate prescribing and use of benzodiazepines in the elderly population. Overall, pharmacists should be knowledgeable on the appropriate use of benzodiazepines, associated side effects

Introduction Despite the potentially detrimental effects of benzodiazepine use, benzodiazepines remain a commonly prescribed medication in the United States. In 2012, Ohio prescribers wrote 41.3 prescriptions for benzodiazepine medications per 100 people, ranking Ohio 20th compared to other states.1 Ohio is slightly above the national rate of 37.6 prescriptions per 100 people. The high usage of benzodiazepines is especially a concern in the elderly population, in part because elderly patients respond to and metabolize drugs differently. Even if a patient has been on a benzodiazepine for many years, it may begin to have different or more severe adverse effects as the patient ages. Elderly patients, generally defined as 65 years of age and older, are also more likely to be taking several medications, which may include other centrally-acting drugs. The combination of these factors leads to an increased risk of cognitive impairment, motor vehicle accidents, decline in physical performance, falls and subsequent fractures, and sleep disturbances in the elderly population. Benzodiazepines are included on the American Geriatric Societyâ&#x20AC;&#x2122;s Beers Criteria, which notes that elderly patients are known to have higher sensitivity to and slower metabolism of long-acting benzodiazepines, increasing the risk of negative effects.2 Studies have found these effects can also be seen with short-acting formulations.3 It can be concluded that if detrimental effects are seen with both short-acting and longacting formulations of benzodiazepines, then these effects can also be observed with the intermediate-acting medications (Table 1).4 The Beers Criteria recommendation for benzodiazepine use is classified as â&#x20AC;&#x2DC;strong,â&#x20AC;&#x2122; meaning that the burdens/risks of use outweigh the potential benefits.2 Although benzodiazepines may still be an appropriate option in some instances, per the Beers Criteria their use is not recommended in the elderly to treat insomnia, agitation or delirium. Discontinuation of this class of drugs has been associated with some improvement in their negative effects, especially those effects relating to cognition; however, there are still lasting implications with long-term use. The withdrawal process and associated symptoms are also significant, owing to the addictive properties and dependency effects of this class of drugs.5 As pharmacists, it is important to recognize how these drugs may affect elderly patients differently

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Geriatrics

Table 1. Commonly Prescribed Benzodiazepines.

Short-acting*

 

Midazolam (Versed™) Triazolam (Halcion™)

Intermediate-acting*

     

Alprazolam (Xanax™) Conazepam (Klonopin™) Diazepam (Valium™) Lorazepam (Ativan™) Oxazepam (Serax™) Temazepam (Restoril™)

Long-acting*

 

Chlordiazepoxide (Librium™) Flurazepam (Dalmane™)

*classification based on half-life of active components4 and to manage these medications accordingly. Pharmacists have an essential role in identifying elderly patients being newly prescribed or currently taking long-term benzodiazepines who may be candidates for other treatment options, making alternative medication recommendations to physicians and assisting patients during the withdrawal process. Typical and appropriate indications for benzodiazepine use in the elderly include anxiety, panic disorder, sleep disorder and adjustment disorder which are similar to the indications for use in the nonelderly population. However, in some instances such as in a patient who is refractory to standard treatment, benzodiazepines may be appropriately used for short-term treatment of insomnia or agitation even though the recommendation from the Beers Criteria is to avoid use for these indications.2 Central nervous system (CNS) depression is a typical side effect of benzodiazepines for all age groups. Of significance is that within the older population these side effects are observed more frequently and to a greater extent, and some negative outcomes such as falls, fractures and a decrease in physical performance are unique to the elderly demographic. In the elderly population, these side effects can have substantial implications on the patient’s quality of life, autonomy and independence. This increased severity of side effects is due primarily to pharmacodynamic, rather than pharmacokinetic, changes in the CNS and brain that occur naturally with aging and lead to a greater sensitivity to benzodiazepines.6,7 In fact, elderly patients generally require lower doses of benzodiazepines, corresponding to lower blood concentrations to achieve the effect of sedation, highlighting the increased sensitivity displayed in older patients.8 The pharmacokinetic changes that occur include changes in the elimination and distribution of benzodiazepines in the aging brain; but, more importantly, the pharmacodynamic changes in the CNS make the receptors more sensitive to the drug.7 The target for benzodiazepines to produce their CNS effects are the gamma-aminobutyric acid-a (GABAa) receptors, which are ligand-gated chloride channels. The binding of the benzodiazepine causes the channel to open and results in an influx of chloride, which decreases

neuronal firing.9 The GABAa receptor is made up of several subunits, which contributes to why there are a variety of symptoms associated with this drug class in all patient age groups. The increase in severity of side effects in the elderly may be so extreme for benzodiazepines in particular because GABAa receptors are widely distributed throughout the CNS in the spinal cord, cortex, cerebellum, and limbic system, and the distribution of the GABAa receptors changes with age, altering the excitability of the brain.6,9 With the high number of receptors and an increased sensitivity with the aging process, many of the effects seen in a younger person will be exaggerated in the elderly such as greater sedation, less coordination of movement and less inhibition.7 Changes in psychomotor abilities, reaction time, delirium, coordination and attention are also potential effects of benzodiazepine use in the elderly.10,11 Cognitive Impairments The use of benzodiazepines can negatively impact cognition or exacerbate normal age-related cognitive decline in elderly patients. However, the length of time the patient is taking the medication is a significant predictor of cognitive decline.12 Associated risks are increased with the long-term use of benzodiazepines even in those patients who used benzodiazepines chronically and have already successfully discontinued therapy. The length of time a patient has been taking benzodiazepines is a significant predictor of cognitive decline and has been shown to have a greater effect on sustained cognitive impairment compared to the dose alone. Evidence supporting the long-term implications on cognition is varied. Not all patients taking therapeutic doses of benzodiazepines long-term will experience these cognitive and memory impairing effects, or the effects they do experience may be minimal.12,13 However, several studies have found that cognitive impairment does occur with chronic benzodiazepine use.10 Central nervous system depression and decline in cognition, alertness and decision-making capacity are all recognized side effects of therapy. Notable short-term effects include anterograde amnesia, or difficulty learning new information, a decrease in mental alertness and the capacity to coordinate

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The Effects of Long-Term Benzodiazepine Use and Withdrawal in the Elderly

fine movements.13 Long-term users tend to develop some tolerance to the sedative effects (for example, the drowsiness is less severe over time when compared to initiation of therapy), but effects on memory and cognition continue throughout use. Patients taking benzodiazepines chronically may also struggle to process information quickly and sustain attention on a task for an extended amount of time, as well as have difficulty with visuospatial skills. These effects are more detrimental in the elderly population in terms of severity and persistence of symptoms, even after the medication has been discontinued. These negative cognitive effects impact the elderly patientâ&#x20AC;&#x2122;s quality of life, memory and independence. The negative effects of benzodiazepine use in the elderly may extend beyond the duration of therapy to a greater extent than in the nonelderly population. Cognitive impairment was found to persist for at least six months after discontinuation, in comparison to patients who had not been on benzodiazepines, suggesting that this class of drugs may cause functional changes in the brain that are permanent or at least slowly reversible.10 While there is strong evidence that benzodiazepines have negative effects on cognitive performance while using the medication, not all studies support the same conclusion, and research is inconclusive as to how long the damage lasts once the medication is discontinued. A metaanalysis involving 13 studies that lasted for at least one year and were published between 1980 and 2000 examined the effects of long-term benzodiazepine use on cognition.5 The authors were not able to make conclusions about whether or not the cognition and memory impairment of benzodiazepines extended beyond therapy termination due to the heterogeneity and limited number of studies in the meta-analysis. The study points to the complicated nature of assessing cognition considering the impact of test-induced anxiety in patients who may already be prone to anxiety. In practice, however, the most conservative treatment plan should be used if possible; the potential risk of lingering CNS effects impacting cognition is high enough to discourage long-term use of benzodiazepines if another treatment of equal efficacy is available. Motor Vehicle Accidents Decreased alertness, altered decision-making capacity and changes in perception are cognitive-based factors that contribute to an increased risk of motor vehicle accidents in elderly patients taking benzodiazepines.14,15 Reaction time is another critical factor that is negatively impacted by benzodiazepine use.14 Crashes that involve elderly drivers are generally related to perception and cognitive difficulties, such as crossing the center into the adjacent lane, inappropriate judgment of gaps between vehicles and not giving way to other vehicles. Although studies still show that younger drivers are more likely to be in car accidents than older drivers, the risks are highest in those ages 18 to 25 years and ages 65 years and greater.14,15 Importantly, in the 65 years of age and greater population, there is an even higher risk of accidents in those taking benzodiazepines.14 In fact, benzodiazepines are commonly found at detectable blood levels in people involved in car accidents when it is suspected that they were impaired due to substances. This finding includes both ben-

zodiazepines being used therapeutically and as drugs of abuse, meaning it includes those taking benzodiazepines for reasons other than prescribed or at doses higher than prescribed. As expected, the risks associated with benzodiazepines and traffic accidents increase with the size of the dose, the number of benzodiazepines being used, combinations with other CNS depressants (e.g., alcohol) and how long the driver has been taking the medication. This may even suggest that tolerance develops to the side effects of the medication with chronic use compared to the cognitive changes seen initially in a patient on a benzodiazepine.16 Physical Disability Benzodiazepines increase the risk for mobility impairments and difficulties with completing daily tasks such as bathing, dressing and feeding.3,17 The decline in physical performance is due to the effects on the patientâ&#x20AC;&#x2122;s neuromuscular processing and psychomotor abilities, as well as the sedation, that is caused by benzodiazepine use.3 Again, there is some natural risk of declining mobility and ability to perform daily tasks associated with aging, but benzodiazepine use in the elderly has been found to increase the risk for physical disability by 23 percent. Specifically, women are at a greater risk for these changes than elderly men likely due to poorer muscle strength and control initially.3,17 Although it was previously believed that these physical impairments would be lessened if the patient was prescribed short-acting rather than long-acting formulations due to the shorter half-life, not all studies support this theory.3 Short-acting benzodiazepines are more likely to be taken in higher doses, therefore increasing total drug exposure and leading to higher peak concentrations. Overall, risk for physical disability is greatest in patients using higher doses and long-term therapy, defined as three years or more in this study specifically.17 Unfortunately, the negative effects on physical functioning can still be seen even at low doses of benzodiazepines.3 Although higher drug exposure does tend to lead to more detrimental effects, there are still many interindividual differences that allow low doses to have an equally negative impact in some patients. One study examined whether the physical disability was resulting from benzodiazepine use itself or from a shift to a less active lifestyle due to the sedative effects of the medication. It was concluded that activity level was not a confounder in decreasing physical performance, so it can be concluded that the effects of the benzodiazepine were likely the reason for the decline in physical function. Fall Risks Benzodiazepines are one of many drug classes that pose a fall risk in the elderly population owing to an increase in the risks associated with falls, such as impaired muscle strength, coordination and balance. Although risk of falls increases naturally with aging, benzodiazepine use can exacerbate this risk. In a study, handgrip strength and balance were used as indicators to assess fall risk in elderly patients taking the intermediate-acting benzodiazepine, temazepam, or one of two Z-drugs, zolpidem or zolpiclone, which work similarly to benzodiazepines.18 Successful discontinuation from longterm benzodiazepine use led to an improvement in handgrip strength and balance in elderly patients. The findings showed

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The Effects of Long-Term Benzodiazepine Use and Withdrawal in the Elderly

that benzodiazepine usage does play a significant role in fall risk, and the incidence among some elderly patients may be due to more than typical age-related decline. This fact increases the importance of identifying patients who could be switched to an alternate therapy. As women are at a greater risk of physical disability than men, as noted earlier, this also places them at a greater risk for falls than men. Considering overall health care economics, benzodiazepines are relatively inexpensive medications, but the financial burden of treating falls and fall-related injuries attributed to benzodiazepine use can be significant. Fractures In the elderly population, fractures and other musculoskeletal injuries are often sustained due to falls. As expected, there is an increase in fractures in long-term benzodiazepine users.19 Similar to the research regarding physical disability in general, there was not a difference in fractures sustained due to benzodiazepines based on whether they were short-acting or long-acting products.3,19 In a study that compared the United States with several large European countries, the overall average of hip fractures that could be attributed, at least in part, to benzodiazepine use was 1.8 to 8.2 percent.19 Although this is a large range, even the most conservative finding of 1.8 percent shows that fractures as a consequence of benzodiazepine use are still meaningful when considering the other age-related and drug-related causes for fractures and falls in the elderly population and the individual impact a fracture has on a patient’s quality of life.

Sleep Problems Sleep disturbances are a frequent reason for an elderly patient to be prescribed a benzodiazepine, yet approximately 80 percent of the elderly population who are taking benzodiazepines report having problems with sleep.20,21 Despite the indication for benzodiazepines to help with sleep, a study found that overall sleep quality declined in adults 65 years of age or older when using benzodiazepines long-term.20 Though these medications are generally only recommended to be used for three months, regardless of age and indication, most patients use them for much longer. Another metaanalysis that examined 45 randomized controlled trials testing benzodiazepine use for insomnia found that although benzodiazepines are slightly beneficial in increasing the length of time a patient is asleep, there are not any significant benefits on the length of time for sleep onset, and there are additional negative effects associated with their use.21 The most common negative effects patients reported in the studies included being drowsy during the day, dizziness and lightheadedness. For long-term users of benzodiazepines, the risks and negative effects associated with usage outweigh the potential benefit for sleep. Like most of the effects discussed previously, sleep disturbances are seen more significantly in the elderly population due to the negative impacts of benzodiazepine use being compounded with natural, age-related decline in sleep quality.20 Importantly, not only did the benzodiazepine users have poorer sleep quality than nonusers, but those taking benzodiazepines long-term had the worst sleep quality overall

Geriatrics

when compared to those who only took the medications short-term. This result is not often seen in initial clinical trials assessing medications’ effects on sleep because research is often not conducted for a long enough time to appropriately examine the effects of the drug long-term, which is how the drugs are often used in practice. Withdrawal Although cognitive impairment, physical disabilities and sleep problems are possible adverse effects of taking benzodiazepines, withdrawal is perhaps the biggest controversy pertaining to their use. However, due to prescribing traditions and patient preference, long-term use of benzodiazepines occurs in more than one-third of patients.22-24 This is a cause for alarm due to the risks of adverse effects and continued efficacy. A study by Salzman and colleagues found the memory and cognitive functioning of elderly nursing home patients improved in those tapered off benzodiazepines when compared to those who remained on the medications.25 The recommendation for those patients on benzodiazepines for longer than three months is to gradually reduce the dosage through a tapering schedule.26 This taper should last less than six months or else this process occupies all of the patient’s focus.25 Before interrupting benzodiazepine use, health care providers should ensure the patient is in good health, and that he or she is fully educated about the possible recurrent, rebound or new symptoms that can occur.22,27 The original indication for benzodiazepine use, whether insomnia or anxiety, may worsen to pretreatment levels during the tapering period.24 In some cases, the symptoms may elevate beyond pretreatment levels and is considered a rebound symptom. Therefore, it is necessary to evaluate the patient’s underlying medical or psychiatric conditions before ceasing benzodiazepine use.22 Symptoms of withdrawal and rebound are enhanced with the use of short-acting benzodiazepines due to their short half-life, rapid elimination and increased dosing frequency (Table 1).24 The short-acting agents, midazolam and triazolam, are generally not used throughout the day, so the withdrawal and rebound may not be as evident, although rebound effects have been reported with the use of triazolam.28 Alprazolam and oxazepam, which are considered intermediate-acting agents with half-lives of about three to 20 hours, may be dosed more frequently and are associated with symptoms of withdrawal and rebound if discontinued abruptly. 27 Rebound symptoms may occur after long-term use of any benzodiazepine, and may require a nonbenzodiazepine substitute for those experiencing exacerbations of their sleep disorders or anxiety. Selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) are acceptable alternatives for those with rebound depressive symptoms, and melatonin agonists, such as ramelteon (Rozerem®), may aid in sleep disorders.23,25,29,30 Psychological support, spanning from encouragement to cognitive or behavioral therapy, should also be provided for those patients in need of anxiety management and should be available long after tapering is complete.23 Decreased use of caffeine and alcohol, along with proper sleep, hygiene and relaxation techniques, may be enough to help insomnia without the need to initiate medications. Overall, the entire health

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care team needs to be prepared to help the patient pharmacologically and nonpharmacologically with any issues resulting from rebound symptoms throughout tapering. Along with possible rebound symptoms, withdrawal symptoms add to the difficulty of the benzodiazepine tapering process. The most frequent withdrawal symptoms include insomnia, anxiety, mood swings, myalgia/muscle twitching, tremor, headache, nausea/vomiting, loss of appetite, hypersensitivity to noise, changes in movement and feelings of unreality.29 Throughout the withdrawal process these symptoms wax and wane and can differ in severity for each patient.23 The 20-item Benzodiazepine Withdrawal Symptom Questionnaire or the Physician Withdrawal Checklist can be used to measure patientâ&#x20AC;&#x2122;s symptoms during each case of withdrawal.31 Due to these occasionally unbearable symptoms, slow dosage reduction and proficient psychological support are necessary for the success of benzodiazepine tapering.23 Abrupt withdrawal could cause convulsions, panic reactions and acute psychotic states. The occurrence of seizures upon withdrawal, although rare, is more likely in patients with an underlying seizure disorder or when receiving concomitant medications that may lower the seizure threshold.27 As previously mentioned, tapers should last less than six months, but this process should be adapted to each individual patient based on lifestyle, personality, environment and available support. 23,25 Dosage reduction is an individualized process based on each patientâ&#x20AC;&#x2122;s characteristics.23 Those on higher doses of benzodiazepines can tolerate larger dosage cutbacks, and the majority of patients take therapeutic doses less than 20 mg diazepam or equivalent daily. The usual dose of diazepam for the treatment of anxiety is 2 mg to 10 mg two to four times daily if needed, allowing for a maximum dose per day of 40 mg.32 Generally, it is recommended to reduce the dose by 10 percent to 25 percent each week.22 Reductions of 1 mg diaze-

pam every one to two weeks are usually well tolerated.22 Yet, if the patient is taking 40 mg of diazepam daily, an initial reduction of 2 mg every one to two weeks may be more appropriate, as the patient is considered to be on a higher dose. Once the daily dosage reaches 4 mg to 5 mg, decreasing by 0.5 mg may be preferred to prevent negative effects. In order to improve adherence and patientâ&#x20AC;&#x2122;s peace of mind, a written withdrawal schedule should be provided rather than just verbal instructions. A chart to check off days and doses is helpful for patients to stay goal-oriented. These schedules will be flexible to changes upon the appearance of any problems, such as severe symptoms or stressors. If at any point in the process withdrawal symptoms become notably severe, the tapering can be slowed. Diazepam, an intermediateacting agent, is the easiest benzodiazepine for tapering since it has multiple available strengths including 10 mg, 5 mg and 2 mg tablets. Therefore, many patients are switched from their original benzodiazepine medication to an equivalent diazepam dosage (Table 2) especially within one month of complete discontinuation.22,23,27 Keep in mind, psychological and anxiety management should be provided throughout the entire dosage reduction process. Benzodiazepine withdrawal is a very complex and taxing process for patients. As a result, it is recommended any patient dependent on benzodiazepines and going through withdrawal attends self-help groups run by ex-benzodiazepine users, psychologists, counselors or trained paramedical workers.23 Along with these group meetings, it is important for the patients to receive individualized psychological care in which they can confront personal or social problems underlying their anxiety and need for long-term benzodiazepine use. Involvement of family members in this practice is significant because it allows the patient to feel supported and to expose themselves to others, which increases their confidence and self-esteem. These individuals need to be highly self-motivated in order to succeed with the tapering regi-

Table 2. Benzodiazepine Equivalent Doses.22,23,27 Benzodiazepines

Alprazolam (Xanax)

Oral Doses (mg) Equivalent to 10 mg Diazepam

0.5 - 1

Chlordiazepoxide(Librium)

Clonazepam (Klonopin)

0.5

Clorazepate (Tranxene)

Diazepam (Valium)

Flurazepam (Dalmane)

Lorazepam (Ativan)

1-2

Oxazepam (Serax)

Quazepam (Doral)

Temazepam (Restoril)

Triazolam (Halcion)

0.25 - 0.5 The Pharmacy And Wellness Review Summer 2015 Volume 6, Issue 3

The Effects of Long-Term Benzodiazepine Use and Withdrawal in the Elderly

mens. As stated earlier, it is important to inform patients of the possible problems that can occur during withdrawal and ensure they are dedicated and willing to fully adhere to the program. Health care providers for any patients going through withdrawal or abusing benzodiazepines can educate them regarding the advantages of withdrawal and establish trust with them each step of the way. Even though psychological support is available to patients throughout benzodiazepine tapering, the withdrawal symptoms may be perceived as too difficult to handle. Several medications have been evaluated as possible withdrawal and symptom-relief aids in order to allow more patients to be successful. Flumazenil is a benzodiazepine partial agonist which normalizes receptor function and has been evaluated for decreasing patientsâ&#x20AC;&#x2122; craving and relapse rates and even reducing the hostile and aggressive behaviors that are often associated with withdrawal.33,34 A randomized, placebocontrolled study found that when compared to oxazepam, flumazenil can counteract benzodiazepine effects and control benzodiazepine withdrawal.33 Topiramate and carbamazepine, both anticonvulsants, have also been investigated in the treatment of withdrawal symptoms and possibly relapse prevention.35 However, none of these medications have been found to be fully successful in preventing benzodiazepine withdrawal. Role of the Pharmacist Long-term use of benzodiazepines can lead to many adverse effects, cognition issues and withdrawal symptoms. As one of the most accessible health care providers, pharmacists can have significant impact by aiding patients throughout this complicated and difficult process. First, pharmacists in all institutions and fields of pharmacy can identify elderly patients taking long-term benzodiazepines and use their professional judgment and knowledge to evaluate if the benefits outweigh the risks for each individual patient. Community pharmacists can assist in drug adherence and patient education by identifying potential drug interactions or adverse reactions, supplying weekly pill dispensers or other compliance aids and administering information about specific drugs.36 However, the pharmacistâ&#x20AC;&#x2122;s responsibility expands far beyond the patient. Pharmacists are in a good position to communicate with prescribers in both the inpatient and community settings to determine if patients could be switched to another less risky therapy to treat their condition. Also, pharmacists should educate other health care professionals and ensure benzodiazepines are being prescribed only for appropriate conditions when other options are not available. Additionally, information should be exchanged between pharmacists and physicians about medication reviews, prescribing committees, compiling drug formularies, dose reduction regimens and possible ways to deal with benzodiazepine withdrawal. Conclusion Benzodiazepines are a commonly prescribed class of medications in the elderly for anxiety and insomnia. However, long-term use of this class of medications is associated with detrimental effects including cognitive impairment,

Geriatrics

sleep disturbances and physical disabilities. These drugassociated effects can lead to an increase in motor vehicle accidents in the elderly patient population as well as an increased fall risk leading to more fractures and a decreased quality of life. Withdrawal is one of the greatest issues with long-term benzodiazepine treatment which can lead to rebound symptoms plus mood swings, tremor, headache, loss of appetite and more. A taper of less than six months is recommended when discontinuing long-term benzodiazepine use. Pharmacists can be beneficial during the tapering process, but also have the professional responsibility to identify inappropriate prescribing and use of benzodiazepines in the elderly population, which could circumvent many of these issues altogether. Overall, the continued use of benzodiazepines in this patient population requires pharmacists to stay updated on appropriate indications, side effects and withdrawal concerns as well as educate other health care professionals when necessary. References 1. Paulozzi L, Mack K, Hockenberry J. Vital signs: variation among states in prescribing of opioid pain relievers and benzodiazepines- the United States, 2012. Centers for Disease Control and Prevention MMWR. July 2014;63. 2. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. April 2012;60(4):616-631. 3. Gray S, LaCroix A, Hanlon J, et al. Benzodiazepine use and physical disability in community-dwelling older adults. J Am Geriatr Soc. 2006 Feb;54(2):224-230. 4. Trevor A, Way W. Chapter 22. Sedative-Hypnotic Drugs. In: Katzung B, Masters S, Trevor A, editors. Basic & Clinical Pharmacology, 12e. New York, NY: McGraw-Hill; 2012. p. 373-388. 5. Barker M, Greenwood K, Jackson M, et al. Cognitive effects of long term benzodiazepine use. CNS Drugs. 2014;18(1):37-48. 6. Trifiro G, Spina G. Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Current Drug Metabolism. 2011;12(7):611-620. 7. Bogunovic OJ, Greenfield SF. Use of benzodiazepines among elderly patients. Practical Geriatrics. 2004 March; 55(3):233-235. 8. Swift C, Ewen J, Clarke P, Stevenson I. Responsiveness to oral diazepam in the elderly: relationship to total and free concentrations. Br J Clin Pharmacol. 1985;20:111-118. 9. Meyer J. Chapter 16. Pharmacotherapy of Psychosis and Mania. In: Brunton L, Chabner B, Knollmann B, editors. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. 10. Puustinen J, Lahteenmaki R, Polo-Kantola P, et al. Effect of withdrawal from long-term use of temazepam, zopiclone or zolpidem as hypnotic agents on cognition in older adults. Eur J Clin Pharmacol. 2014;70:319329. 11. Rothberg M. Association between sedating medications and delirium in older inpatients. J Am Geriatr Soc. 2013;61(6):923-930. 12. Bierman E, Comijs H, Gundy C, et al. The effect of chronic benzodiazepine use on cognitive functioning in older persons: good, bad or indifferent? Int J Geriatr Psychiatry. 2007;22:1194-1200. 13. Barker M, Jackson M, Greenwood K, Crowe S. Cognitive effects of benzodiazepine use: a review. Australian Psychologist. 2003 Nov;38 (3):202-213. 14. van Laar MW, Volkerts ER. Driving and benzodiazepine use: evidence that they donâ&#x20AC;&#x2122;t mix. CNS Drugs. 1998;10(5):383-396. 15. Neutel I. Benzodiazepine-traffic related accidents in young and elderly drivers. Hum Psychopharmacol Clin Exp. 1998;13:S115-S123. 16. McAndrews MP. Cognitive effects of long-term benzodiazepine use in older adults. Hum Psychopharmacol Clin Exp. 2003; 18:51-57. 17. Gray S, Penninx B, Blough D, et al. Benzodiazepine use and physical performance in community-dwelling older women. J Am Geriatr Soc. 2003 Nov;51(11):1563-1570. 18. Nurminen J, Puustinen J, Lahteenmaki R. Handgrip strength and balance in older adults following withdrawal from long-term use of temaz-

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19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

29. 30. 31.

32. 33. 34. 35. 36.

The Effects of Long-Term Benzodiazepine Use and Withdrawal in the Elderly

epam, zopiclone or zolpidem as hypnotics. BMC Geriatrics. 2014;14:121-131. Khong T, de Vries F, Goldenburg J, et al. Potential impact of benzodiazepine use on the rate of hip fractures in five large European countries and the United States. Calcif Tissue Int. 2012;91:24-21. Beland S, Preville M, Dubois M, et al. The association between length of benzodiazepine use and sleep quality in the older population. Int J Geriatr Psychiatry. 2011;26:908-915. Holbrook A, Crowther R, Lotter A. Meta-analysis of benzodiazepine use in the treatment of insomnia. Canadian Medical Association Journal. 2000;162(2):225-233. Cloos J. Benzodiazepines and addiction: long term use and withdrawal. Psychiatric Times. 2010;27(8):34-36. Ashton H. The treatment of benzodiazepine dependence. Addiction. 1994; 89(11):1535-1541. Cloos J-M. Benzodiazepines and addiction: myths and realities (Part 1). Psychiatric Times. 2010 Aug;27(7):26-29. Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;2(1):19-34. Parr J, Kavanagh D, Cahill L, Mitchell G, et al. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta analysis. Addiction. 2009;104(1):13-24. Chouinard G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psych. 2004;65:7-12. Silvestri R, Ferrillo F, Murri L, et al. Rebound insomnia after abrupt discontinuation of hypnotic treatment: double-blind randomized comparison of zolpidem versus triazolam. Hum Psychopharmacol. 1996;11:225-33. Janhsen K, Roser P, Hoffman K. The problems of long-term treatment with benzodiazepines and related substances. Dtsch Arztebl Int. 2015;112:1-7. Rozerem (ramelteon). Center Watch [Internet]. [cited Feb 29]. Available from: www.centerwatch.com/drug-information/fda-approv ed-drugs/drug/882/rozerem-ramelteon. Couvee J, Zitman F. The benzodiazepine withdrawal symptom questionnaire: psychometric evaluation during a discontinuation program in depressed chronic benzodiazepine users in general practice. Addiction. 2002;97(3):337-345. Valium (diazepam) package insert. Nutley, NJ: Roche Laboratories, Inc.; 2008 Jan. Gerra G, Zaimovic A, Giusti F, et al. Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study. Addict Biol. 2002; 7(4):385-395. Saxon L, Borg S, Hiltunen AJ. Reduction of aggression during benzodiazepine withdrawal: effects of flumazenil. Pharmacol Biochem Behav. 2010;96(2):148-151. Cheseaux M, Monnat M, Zullino D. Topiramate in benzodiazepine withdrawal. Hum Psychopharm Clin. 2003;18(5):375. Denham MJ, Barnett NL. Drug therapy and the older person: role of the pharmacist. Drug Safety. 1998;19(4):243-250. The authors have no conflict of interest or funding support to disclose.

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The Effects of Long-Term Benzodiazepine Use and Withdrawal in the Elderly

Geriatrics

Assessment Questions 1.

Why is the high usage of benzodiazepines especially a concern in the elderly population? A. Elderly patients respond to and metabolize benzodiazepines differently. B. Elderly patients are more likely to be taking multiple medications, which may include other centrally-acting ones. C. Benzodiazepines, as a class, are more expensive compared to other medications with similar indications. D. Two of the above are correct.

According to the Beers Criteria, which is not a recommended indication for benzodiazepine use in elderly patients? A. insomnia B. anxiety C. panic disorder D. Two of the above are correct.

The increase in the severity of negative side effects with benzodiazepine use in the elderly population is primarily because of ______ changes. A. pharmacokinetic B. pharmacogenomic C. pharmacodynamic D. pharmacoeconomic

When considering the impact of benzodiazepines on cognition, which is true? A. Negative effects may extend beyond the duration of therapy. B. Dose is a greater predictor of negative cognitive effects than the length of therapy. C. Both A and B are correct. D. Neither statement is correct.

In regard to benzodiazepines and physical function, which is true? A. Women are at a higher risk to suffer from a decline in physical function and fractures. B. Negative effects on physical function are not seen with short-acting benzodiazepines. C. The sedative effects of benzodiazepines decrease the activity level and lead to a decline in physical function. D. Two of the above are true.

Although typically used much longer, the recommended length of time for using benzodiazepines is ___________. A. Six weeks B. Three months C. No more than one year D. There is no recommended length of time; long-term use needs to be monitored.

When considering the impact of benzodiazepine use on motor vehicle accidents, which is true? A. Benzodiazepines can have detrimental impacts on driving only when used abusively. B. Due to benzodiazepine use (along with other sedative substances), elderly drivers are the most likely to be involved in a motor vehicle accident compared to other drivers. C. Benzodiazepine use can impair reaction time and alertness of an elderly driver. D. Benzodiazepines have not been found to have a significant impact on motor vehicle accidents.

The taper schedule for benzodiazepines should be no longer than: A. Two months B. Four months C. Six months D. One year

In regard to the tapering process, the recommended dosage reduction of benzodiazepines per week is: A. 10-25% B. 5-10% C. 25-30% D. 15-35%

10. The benzodiazepine partial agonist that has been evaluated for decreasing patientâ&#x20AC;&#x2122;s craving and relapse rates, normalizing benzodiazepine receptor function and even reducing hostile and aggressive behavior often associated with withdrawal is: A. oxazepam B. topiramate C. carbamazepine D. flumazenil

Ohio Northern University is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is eligible for credit until 5/21/2018.

Summer 2015 Volume 6, Issue 3 The Pharmacy And Wellness Review

To receive continuing education credit for this program, visit www.raabecollegeofpharmacy.org/PAW OR fill out the form below including your indicated answers to the assessment questions and return to: Office of Continuing Education at The Raabe College of Pharmacy Ohio Northern University 525 South Main Street Ada, Ohio 45810 Continuing Education Registration & Evaluation Form Program Title: The Effects of Long-Term Benzodiazepine Use and Withdrawal in the Elderly UAN: 0048-0000-15-209-H01-P CEUs: 0.1 All information must be printed CLEARLY to ensure accurate record keeping for attendance and the awarding of continuing education credit. You MUST provide your CPE Monitor# and Month and Day of birth to receive credit.

Name: Address: City:

State:

Phone:

Email:

Check one: Pharmacist

Technician

CPE Monitor #:

Zip:

License #:

State:

Birthday (MM/DD):

Program Content:

Strongly Disa gree

The program objectives were clear. The program met the stated goals and objectives: 1. Explain how benzodiazepines differentially affect the elderly population in terms of pharmacokinetics and pharmacodynamics. 2. Discuss specific adverse effects of benzodiazepines in the elderly population and how these adverse effects impact quality of life. 3. Identify patients who are at highest risk of adverse effects with benzodiazepine use. 4. Describe symptoms of and possible treatments for patients experiencing withdrawal from benzodiazepines. 5. Identify ways a pharmacist can improve medication management in the elderly population. The program met your educational needs. Content of the program was interesting. Material presented was relevant to my practice. Audio/visual and/or printed materials aided the learning process. The program used effective teaching/learning methods. The learning assessment activities were appropriate. The program showed good objectivity and no commercial bias. Would you recommend this program to a colleague? What was the most valuable part of this program?

Strongly Agree

1 1 1 1 1 1 1 1

2 2 2 2 2 2 2 2

3 3 3 3 3 3 3 3

4 4 4 4 4 4 4 4

5 5 5 5 5 5 5 5

Strongly Di sagree 1 1 1

2 2 2

Strongly Agree 3 3 3

4 4 4

5 5 5

Suggestion for future programs you would like to see:

A B C D

Answers to Assessment Questions â&#x20AC;&#x201D;Please Circle Your Answer 3. A B C D 5. A B C D 7. A B C D 9. A B C D 4.

A B C D

6. A B C D

8. A B C D

10. A B C D

Ohio Northern University is accredited by the Any questions/comments regarding this continuing education program can Accreditation Council for Pharmacy Education as a be directed to Lauren Hamman, Advanced Administrative Assistant for provider of continuing pharmacy education. This the Office of Continuing Education (email: l-hamman@onu.edu, phone program is eligible for credit until 5/21/2018. 419-772-2280). 18 The Pharmacy And Wellness Review Summer 2015 Volume 6, Issue 3

Pain

Pain Management in Dementia Patients in Nursing Homes Tiffany Kneuss, fifth-year pharmacy student from Dennison, Ohio; Kelsey Weisenburger, fifth-year pharmacy student from Perrysburg, Ohio; Hannah Stewart, fifth-year pharmacy student from Brazil, Ind.; Kelly Reilly Kroustos, PharmD, CGP, CDP, associate professor of pharmacy practice Abstract Pain in the elderly, especially those with dementia, is often undertreated and misdiagnosed by health care professionals in the long-term care setting. Communication barriers in patients with cognitive impairment force pain assessment to rely heavily on subjective interpretation of behavioral factors due to the inability of patients to self-report pain symptoms. It is important for clinicians to develop a standard method of identifying and assessing signs of pain in patients with dementia in order to appropriately treat those experiencing discomfort. Patients with dementia who present with a sudden onset of behavioral changes should receive a comprehensive evaluation that includes a patient questionnaire, standardized pain assessment scale, an observational method of assessment and family member or caregiver interviewing to assess if these changes in behavior could be a result of undiagnosed pain. Proper differential diagnosis of symptom presentation is the only way to ensure that cognitively impaired patients receive the correct diagnosis and treatment to resolve the underlying cause of symptomatology. Key Terms Dementia; Nonverbal; Nursing Homes; Pain; Pain Scores Introduction The U.S. Census Bureau projects the population aged 65 years and older to nearly double by 2050, with a significant increase in the cohort of individuals aged 85 years and older.1 Increasing life expectancy is attributed to overall improved management of chronic disease states, medical innovations, and advances in the health care system. Secondary to this anticipated population increase, the number of nursing home residents is expected to double by 2030, reaching more than 3 million long-term care residents.2 The nursing home setting presents an opportunity for residents to receive management of their chronic health conditions, in conjunction with palliative care such as pain management. Reportedly up to 80 percent of nursing home residents have unmanaged, mismanaged or undermanaged pain resulting in functional impairment and decreased quality of life. 3 There is a great need for health care professionals to step in with a structured system to assess, manage and treat pain. The need for improved pain management within the nursing home setting can be attributed to multiple barriers including system, clinician and patient factors.4 System barriers can be attributed to the large number of nursing home residents and the facility challenges of providing adequate health care staff and resources to serve this increased patient base. Additionally, ensuring that all health care staff are trained and adequately educated in appropriate pain assessment and

treatment strategies is an issue faced at many nursing facilities.2,3 Secondary complications from advanced diseases and their treatments are often challenging for the health care staff to anticipate and address with appropriate medical interventions. Patients may not always report their pain for multiple reasons including denial of a worsening condition, fear of addiction or dependence to prescribed medications or simply not wanting to be a “bother” to the staff. Patients with some form of cognitive impairment may not be able to adequately notify the health care staff at the facility if they have pain. Regardless of the reason, when pain is not reported by the patients to the health care staff it goes unrecognized, and access to appropriate treatment is not provided. Consequently, pain is not managed optimally. Pain in Dementia There are several causes of pain in nursing home patients including immobility due to dementia, cancer, arthritis, tendonitis, neuralgia, surgery, circulatory problems, bowel disorders and falls.2 Patients diagnosed with dementia have a high prevalence of pain and present many challenges for pain assessment. During moderate-advanced stages of dementia, the patient’s ability to verbalize and self-report pain is impaired while immobility contributes to the overall presence of pain. Access to the patient’s past medical history can serve as a valuable resource to determine the etiology of the patient’s pain. For example, a past injury may be causing present pain. Utilizing patient charts to obtain a patient’s history can help health care professionals efficiently identify potential pain sources. Family members and other caregivers are a valuable source of not only historical information but can provide clarity regarding recent health-related complications and injuries. As dementia progresses in severity, symptoms other than cognitive impairment begin to develop and further complicate pain assessment strategies. These symptoms are identified as behavioral and psychological symptoms of dementia (BPSD) and are present in more than half of patients with dementia.5 This refers to any form of disinhibited behavior, delusions, hallucinations, aggression, agitation, anxiety and depression.6 Patients with dementia who cannot clearly articulate the presence of discomfort or pain often express these issues through behaviors which can closely mirror behaviors observed in BPSD. Common pain behaviors include grimacing, sighing, moaning, verbal agitation, guarding, aggressiveness, withdrawal, sleep changes and increased confusion.7 Adequately assessing and treating pain in patients with dementia can be difficult because communication barriers prevent the caregiver’s ability to obtain information by selfreports. Assessments must rely heavily on observational

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Pain

Pain Management in Dementia Patients in Nursing Homes

measures and the subjective interpretation of patient behaviors. In nonverbal patients, pain symptoms are commonly mistaken for normal behavioral symptoms associated with dementia such as agitation and anxiety or BPSD. This misinterpretation often leads to the inappropriate use of antianxiety and antipsychotic medications instead of utilizing the appropriate pain therapy options.8 See Table 1 for pharmacologic pain treatment options. Differential Diagnosis Any sudden changes in behavior may be classified as delirium and indicate the need for further investigation. Delirium is a medical condition characterized by acute confusion or other disturbances in mental function and behavior.9 Compared to dementia, which is associated with a slow decline in memory and mental status over a period of months or years, episodes of delirium consist of rapid-onset confusion or changes in behavior appearing over the course of days or weeks. Symptoms of delirium can also fluctuate in appearance throughout the day.10 These changes are common presentation factors for patients experiencing pain caused by an infection and can also be precipitated by adverse reactions to medications, stroke or other head injury and abrupt withdrawal of a medication, nicotine or alcohol. If pain is suspected to be the causal factor of behavioral changes, initiation of a limited trial of analgesic therapy should be considered while ruling out all other causes.11 Recommendation of an analgesic agent should be based on the type of pain identified by self-reports and observational measures.

Determining Pain Types Determining and understanding the types of pain are critical in order to identify pain early and treat it adequately. Noting potential sources through patient history can be extremely helpful in determining the type of pain in patients with dementia. There are two main pain types: neuropathic pain or nociceptive pain.12 Beuropathic pain manifests as burning, tingling, shooting, radiating pain.4 Recent data indicates that neuropathic pain is by far the most undertreated type of pain in patients with dementia.12 Contrastingly, nociceptive pain typically presents as sharp, aching or throbbing pain also known as somatic pain. However, nociceptive pain can also present as dull, pressured pain in the organs which is known as visceral pain. Determining the type of pain is challenging in patients with dementia. Attention to detail is essential regarding evaluation of the patient’s movement, past medical history and eliciting information from the caregivers. Close observation of activities of daily living and limitations in engagement, as well as nonverbal cues of pain, can serve as an indication of the source of the pain. For example, if a patient grimaces when his or her leg is shifted to get into a bathtub, the pain source is likely in the leg. Pain Assessment In the general population, pain assessment techniques are an essential tool in recognizing pain, assessing the intensity and type of pain, and choosing a successful management and treatment strategy. In patients with mild-moderate dementia, the ability to self-report may remain intact and is therefore the gold standard of pain assessment.4 A valid patient

history can be established through use of the pain assessment mnemonic SOCRATES: Site Onset Character Radiation Association Time course Exacerbating/Relieving factors Severity By assessing these eight characteristics of pain, health care professionals are able to gain insight into the site of pain and pattern of muscle and joint involvement. Determining if the onset was gradual or sudden, how the pain changes over time, whether the pain is dull, sharp, stabbing, aching, or burning, if the pain radiates from one part of the body to another, the timing and association with activities, and other features that come with the pain is essential. A patient’s description of pain can be extremely helpful for clinicians in the process of choosing appropriate treatment. Another useful tool commonly used in patients able to communicate effectively is the Edmonton Functional Assessment Tool (EFAT).4 The EFAT gives patients the ability to quantify pain using a 0 to 10 scale where 0 equals no pain and 10 equals most severe pain. This tool can also be used to quantify other aspects of a patient’s health such as nausea, appetite or sleep. Quantification gives clinicians a clearer idea of the pain they are strategizing to treat. However, as mentioned above, many patients in later stages of dementia are unable to verbally describe pain. This presents a challenge for clinicians and requires use of other methods of pain assessment. A variety of pain scoring methods exist for nonverbal patients that can be utilized to assess physical symptoms, psychological symptoms and function.13 For example, the Abbey pain scale is a validated tool commonly utilized in Australia to measure pain in patients with dementia who cannot verbalize. The scale looks at six nonverbal components in order to calculate a “total pain score.” The six components are vocalization, facial expression, change in body language, behavioral change, physiological change and physical change.14 There are several nonverbal cues of pain, and it is important for nursing home staff to be watchful for these. The Abbey pain scale is especially useful because it lists these nonverbal cues, making clinicians more aware of their significance and potential indication of pain. Some examples of common nonverbal cues of pain that the Abbey pain scale notes are grimacing, whimpering, crying, fidgeting, increased confusion, refusal to eat, perspiration, flushing, pallor or vital signs outside of normal limits. Pain within the dementia population is quite often confused with agitation or anxiety and is not appropriately approached. It is difficult, yet critical, for clinicians to recognize the nonverbal actions that could be indicating pain in order to provide the care that patients with dementia need for comfort. Other direct observational scoring tools useful in assessing pain in nonverbal patients or patients with cognitive impairment and reduced consciousness include the Face, Legs, Activity, Cry and Consolability

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Pain Management in Dementia Patients in Nursing Homes

Pain

Table 1. Selected Medications Used to Manage Pain.16-24 Class

Nonopioids

Mild Opioids

Medication

Type of Pain

Renal Adjustment

Ibuprofen

Mild Nociceptive

Yes

Naproxen

Mild Nociceptive

Yes

Acetaminophen

Mild Nociceptive

Yes

Hydrocodone/ Acetaminophen

Moderate Nociceptive

Use with Caution

Moderate Nociceptive

Use with Caution

Moderate Nociceptive

Yes

Morphine

Severe Nociceptive

Yes

Fentanyl

Severe Nociceptive

Yes

Methadone

Severe Nociceptive

Yes

Gabapentin

Neuropathic

Yes

Pregabalin

Neuropathic

Yes

Oxycodone/ Acetaminophen

Codeine/ Acetaminophen

Strong Opioids

Anticonvulsant/Analgesic (FLACC) scale, Pain Assessment in Advanced Dementia (PAINAD) scale, and the Mobilization Observation Behavior Intensity Dementia (MOBID) pain scale, which evaluate aspects of patient behavior through monitoring and observation of activities of daily living similarly to the Abbey pain scale.4,15 Physical examinations with focus on the musculoskeletal and nervous systems should be done regularly in nursing home patients to help diagnose pain.3 Necessary components of physical examinations include palpation for inflammation and trigger points from muscle strain, tendonitis, and nerve irritation, as well as physical maneuvers that can reproduce the pain such as straight-leg raises and joint movements. Neurologic examinations should also be performed routinely with special attention to autonomic, sensory and motor deficits that may suggest neuropathic conditions. In order to maximize quality of life and mobility, functional status should be evaluated regularly through activities of daily living, ambulation and psychosocial status. Functional status is likely to correlate with the presence and significance of pain. Conclusion In patients with cognitive impairment, a thorough evaluation of behavioral changes should occur before any pharmacological interventions occur. The American Society for Pain Management Nursing’s Task Force recommends a comprehensive, step-wise approach to assessing pain in older adults with dementia.11 Health care professionals should first attempt to obtain self-reported information on symptoms by asking the patient questions about the presence of pain. A standardized evaluation tool such as the numeric rating scale (NRS) should be implemented, followed by the utilization of

an observational tool such as the PAINAD. Finally, family members and caregivers should then be questioned about the current behavior to determine if the patient’s actions differ from normal individual composure. References 1. Ortman J, Velkoff V, Hogan H. An aging nation: the older population in the United States: population estimates and projections. US Department of Commerce. 2014:25-1140. Available from: www.census.gov 2. Meier D. Tomorrow’s nursing homes must integrate palliative care. McKnight’s: The news you need [Internet]. 9 Jan 2015;Guest columns. Available from: www.mcknights.com/diane-e-meier-md-facp/article/ 391683/. 3. Ferrell B. Pain evaluation and management in the nursing homes. Ann Intern Med. 1 Nov 1995;123(9):681-687. 4. Hughes L. Assessment and management of pain in older patients receiving palliative care. NOP. 8 May 2012;24(6):23-29. 5. Hersch EC, Falzgraf S. Management of the behavioral and psychological symptoms of dementia. Clin Interv Aging. 2007 Dec; 2(4):611-621. 6. Carson S, McDonagh M, Peterson K. A systematic review of the efficacy and safety of atypical antipsychotics in patients with psychological and behavioral symptoms of dementia. J Amer Geri Soc. 2006;54:354–61. 7. Snow AL, Shuster JL Jr. Assessment and treatment of persistent pain in persons with cognitive and communicative impairment. J Clin Psychol. Nov 2006;62(11):1379-87. 8. Achterberg W, Pieper M, van Dalen-Kok A, et al. Pain management in patients with dementia. Clin Interv Aging. 2013;8:1471-1482. 9. Alzheimer’s Association [Internet]. Chicago (IL): Alzheimer’s Association; c2015. Delirium or dementia- do you know the difference?; [cited 23 Mar 2015]; [about 3 screens]. Available from: www.alz.org/norcal/ in_my_community_17590.asp. 10. Mayo Clinic [Internet]. Mayo Foundation for Medical Education and Research; c1998-2015. Diseases and conditions-delirium; [updated 15 Aug 2012; cited 23 Mar 2015]; [about 3 screens]. Available from: www.mayoclinic.org/diseases-conditions/delirium/basics/definition/ CON-20033982. 11. Horgas AL. Assessing pain in older adults with dementia. Ann Longterm Care. 2012; D2:1-2. 12. Scherder E, Herr K, Pickering G, Gibson S, Benedetti F, Lautenbacher S.

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Pain

Pain Management in Dementia Patients in Nursing Homes

Pain in dementia. PAIN. 2009;1-3. 13. The Carolinas Center for Medical Excellence [Internet]. Cary (NC): The Carolinas Center for Medical Excellence. Assessment instruments for end of life care [cited 23 Mar 2015]. Available from: www.the carolinascenter.org. 14. Abbey J, DeBellis A, Piller N, Esterman A, Giles L, Parker D, et al. Abbey pain scale. The Australian Pain Society; 1998-2002 [cited 23 Mar 2015]. Available from: www.apsoc.org.au/PDF/Publications/4_Abbey_ Pain_Scale.pdf. 15. Nilsson S, Finnstrom B, Kokinsky E. The FLACC behavioral scale for procedural pain assessment in children aged 5-16 years. Pediatr Anesth. 2008;18:767-774. 16. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Health; c1978-2015. Ibuprofen; [cited 23 Mar 2015]. Available from: online. lexi.com/lco/action/doc/retrieve/docid/patch_f/7066. 17. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Health; c1978-2015. Naproxen; [cited 23 Mar 2015]. Available from: online. lexi.com/lco/action/doc/retrieve/docid/patch_f/7344. 18. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Health; c1978-2015. Aspirin; [cited 23 Mar 2015]. Available from: online. lexi.com/lco/action/doc/retrieve/docid/patch_f/6388. 19. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Health; c1978-2015. Hydrocodone and Acetaminophen; [cited 23 Mar 2015]. Available from: online.lexi.com/lco/action/doc/retrieve/docid/patch_f /7040. 20. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Health; c1978-2015. Oxycodone and Acetaminophen; [cited 23 Mar 2015]. Available from: online.lexi.com/lco/action/doc/retrieve/docid/patch_f /7417. 21. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Health; c1978-2015. Codeine and Acetaminophen; [cited 23 Mar 2015]. Available from: online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6267. 22. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Health; c1978-2015. Morphine; [cited 23 Mar 2015]. Available from: online. lexi.com/lco/action/doc/retrieve/docid/patch_f/1799128. 23. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Health; c1978-2015. Fentanyl; [cited 23 Mar 2015]. Available from: online. lexi.com/lco/action/doc/retrieve/docid/patch_f/6903. 24. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Health; c1978-2015. Methadone; [cited 23 Mar 2015]. Available from: online. lexi.com/lco/action/doc/retrieve/docid/patch_f/7262. The authors have no conflict of interest or funding support to disclose.

The Pharmacy And Wellness Review Summer 2015 Volume 6, Issue 3

Infectious Disease

Combating Antibiotic Resistance in the 21st Century Kevin Krivanek, fifth-year pharmacy student from Brecksville, Ohio; Brian Heilbronner, fourth-year pharmacy student from Lorton, Va.; Brendan Rasor, fourth-year pharmacy student from Kettering, Ohio; Kelsey Lindsley, fifth-year pharmacy student from Port Clinton, Ohio; Andrew Roecker, PharmD ’00, BCPS, chair of the department of pharmacy practice, professor of pharmacy practice Abstract Antibiotic resistance is one of the most significant challenges facing the medical community today. In response, the Centers for Disease Control and Prevention (CDC) created a list of the greatest antibiotic resistance threats, a number of which are gram-positive bacteria. The cell wall of these organisms has long been a favored target of antibiotic therapies, but the development of numerous resistance mechanisms has led to widespread resistance against nearly all major antibiotic compounds on the market. The medical community is faced with the task of developing better antibiotic compounds that preclude the spread of bacterial resistance and also increasing the screening of natural antimicrobials from organisms not readily cultured in the laboratory. The iChip is a novel in situ cultivation device that allows researchers to grow cultures of bacterial species that could not otherwise be cultured in a laboratory setting. This technology has already led to the discovery of several promising novel antimicrobial compounds, including teixobactin. This depsipeptide has excellent activity in vitro against gram-positive organisms including Clostridium difficille, Bacillus anthracis, Enterococcus strains (including vancomycin resistant enterococci), Mycobacterium tuberculosis and Staphylococcus aureus. Pharmacists have a significant impact in the education of patients receiving antibiotic therapy about the issue of drug resistance and how alternative courses of treatment may be needed if antibiotic therapy is unsuccessful. Key Terms Antibiotic Resistance; Bacterial; Cell Wall; Drug Resistance; Gram-Positive Bacteria; iChip; Teixobactin An Overview of Antibiotic Resistance Antibiotic resistance is one of the most significant challenges facing the medical community today. Not only are bacteria adapting at an increasingly rapid rate, but researchers are developing new antibiotics at the slowest rate since the advent of modern antimicrobials.1 Governments around the world have realized that antibiotic resistance is a serious threat, and in the United States numerous federal and state agencies are now releasing guidelines and plans on how to face this issue. It is generally agreed upon that in order to effectively combat resistance, the medical profession must: 1) prevent infections and further spread of resistance, 2) track resistant bacteria, 3) improve the use of current antibiotics, 4) promote the development of new antibiotics and diagnostic tests for resistant bacteria and 5) promote better public education about proper antibiotic use and antibiotic resistance.1,2 According to the Centers for Disease Control and Prevention (CDC), over 2 million illnesses and 23,000 deaths occur each

year in the United States due to antibiotic resistant organisms.1 These infections are also vastly more difficult and expensive to treat. Estimates of the economic impact of antibiotic resistance range up to $20 billion, with an even higher cost in lost productivity. Antibiotics in general are also responsible for nearly one in five emergency department visits due to adverse drug events (ADEs) and are the leading cause of adolescent emergency department visits for ADEs. The CDC created a list of the greatest antibiotic resistance threats categorized as urgent, serious and concerning. Gram-positive Clostridium difficile and carbapenem-resistant enterobacteriaceae (CRE) are two of the three “urgent” threats, and there are also a significant number of gram-positive species in the lower categories. A brief examination of the history of antibiotic development, as compared to antibiotic resistance, helps illustrate the increasing difficulty of not only developing new antimicrobial agents but also fostering proper and effective use of currently available compounds.1 Several years before the widespread use of penicillin in 1943, there were already known isolates of resistant Staphylococcus species. With the development of additional β-lactams and tetracyclines, bacterial species resistant to these compounds also rapidly emerged. As the 20th century closed, every major antimicrobial compound had known resistant isolates. The first decade of the 21st century has seen relatively few new antibiotics introduced to market, yet even these compounds are already associated with resistant species. Common Cell Wall Associated Mechanisms of Resistance in Gram-Positive Bacterial Species The bacterial cell wall and its synthesis are common targets among natural and synthetic antibacterial compounds. This section discusses numerous drug targets associated with cell wall synthesis as well as resistance mechanisms. The oldest and largest class of modern antibiotics are the β-lactams, some examples of which include the penicillins, cephalosporins and carbapenems.3 Transpeptidases involved in cell wall synthesis act as penicillin binding proteins (PBPs) due to their affinity for the β-lactam ring. By mimicking endogenous precursors, β-lactams inhibit transpeptidase activity. However, bacterial species that produce enzymes capable of hydrolyzing the β-lactam ring are able to inactivate the drug. β-lactamase associated resistance is a leading cause of resistance to the β-lactams.4 Another common cause of β-lactam resistance is the protein PBP2a. Bacteria that acquire and express the mecA gene are able to synthesize PBP2a, which then crosslinks peptidoglycan (PG) when the normal transpeptidase PBPs are inactivated by β-lactams.5

Summer 2015 Volume 6, Issue 3 The Pharmacy And Wellness Review

Combating Antibiotic Resistance in the 21st Century

Infectious Disease Figure 1. Isolation Chip (iChip) Design.

(a & b) sample illustration of how the iChip is placed in suspension to capture single cells per each through-hole; (c) two outer plates are fastened to the center plate in the assembly of the iChip. Adapted from: Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015 Jan 22;517(7535):455-9. Used with permission of the authors.

Wall teichoic acid (WTA) and its synthesizing enzyme TarO are also viable targets for antibiotic compounds. 5 It is hypothesized that WTAs play a role in stability of the cell wall during division. Inhibition of WTA synthesis via gene deletion or pharmacological intervention results in defective and inefficient bacterial cell division. Furthermore, Campbell et al. demonstrated a “synthetic lethality” when they combined an inhibitor of TarO with β-lactam antibiotics. In one of the experiments, investigators observed that methicillin resistant Staphylococcus aureus (MRSA) strains treated with tunicamycin developed a significant sensitivity to a number of β-lactam antibiotics. However, this synergistic effect did not carry over to other classes. A possible reason for this specific synergism is that inhibition of WTAs results in misplacement of PBP targets of the β-lactam class, allowing these drugs to overcome resistance mechanisms. Two additional targets for inhibiting cell wall synthesis are Lipid II and Lipid III. These compounds are associated with the movement of PG building blocks across the cell membrane.3,6 Lipid II is a precursor of PG that is transported across the cell membrane by flippase-type transporters.7,8 Once outside the cell, Lipid II is incorporated into the cell wall. Glycopeptide antibiotics, such as vancomycin and teicoplanin, are known to inhibit Lipid II. Despite the large number of naturally occurring antimicrobials that favor this target, vancomycin resistant organisms are becoming increasingly common.1 This is due to the presence of the vanA-

type resistance operon which changes the terminal amino acids on Lipid II from D-alanine-D-alanine to D-alanine-Dlactate.3 This change adversely impacts the binding affinity of vancomycin for Lipid II, resulting in resistance. Lipid III is involved in WTA synthesis. As mentioned previously, WTAs are not essential to cell survival, however, inhibition of WTA synthesis at Lipid III can lead to the buildup of toxic intermediates as well as autolysin mediated degradation of PG.5,6 The Need for Better Antibiotics and Techniques of Discovery As the above sections highlight, there are numerous and diverse pathways by which antibiotic drugs target grampositive bacteria. However, these organisms have developed highly efficient means of evading both natural and synthetic antimicrobial compounds, and this capability threatens to render the vast majority of current antibiotics useless. Moving forward, the medical community has several options: develop better antibiotic compounds that preclude the development of bacterial resistance and/or find ways to increase the screening of natural antimicrobials from organisms not readily cultured in the laboratory.1,6 One of the greatest limitations in modern antimicrobial discovery is that traditional, yet current cultivation methodologies, such as petri dish cultivation, are unable to effectively cultivate certain microbial phyla with known or suspected cultivable representatives. As a result, both the potential to

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Combating Antibiotic Resistance in the 21st Century

Infectious Disease

Table 1. Bactericidal Activity of Teixobactin.9 Organism and Genotype

Teixobactin MIC (µg/mL)

Staphylococcus aureus (MSSA)

0.25

Staphylococcus aureus (MRSA)

0.25

Enterococcus faecalis (VRE)

0.5

Bacillus anthracis

≤ 0.06

Clostridium difficile

0.005

Haemophilus influenzae

Escherichia coli

Escherichia coli (asmB1)

2.5

Pseudomonas aeruginosa

> 32

Klebsiella pneumoniae

> 32

MSSA = methicillin-sensitive Staphylococcus aureus; MRSA = methicillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant Enterococci; asmB1 = a cell membrane assembly suppressor mutation. Minimum inhibitory concentration (MIC) values were determined by broth microdilution. Adapted from: Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015 Jan 22;517(7535):455-9. Used with permission of the authors.

screen for and culture new anti-infective agents is limited in the drug discovery process.9 In 2009, however, the development and introduction of a novel in situ cultivation method, referred to as an isolation chip (iChip), demonstrated a promising capacity to cultivate environmental microorganisms that were formerly considered “uncultivable.” Specifically, the iChip (Figure 1) is an assembly of three sealed hydrophobic plastic polyoxymethylene plates (one central plate and two outer panels), with each containing several hundred “through-holes,” which permit the capture of single microbial cells when suspended in an agar-based liquid medium. On each side of the central plate and between each of the outer panels are two 47-mm polycarbonate membranes which prohibit the migration of single cells captured in the through-holes. Collectively, these technological features enable the isolation of monospecific cultures, particularly of microbial phyla that could not be previously cultured in conventional methods such as petri dishes. Isolation of Teixobactin Using iChip Cultivation The ability of iChip to isolate formerly uncultivable microorganisms indicates its promising potential to expand the drug discovery effort of anti-infective agents, especially those that may be able to combat the problem of drug resistance among current anti-infective agents available in the United States’ pharmaceutical market. In fact, in January 2015, Ling et al. of

NovoBiotic Pharmaceuticals in Cambridge, Massachusetts, utilized iChip cultivation among 10,000 different microbial isolates and identified a new antibiotic—teixobactin—that demonstrated notable bactericidal activity against commonly known drug-resistant microbes, including Staphylococcus aureus, difficult-to-treat enterococci, Mycobacterium tuberculosis, Clostridium difficile and Bacillus anthracis (Table 1).9 Teixobactin (Figure 2), an unusual depsipeptide which contains enduracididine, methylphenylalanine and four D-amino groups, is proposed to inhibit bacterial cell wall synthesis in gram-positive microbes by binding to Lipid II and Lipid III, precursors of peptidoglycan and teichoic acid, respectively. Therapeutic Implications of Teixobactin in Combating Antibiotic Resistance The bactericidal activity and undeveloped resistance of teixobactin gives the compound an edge over anti-infective agents displaying resistance profiles and bacteriostatic properties. Researchers found teixobactin had excellent activity in vitro against gram-positive organisms including drug-resistant strains.6 Data results showed the compound had exceptional activity against Clostridium difficille and Bacillus anthracis, and also displayed excellent activity against Enterococcus strains, Mycobacterium tuberculosis and Staphylococcus aureus. The advantage of teixobactin compared to current anti-

Summer 2015 Volume 6, Issue 3 The Pharmacy And Wellness Review

Infectious Disease

Combating Antibiotic Resistance in the 21st Century

Figure 2. Teixobactin Predicted Structure and Biosynthetic Gene Cluster.

Adapted from: Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015 Jan 22;517(7535):455-9. Used with permission of the authors.

infective agents is based on the inability of bacteria to develop resistance. Teixobactinâ&#x20AC;&#x2122;s major targets, Lipid II and Lipid III, are a new way to inhibit cell wall biosynthesis, which is why bacteria have not been able to show resistance yet. Researchers were unable to obtain mutants of Staphylococcus aureus or Myobacterium tuberculosis resistant to teixobactin, even when plating on media with a low dose (four times Minimum Inhibitory Concentration) of the compound. Table 2 shows a summary of common antibiotic drugs, their targets and mechanisms of resistance. Although the table is not comprehensive, it displays the mechanisms of resistance relative to drug targets. It also shows teixobactin targets a slightly different part of the bacterial cell wall than what has been targeted in the past by other anti-infective agents. Unfortunately, teixobactin is mostly ineffective against gramnegative bacteria because the compound does not target the components in the gram-negative wall. The bacteria from which teixobactin was isolated, Eleftheria terrae (betaproteobacteria), is a gram-negative bacteria, and the organism would not survive if it inhibited its own cell wall. Animal studies establishing safety and efficacy data are the next step in pushing teixobactin toward approval by the U.S. Food and

Drug Administration (FDA). Researchers have shown that teixobactin had no toxicity against mammalian cells at 100 Âľg/mL (the highest dose tested) in vitro. Teixobactin showed no hemolytic activity, did not bind DNA, and was tested in vivo in mice infected with Streptococcus pneumonia; it was shown to be highly efficacious because it caused a 6 log10 reduction of colony forming units in the lungs. The Role of the Pharmacist The role of pharmacists is to prevent antibiotic resistance from progressing by thoroughly explaining antibiotic drug regimens to patients and educating patients on the importance of finishing a regimen although symptoms may have subsided. Furthermore, pharmacists can educate patients on antibiotic resistance in the community and can help patients understand that antibiotics do not work against viral infections. Lastly, pharmacists can stay informed on the latest news for antibiotic discovery so that they understand the indications and mechanisms of new antibiotic compounds for when these drugs are placed on the shelf in the pharmacy for the first time. This will allow pharmacists to give physicians and other health care professionals with pre-

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Combating Antibiotic Resistance in the 21st Century

Infectious Disease

Table 2. Summary of Select Antibiotic Drugs, Targets and Resistance. 3,5,6 Drug Class

Select Compounds

Drug Targets / Mechanism of Action

Common Resistance Mechanisms

ß-lactams

penicillins, cephalosporins, carbapenems

PBPs / inhibition of transpeptidases

ß-lactamase, PBP2a activity

Sugar substrate analogue

tunicamycin

WTA synthesis, TarO / decreased efficiency of cell division, increased susceptibility to ß-lactams

“Synthetic lethality” unique to combination TarO inhibitor and ß-lactam. Not effective with other classes.

Glycopeptides

vancomycin, teicoplanin

Lipid II / incomplete cell wall biosynthesis

Alteration of Lipid II terminal amino acids

Novel depsipeptide

teixobactin

Lipid II, Lipid III / incomplete cell wall biosynthesis, toxic intermediates of WTA synthesis

None yet observed

scribing abilities expert advice in choosing the best antibiotic regimen possible for patients. Conclusion Due to the fact that bacteria are becoming more resistant to antibiotic compounds at an increasing rate, it is vital for the well being of patients presenting with infections to discover new antibiotics that can help better fight off these resistant pathogenic organisms. These organisms have developed highly efficient means of evading both natural and synthetic antimicrobial compounds, and this ability threatens to make the vast majority of current antibiotics useless. The development of iChip as a novel in situ cultivation method for environmental microorganisms that were once thought to be uncultivable demonstrates a promising capacity to discover antibiotic compounds that can be used to combat highly resistant bacterial infections.

8. 9.

Sham L, Butler EK, Lebar MD, Kahne D, Bernhardt TG, Ruiz N. MurJ is the flippase of lipid-linked precursors for peptidoglycan biogenesis. Science. 2014 Jul 11;345(6193):220–2. Nichols D, Cahoon N, Trakhtenberg EM, Pham L, Mehta A, Belanger A, et al. Use of iChip for high-throughput in situ cultivation of “uncultivable” microbial species. Appl Environ Microbiol. 2010 Apr;76(8):2445-50. The authors have no conflict of interest or funding support to disclose.

References 1. Centers for Disease Control and Prevention [Internet]. Atlanta, GA: Centers for Disease Control and Prevention; 2015. Antibiotic resistance threats in the United States [cited 2015 Feb 21]. Available from: www.cdc.gov/drugresistance/threat-report-2013/index.html. 2. Bush K, Courvalin P, Dantas G, Davies J, Eisenstein B, Huovinen P, et al. Tackling antibiotic resistance. Nat Rev Microbiol. 2011 Nov;9(12):894–6. 3. Schneider T, Sahl H. An oldie but a goodie – cell wall biosynthesis as antibiotic target pathway. Int J Med Microbiol. 2010;300:161–9. 4. Rice L. Antimicrobial resistance in gram positive bacteria. Am J Med. 2006;119(6A):S11–9. 5. Campbell J, Singh A, Santa Maria J, Kim Y, Brown S, Swoboda JG, et al. Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosyntheses in Staphylococcus aureus. ACS Chem Biol. 2011 Jan 21;6(1):106–16. 6. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015 Jan 22;517(7535):455-9. 7. Mohammadi T, van Dam V, Sijbrandi R, Vernet T, Zapun A, Bouhss A, et al. Identification of FtsW as a transporter of lipid linked cell wall precursors across the membrane. EMBO J. 2011;30:1425–32.

Summer 2015 Volume 6, Issue 3 The Pharmacy And Wellness Review

Gastroenterology

What is the SmartPill®? Christina Ciccone, fourth-year pharmacy student from Pickerington, Ohio; Pul Lee, fourth-year pharmacy student from Seoul, South Korea; Kimberly Loughlin, fifth-year pharmacy student from Mishawaka, Ind.; David Koh, PharmD, assistant professor of pharmacology Abstract The SmartPill® is a new, noninvasive technology to evaluate the gastrointestinal tract. It is a nondigestible capsule that migrates through the gastrointestinal tract to measure pH, pressure, and temperature. It was approved by the FDA in 2006 for the evaluation of colonic transit time in patients with chronic constipation and to evaluate gastric transit time in patients with suspected gastroparesis. Other currently used gastrointestinal monitoring systems have some disadvantages, and the SmartPill® is suggested as an alternative. The SmartPill® has also been used for research purposes in various studies and has the potential to be used in diagnosis and monitoring of other gastrointestinal diseases. The aim of this article is to evaluate the clinical significance of the SmartPill® by comparing it to other previous gastrointestinal monitoring methods, examining the FDA approved indications, assessing other possible uses for it and providing health care professionals with key counseling points for patients. Key Terms Ambulatory; Constipation; Gastric Emptying; Gastrointestinal Motility; Gastroparesis; Monitoring Introduction The SmartPill®, or wireless motility capsule (WMC), is a relatively new, noninvasive gastrointestinal (GI) monitoring device.1 It comes in the form of a capsule and can be used to measure pressure, pH and temperature in the GI tract. Once it is ingested, the WMC monitors conditions in the GI tract as it travels through the body until it is excreted naturally in the feces.2 The WMC was developed by the SmartPill ® Corporation based in Buffalo, New York, and successfully received U.S. Food and Drug Administration (FDA) approval in 2006 to market in the United States.3 When funds to cover the production and development costs were exhausted, the SmartPill® Corporation was sold to Given Imaging, an Israeli company that develops similar devices, through which the SmartPill® is currently made available.4 Why should pharmacists be familiar with the WMC?  The WMC has various applications for research on the effect that drugs and disease states can have on GI motility.  Patients and doctors may approach pharmacists with questions about the WMC.  It is important to understand new monitoring methods so that they can be compared to current methods in order to recommend the best procedure for patients.  To help improve the care of patients.

This article will highlight the important aspects of the WMC and compare it to several other GI monitoring methods available. Current FDA indications of WMC will also be examined, as well as the applications for research and potential future uses. Finally, important counseling points for pharmacists regarding the WMC will be reviewed. About the SmartPill® The WMC is a nondigestible, disposable capsule.1 Its size is 26 mm by 13 mm, which is slightly larger than a multivitamin tablet. It contains sensors that measure pH, pressure and temperature as it travels through the GI tract. The range of the pH sensor is 0.5 to 9.0 (accurate to ± 0.5), the pressure range is 0 to 350 mmHg (accurate to ± 5 mmHg), and the temperature range is 25 to 49°C (accurate to ± 1°C).5 The capsule uses amplitude-shift keying (ASK) modulated radio frequency signals of 434 MHz to transmit the data gathered from these sensors to a portable receiver (sized 14 cm by 11 cm by 3 cm).5,6 The receiver is worn on either a belt clip or lanyard by the patient throughout the procedure.1 After the test, the receiver is connected to a docking station that downloads the data onto a computer with MotiliGITM Software. The program analyzes the results and converts them into a printable report.6,7 Specifically, the WMC can measure and differentiate between gastric emptying time (GET), small bowel transit time (SBTT), combined small and large bowel transit time (SLBTT), colonic transit time (CTT) and whole gut transit time (WGTT).6 Figure 1 shows a sample of the data obtained from the WMC and its interpretation of GI transit times.8 Cassilly and colleagues determined the WMC usually empties from the stomach during phase III migrating motor complexes (MMC) that follow the end of the fed state by comparing it with data from gastric emptying scintigraphy (GES) and antroduodenal manometry.9 This confirmed that the WMC mimics the emptying pattern of nondigestible solids, rather than digestible foods. Other studies found varying levels of correlation, so the mechanism needs further studies to be fully understood. The WMC is primarily used in the setting of a clinic or physician’s office as a GI motility monitoring test to diagnose motility disorders, such as gastroparesis (determined by delayed GET) and chronic constipation (using CTT or SLBTT as a surrogate in cases of undetermined CTT).1,6 Usually, the WMC test is prescribed when the patient is experiencing unexplained GI symptoms including nausea, bloating, constipation, abdominal pain and/or vomiting.1 By measuring GI transit times, it is possible to more accurately diagnose and treat the disease and thus eliminate much trial and error.

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What is the SmartPill®?

One limitation of the WMC is its relatively large size, which makes it difficult to swallow, as well as the possibility that it can be temporarily wedged in the stomach, leading to prolonged GET and WGTT.10 Other limitations include the fact that the receiver must be kept in close proximity throughout the procedure and the limited battery life. Also, if the capsule exit cannot be confirmed due to technical issues of the receiver, in which case an X-ray is required, this will add extra costs and difficulty for the patient. These issues must be carefully considered before deciding on the best option for the patient. How to use the SmartPill® Given Imaging has a patient education pamphlet that instructs patients on how to prepare for the test and about the administration of the WMC.2 Eight hours before the test, patients are instructed not to eat or drink anything except water. This is unlikely to be an issue since the WMC is usually administered in the morning, so the fasting prior to the test is simply overnight.

Gastroenterology When the patient arrives at the clinic or the physician’s office for the appointment (which typically lasts only 30 minutes), they are given a SmartBar® to eat before swallowing the capsule.2 The SmartBar® is a standardized nutrient bar containing 66 percent carbohydrates, 17 percent protein, 2 percent fat and 3 percent fiber.11 It stimulates the post-prandial state of the stomach so that each patient has a consistent starting point for the administration of the WMC to allow an accurate measurement of GI transit times.2 Once the patient has eaten the SmartBar®, the physician activates the WMC by placing it on the activation fixture.12 The WMC is then ingested and the patient is given the receiver that records the data from the capsule.2 At this point the patient is free to leave and resume their normal daily activities as long as they fast for six hours after the administration of the WMC and wear the receiver. Even when sleeping or bathing, the receiver should be kept no more than a few feet away from the patient to allow for complete data collection. The test lasts about three to five days or as long as it takes for the WMC to be excreted.2 If not excreted within five days,

Figure 1. Sample Data From a Wireless Motility Capsule.

Sample of pH, temperature and pressure data collected by the wireless motility capsule (WMC) and the three main transit times that can be determined by its utilization: gastric emptying time, small bowel transit time and colonic transit time.8 Upon ingestion, WMC detects temperature increase to body temperature. The GET is determined by the abrupt rise in pH ≥ 2, which signals the WMC’s exit from the acidic stomach into the basic intestine. The SBTT is measured as the time period from GET to a second major pH change (abrupt drop ≥ 1 pH units), which represents WMC exit from the ileum and entrance into the relatively more acidic cecum. The CTT is the time from WMC entry into the cecum to its excretion from the body, detected by an abrupt and sustained temperature drop. Used with permission from: Saad RJ, Hasler WL. A technical review and clinical assessment of the wireless motility capsule. Gastroenterol Hepatol (N Y). 2011;7 (12):795-804. Summer 2015 Volume 6, Issue 3 The Pharmacy And Wellness Review

What is the SmartPill®?

Gastroenterology the battery life of the capsule/receiver set may expire, resulting in incomplete data collection. Patients should allow bowel movements to remain in the toilet for five minutes to allow the capsule to detect the temperature change once it has been excreted, which will trigger the indicator light on the receiver.10 After one week, if neither the receiver nor the patient can confirm the passage of the capsule, the patient may have to undergo an abdominal X-ray to ensure excretion.11 Once data collection is finished, the patient returns the receiver to the physician’s office where the results can be downloaded and analyzed.2 It is not necessary for the patient to retrieve the capsule. Comparison with Other Methods Scintigraphy Scintigraphy and radiopaque markers have commonly been used to evaluate whole gut transit.13 Whole gut transit scintigraphy (WGTS) involves a three to four day test. Patients are required to stop medications that may have effects on GI motility for 48 hours before the test. Patients then ingest two large scrambled eggs labeled with 500μCi of 99m-Tc sulfur colloid served between two pieces of toasted white bread, and 300ml of water containing 125μCi of 111-In-DTPA. The data is obtained by a large field of view camera with a medium energy collimator and a nuclear medicine computer. 14 Although scintigraphy involves minimal exposure to radiation and is able to assess whole gut transit, it is expensive and has a long duration of time to study, making it unsuitable for practice. A study by Maqbool and colleagues suggested that the WMC can be the next improved method for assessing GI motility. The study compared the whole gut transit of 10 healthy subjects using scintigraphy and the WMC simultaneously, and the transit time between the two methods was strongly correlated, indicating that the WMC gives comparable results to scintigraphy.13 Furthermore, a study by Cassilly and colleagues also observed the strong correlation between scintigraphy and the WMC for measuring GET. Their experiments were conducted with 15 normal subjects receiving antroduodenal manometry, scintigraphy, and the WMC. 9 Because the WMC is convenient and requires less work by an administrator as compared to scintigraphy, it may represent a superior choice as an examination tool due to its similar level of accuracy.13

Antroduodenal Manometry The migrating motor complex (MMC) is one of the most studied and well-known patterns of GI motor function to detect various GI disorders, such as irritable bowel syndrome, functional dyspepsia, gastroparesis and constipation.15 Phase III MMC in the stomach and small intestine has been a challenging region to evaluate, and the standard method of antroduodenal manometry is invasive in nature. The instrument requires cleaning out of the intestinal tract to insert the water perfused or solid state catheter to measure the intraluminal pressure.16,17 In contrast, the WMC’s noninvasive characteristic can be an alternative method to detect phase III MMC. A study from Brun and colleagues conducted a comparative analysis of phase III MMCs in the stomach and small bowel by administering the WMC and antroduodenal manometry concurrently to 18 patients. The outcomes of the

study revealed that the WMC was able to detect with good precision the phase III MMC, which was identified as high amplitude contractions. In the study, the researchers stated that the WMC’s characteristic of freely floating inside the gut might have resulted in differences in luminal pressures, requiring different parameters for interpretation. However, this limitation of needing a new set of interpretation tools can outweigh the benefits for the noninvasive nature of the WMC when compared to the standard test of the antroduodenal manometry.15 Additionally, antroduodenal manometry has disadvantages not shared with the WMC. A study by Hasler and colleagues indicated that cleansing the colon with a lavage solution to perform antroduodenal manometry might disrupt physiological conditions of fecal retention, which lead to inaccurate assessment in constipation studies. Furthermore, manometry requires specialized equipment and manpower, making it a challenge to use frequently in a clinical setting.17 The WMC technology has shown its potential in the Brun and colleagues study to extend from its FDA indicated uses in the diagnosis of constipation and gastroparesis to accurately detect phase III MMC. Radiopaque Markers Even though radiopaque markers (ROMs) have been used traditionally to measure CTT, this technique requires radiation, and its lack of standardization and compliances makes it a technique that some health care professionals are reluctant to use. The ROMs are plastic beads or rings that are packaged in a capsule, and a single capsule technique or a multiple capsules technique is used to obtain the data.18 The single capsule technique is when the patient ingests a single capsule followed by several abdominal X-rays until all markers are excreted, or a single abdominal X-ray is taken on day 5. Because this method is time-consuming and the patient is exposed to high levels of radiation, the multiple capsules technique is preferred, where the patient ingests one capsule a day for three days, and abdominal X-rays are taken on day 4 and day 7 or only on day 7. A ROM test is not capable of analyzing regional gut transit, and performing the test sometimes requires multiple visits.19 In order to suggest an alternative method to monitor CTT, a study by Rao and colleagues utilized the WMC and ROM to compare CTT, WGTT, SBTT and GET between 78 constipated patients and 87 healthy control patients for five days. The study was designed to assess the ability of the WMC to differentiate between CTT and WGTT and distinguish normal and slow CTT. Furthermore, the study compared the accuracy of the information with that of the ROM method. The study observed a delay in GET, CTT and WGTT with constipation patients. The diagnostic accuracy to determine constipation exhibited specificity of 0.95 and reasonable sensitivity of 0.46 with the WMC, and 0.95 specificity and 0.40 reasonable sensitivity for ROM, which demonstrated a great congruency between these two tests. Additionally, the high specificity indicated the WMC’s ability to distinguish between normal and slow CTT, and its continuous and more direct measure of CTT may be able to indicate the severity of slow transit constipation in the future. Because the WMC does not require radiation and has results agreeable with ROM, it has demon-

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strated its potential to be a comparable measurement method for CTT and become a standardized technique. SmartPill® Uses The WMC was approved as a GI motility monitoring device in 2006 according to the FDA 510K statement, having met all the clinical testing and safety criteria for such devices. 3 It is used mainly to diagnose gastroparesis, but it can also be used to diagnose chronic constipation. Off-label uses include research analyzing how certain diseases and drugs affect GI motility and conditions. The WMC also has the potential to be utilized to diagnose diseases involving hypersecretion of acid.20 Approved Indications Gastroparesis Gastroparesis is a chronic GI disorder in which the emptying of the stomach is delayed for reasons other than a physical obstruction.5 Patients may experience nausea, vomiting, bloating, abdominal pain and dyspepsia. Due to the fact that these symptoms are common to many GI disorders, it can be difficult to pinpoint the exact cause based only on the clinical presentation. A prospective, multicenter study by Kuo and colleagues examined the ability of GET measured by the WMC to differentiate between healthy and gastroparetic subjects compared to GES. The study involved 87 healthy subjects and 61 subjects with gastroparesis.5 All patients were simultaneously given the WMC to assess GET and a [99mTc]-SC radiolabelled meal to measure percent of meal retained at 30 minute intervals by GES. The WMC was taken first, followed by the completion of the radiolabelled meal within 20 minutes of capsule ingestion. A correlation greater than 0.7 was considered to be significant. Results found GET (measured in minutes), GES-2h, and GES-4h (measured in percent of meal retained in the stomach) to be significantly different in healthy subjects as compared to gastroparetic subjects (p-value <0.05). The GET was most strongly correlated with GES-4h (0.73), which was greater than the target 0.7 for significance. The correlation between GET and GES-2h did not reach statistical significance (0.63). Both GET and GES-4h were shown to be clinically useful for diagnosing gastroparesis, so the WMC could be considered a viable replacement for GES. Chronic Constipation There is little known about colonic motility in normal, constipation, and constipation-predominant irritable bowel syndrome (C-IBS). The study from Hasler and colleagues conducted an experiment to characterize regional differences in colon pressure, relate motor differences in constipation to colon transit and quantify the role of irritable bowel syndrome (IBS) in altered contractility with constipation using the WMC.17 Because the capsule continuously measures luminal pH, pressure and temperature, it was used to obtain a greater understanding of the relationship between colon motor activity and constipation, as well as to differentiate C-IBS from constipation not related to IBS. The study recruited 53 healthy and 36 constipated subjects. Twelve of the constipated participants had C-IBS, and 24 had functional constipa-

Gastroenterology tion. The study concluded that colon pressure activity is active distally, rather than proximally, in the control group. Due to IBS, constipated patients with normal or moderate slow transit demonstrated an increase in motor activity, which showed differences in transit and motility among different subtypes of constipated patients. The study discussed some limitations of WMC technology.17 First, the capsule has one pressure sensor, which did not allow it to distinguish between mixing and propulsive motility, identify high-amplitude propagating contractions or differentiate motor artifact from luminal contractions. Second, due to the capsule’s size larger than stool, the capsule was not managed physiologically in the body. Some studies have observed that the WMC moved faster in the colon than small particles or liquids. Finally, it is difficult to detect the position of the capsule accurately, except when the capsule was in ileocecal transit and before excretion. Despite its weaknesses, the WMC may have potential future use in testing responsiveness to laxatives in different patients. Also, it can be a useful method to decide treatment options for difficult constipation cases. Research Purposes Spinal Cord Injury Patients who have experienced spinal cord injury (SCI) sometimes experience a disruption in their GI function.21 It can be difficult to monitor and research their condition with traditional testing methods due to the invasive nature of existing tests or necessity to alter lifestyle during the testing period, both of which can potentially affect results. Williams and colleagues studied the effects of SCI on GET, CTT and WGTT using the WMC as their GI motility monitoring device. Their goal was to determine if the WMC was a viable option for monitoring SCI patients and evaluate their GI function. The study enrolled 20 SCI patients and 10 healthy subjects.21 The SCI patients had complete or incomplete paraplegia and tetraplegia for more than six months as well as abnormal bowel movements. The SCI group had prolonged GI transit times (GET: 10.6 ± 7.2 hours, CTT: 52.3 ± 42.9 hours, WGTT: 3.3 ± 2.5 days) compared to the healthy patients (GET: 3.5 ± 1.0 hours, CTT: 14.2 ± 7.6 hours, WGTT: 1.0 ± 0.7 days) with p-value less than or equal to 0.01. These results supported evidence from previous studies that used more invasive methods that indicated SCI patients had delayed GI transit times. None of the subjects had difficulty swallowing the WMC, and they reported no complications or side effects as a result of taking the WMC. The study concluded that the WMC was most likely a safe and effective method for GI monitoring in patients with SCI. Medications Certain drugs can have an impact on GI motility. Rozov-Ung and colleagues performed a crossover study to test the ability of the WMC to evaluate the effect of erythromycin IV 150 mg versus morphine IV 0.05 mg/kg versus normal saline IV on GET and motor activity.11 Erythromycin is well known to decrease GET while morphine increases GET.

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Gastroenterology The study included 15 healthy adults who were administered each course of therapy, in random order, on three separate occasions at least one week apart.11 The GET for erythromycin was significantly faster than saline (p-value < 0.001), while GET for morphine was somewhat slower compared to saline (p-value = 0.11). Contractility was not significantly different when comparing morphine to erythromycin (p-value = 0.14) or saline (p-value = 0.12). The WMC successfully detected expected changes in GI motility caused by erythromycin and morphine, and thus may be a valuable tool for researching the effects of other drugs on GI motility. Dietary Fiber Dietary fiber is well known to affect GI motility, but for many years the only methods to quantify the effect were either invasive or involved radiolabeled food.10 Timm and colleagues performed a controlled, crossover trial to determine whether the WMC could measure the difference in GI transit times between a wheat bran and a low fiber control diet. Ten healthy subjects were enrolled in the study. 10 Each subject completed both dietary interventions. These interventions involved eating either the control or the wheat bran cereal three days prior to each of their visits and keeping a food diary. The results showed that the wheat bran intervention caused a significant decrease in CTT and WGTT, in which they observed a mean difference of -10.8 (p-value = 0.006) and -8.9 (p-value = 0.02), respectively. The GET and SBTT were not significantly different between the two interventions. The WMC was therefore able to detect differences in GI motility related to dietary interventions and thus demonstrated its potential for use in future digestive studies. Appetite Willis and colleagues designed a randomized crossover study to evaluate the utility of the WMC in research involving GI transit times and also to determine if GET had any relation to appetite.7 The trial compared GET, as measured by the WMC, to appetite, as determined by visual analog scales (VAS) after two different types of meals. These meals were of equivalent caloric and dietary fiber content, but one was a liquid meal and the other a solid meal. Fourteen women were randomized according to which intervention they would receive first: the liquid breakfast consisting of fruit juice and skim milk or the solid breakfast of oatmeal, blueberries and apples.7 The GET was longer with the solid breakfast than the liquid breakfast: 4.2 ± 0.2 hours versus 3.3 ± 0.2 hours, respectively (p = 0.003). Analysis of appetite using VAS showed that patients were less hungry and more satisfied after the solid meal. Thus, there was a negative correlation between GET and appetite. The study concluded that WMC was a reasonable option for assessing GET in a nutrition or appetite study, particularly because the free mobility of the patient using WMC was as “true-to-life” as possible. One of the limitations of the WMC is the fact that the capsule is large and nondigestible, so it does not empty from the stomach until after the smaller, particulate food matter.

Critically Ill Trauma Patients It is widely known that critically ill patients have difficulty with gastric emptying due to insufficient nutrition and delayed digestive function.22 However, monitoring the GI malfunction of these patients is difficult when they are mechanically ventilated. Furthermore, monitoring the small bowel is especially difficult due to its length, location and twisted shape. The WMC has been introduced as an alternative and innovative technique to assess GI motility in critical care patients. The study by Rauch and colleagues compared GET, SBTT and WGTT in eight critically ill trauma patients with 87 healthy volunteers from different trials using the WMC. This prospective cohort study demonstrated that the GET and the SBTT were significantly delayed for the critically ill patients group. Also, the trauma patients required 10 days to process the capsules, as compared to 1.2 days with the control group. The results correlate with other studies that measure delayed gastric empty time with other techniques such as scintigraphy, C-octanoic acid breath test and antroduodenal manometry.22 The WMC demonstrated its ability to become an alternative method to other invasive techniques to monitor critically ill patients’ gastric function, including the small intestine, where traditional technology cannot detect well. Cystic Fibrosis Regulating specific pH ranges in the GI tract is important to digest foods and protect from ingested microorganisms.23 Patients with cystic fibrosis (CF) are characterized by a mutation in the cystic fibrosis transmembrane conductance regulator protein (CFTR) in the pancreas and other organs. This leads to insufficient neutralization of the gastric acid in the duodenum, causing inadequate nutrient absorption and failure to activate enteric-coated pancreatic enzyme replacement therapy (PERT) for patients with pancreatic insufficiency (PI). An antimony sensor in a swallowed pill device was used in some older studies to show that CF patients experience a more acidic small intestine relative to controls. This device is no longer used due to its instability, and a recent study by Gelfond and colleagues utilized the WMC to evaluate its potential uses to provide a distinct pH profile in CF patients. The study found that there was a statistically significant difference between mean pH values during the first 23 minutes of small bowel transit. Cystic fibrosis patients have shown a prolonged time interval to reach and maintain pH 5.5 and pH 6.0, which are pH ranges crucial for PERT dissolution. Accordingly, CF patients experienced an inadequate neutralization of gastric acid in the duodenum. Moreover, patients with CF took significantly longer time in the SBTT, while GET, CTT and WGTT were not significantly different between the two groups. This study demonstrated the ability of the technology in the WMC to provide the distinct gastrointestinal pH profile in CF patients, which may give a valuable understanding in optimizing nutritional and pharmacological interventions in the future.23 For instance, the research excluded CF patients without acid suppression, but there are some studies that have shown that inhibiting gastric acid may have an effect on respiratory disease by eliminating bacterial properties of

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gastric acid, and the WMC can be applied to examine the effects of acid suppression in patients with CF. Furthermore, the WMC can be a useful tool to evaluate new classes of CFTR modulating drugs as well as a pharmacological intervention tool for CF patients to individualize treatments according to their gastrointestinal pH profile. Potential Future Uses Gastroesophageal Reflux Disease (GERD) Although the WMC is not currently approved to diagnose GERD, it is well-equipped to measure gastric acid output (GAO), which is often a key component of GERD and other gastric hypersecretory diseases.20 Weinstein and colleagues evaluated the use of the WMC as a noninvasive alternative to measuring GAO compared to a nasogastric tube. They found the WMC was an accurate and viable method of measuring GAO in healthy patients, and therefore had potential for use in research and management of disorders involving gastric acid secretion such as GERD, Barrett’s esophagus, ZollingerEllison syndrome and atrophic gastritis. They also thought it might be applicable to antisecretory drug development and gastric cancer screening. The WMC and nasogastric tubing were both used to determine the GAO in 20 healthy subjects.20 Additionally, 12 of the subjects were later given a second WMC to test reproducibility. The statistical analysis predetermined a range (r) of 0.5 to 0.7 to be considered an acceptable correlation. Results showed a strong correlation between GAO as measured by the WMC, compared to conventional measurements, such as basal acid output (BAO) (r = 0.51, p-value = 0.02), maximal acid output (MAO) (r = 0.72, p-value = 0.0004) and peak acid output (PAO) (r = 0.60, p-value = 0.006). The only limitations of this study were the small sample size and the rapid GET in some patients causing an overestimation of GAO. Patient Counseling Pharmacists should counsel patients on important points about the function and use of the WMC. Additionally, pharmacists should warn patients to check with their physician about medications they are using that might hinder accurate test results or disease states in which WMC might be contraindicated.2 Medications that might affect the procedure include pain medications, sedatives, tranquilizers, antispasmodics, promotility agents and even medications taken for heart disease, hypertension or diabetes. Pharmacists should advise the patient to complete a medication history review with their physician prior to undertaking the test. The main condition in which the use of WMC is not recommended is in patients with GI obstruction. Severe obesity may also interfere with data collection and may not be effective for these patients. The WMC procedure should not be used in patients under age 18 years. It is important to advise patients and physicians about the cost of the WMC procedure. A capsule alone costs $600 and the startup cost for the entire system is more. 10 As of 2013, the WMC was assigned a reimbursement Category 1 CPT code (91112), stating that the 2013 National Average Medicare Physician Fee was set at $1,188.93.24 This means that

Gastroenterology Medicare and some other insurance companies will cover the physician’s fee for the procedure, but the patient will likely still have to pay for the cost of the equipment. If cost is likely to be a barrier for the patient, the WMC may not be the best option. Conclusion The WMC has proven to be as effective as other GI monitoring methods such as scintigraphy, antroduodenal manometry and ROM for diagnosis of gastroparesis and chronic constipation as well as a variety of research purposes. It also seems to have the potential for monitoring and management of hypersecretory conditions such as GERD. Both the advantages and limitations of the WMC in comparison to other methods need to be taken into consideration when deciding the best course of action for the patient. However, the WMC seems to be a valid option in many situations. References 1. Given Imaging. SmartPill motility monitoring: frequently asked questions [Internet]. Given Imaging Ltd.; c2001-2015 [cited 2015 Feb 2]. Available from: www.givenimaging.com/en-int/Innovative-Solutions/ Motility/SmartPill/Resources-Patients/Documents/SmartPill-PatientFAQs.pdf. 2. Given Imaging. SmartPill patient brochure [Internet]. Given Imaging Ltd.; c2001-2015 [cited 2015 Feb 2]. Available from: www.given imaging.com/en-int/Innovative-Solutions/Motility/SmartPill/resour ces-Patients/Documents/SmartPill-Patient-Brochure.pdf. 3. SmartPill GI Monitoring System [510(K) Summary K053547]. Rockville (MD): FDA; 2006 Jul 7. 4. Robinson D. SmartPill’s painful demise hard to swallow. The Buffalo News [Internet]. 2013 Jan 27 [updated 2013 Jan 28; cited 2015 Feb 20]; [about 3 screens]. Available from: www.buffalonews.com/apps/ pbcs.dll/article?aid=/20130127/business/130129291. 5. Kuo B, McCallum RW, Koch KL, Sitrin MD, Wo JM, Chey WD, et al. Comparison of gastric emptying of a nondigestible capsule to a radiolabelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther. 2007 Oct 25;27:186-96. 6. SmartPill GI Monitoring System, version 2.0 [510(K) Summary K092342]. Silver Spring (MD): FDA; 2009 Oct 30. 7. Willis HJ, Thomas W, Willis DJ, Slavin JL. Feasibility of measuring gastric emptying time, with a wireless motility device, after subjects consume fiber-matched liquid and solid breakfasts. Appetite. 2011 Mar 22;57:38–44. 8. Saad RJ, Hasler WL. A technical review and clinical assessment of the wireless motility capsule. Gastroenterol Hepatol. 2011 Dec;7(12):795– 804. 9. Cassilly D, Kantor S, Knight LC, Maurer AH, Fisher RS, Semler J, et al. Gastric emptying of a non-digestible solid: assessment with simultaneous SmartPill pH and pressure capsule, antroduodenal manometry, gastric emptying scintigraphy. Neurogastroenterol Motil. 2008 Apr;20 (4):311–9. 10. Timm D, Willis H, Thomas W, Sanders L, Boileau T, Slavin J. The use of a wireless motility device (SmartPill®) for the measurement of gastrointestinal transit time after a dietary fibre intervention. Br J Nutr. 2011;105:1337–42. 11. Rozov-Ung I, Mreyoud A, Moore J, Wilding GE, Khawam E, Lackner JM, et al. Detection of drug effects on gastric emptying and contractility using a wireless motility capsule. BMC Gastroenterol. 2014 Jan 2;14 (2):1-6. 12. Given Imaging. SmartPill®: the measure of GI health® [Internet]. Buffalo (NY): The SmartPill Corporation; c2010 [cited 2015 Mar 22]. Available from: www.lifebridgehealth.org/uploads/public/pdf/Gastroenter ology/FAQs_WEB.pdf. 13. Maqbool S, Parkman HP, Friedenberg FK. Wireless capsule motility: comparison of the SmartiPill® GI monitoring system with scintigraphy for measuring whole gut transit. Dig Dis Sci. 2009;54:2167-74. 14. Bonapace ES, Maurer AH, Davidoff S, Krevsky B, Fisher RS, Parkman HP. Whole gut transit scintigraphy in the clinical evaluation of patients with upper and lower gastrointestinal symptoms. Am J Gastroenterol.

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Gastroenterology 2000;95(10):2838-47. 15. Brun R, Michalek W, Surjanhata BC, Parkman HP, Selmer JR, Kuo. Comparative analysis of phase III migrating motor complexes in stomach and small bowel using wireless motility capsule and antroduodenal manometry. Neurogastroenterol Motil. 2012 Apr;24(4):332-e165. 16. Patcharatrakul T, Gonlachanvit S. Technique of functional and motility test: how to perform antroduodenal manometry. J Neurogastroenterol Motil. 2013 Jul;19(3):395-404. 17. Hasler WL, Saad RJ, Rao SS, Wilding GE, Parkman HP, Koch KL, et al. Heightened colon motor activity measured by a wireless capsule in patients with constipation: relation to colon transit and IBS. Am J Physiol Gastrointest Liver Physiol. 2009 Oct 1;297:G1107-14. 18. Kim ER, Rhee P. How to interpret a functional or motility test - colon transit study. J Neurogastroenterol Motil. 2012 Jan;18(1):94-9. 19. Rao SSC, Kuo B, McCallum RW, Chey WD, Dibaise JK, Hasler WL, et al. Investigation of colonic and whole-gut transit with wireless motility capsule and radiopaque markers in constipation. Clin Gastroenterol Hepatol. 2009;7(5):537-44. 20. Weinstein DH, deRijke S, Chow CC, Foruraghi L, Zhao X, Wright EC, et al. A new method for determining gastric acid output using a wireless pHsensing capsule. Aliment Pharmacol Ther. 2013 May 3;37:1198-1209. 21. Williams RE, Bauman WA, Spungen AM, Vinnakota RR, Farid RZ, Galea M, et al. SmartPill technology provides safe and effective assessment of gastrointestinal function in persons with spinal cord injury. Spinal Cord. 2012;50:81â&#x20AC;&#x201C;4. 22. Rauch S, Krueger K, Turan A, Jing You MS, Roewer N, Sessler DI. Use of wireless motility capsule to determine gastric emptying and small intestinal transit times in critically ill trauma patients. J Crit Care. 2012;27(5):534.e7-12. 23. Gelfond D, Ma C, Semler J, Borowitz D. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci. 2013;58(8):2275-81. 24. Given Imaging announces new reimbursement code for its SmartPill wireless motility capsule procedure. Market Wired [Internet]. 2013 Jan 17 [cited 2015 Feb 20]; [about 2 screens]. Available from: www. marketwired.com/press-release/given-imaging-announces-new-reim bursement-code-its-SmartPillr-wireless-motility-capsule-nasdaq-givn1746754.htm. The authors have no conflict of interest or funding support to disclose.

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Leadership

Changing Roles in Leadership for Today’s Pharmacist— A Look Into the New ACPE Draft Leadership Standards Maureen Moynihan, fifth-year pharmacy student from Bloomfield Hills, Mich.; Sabrina Hamman, fourth-year pharmacy student from Westlake, Ohio; Rachel Muhlenkamp, fifth-year pharmacy student from Findlay, Ohio; Steven Martin, PharmD, BCPS, FCCP, FCCM, dean of The Raabe College of Pharmacy; Jenelle Sobotka, PharmD, endowed chair, professor of pharmacy practice Abstract With the advancement of the profession of pharmacy, the demand for pharmacist leadership continues to rise. In order for pharmacists to acquire the necessary leadership skills for the profession, there is a call for colleges of pharmacy to incorporate leadership development into their academic programs. The Accreditation Council for Pharmacy Education (ACPE) has released the new 2016 Standards and Guidance Documents for institutions to follow in order for their pharmacy students to graduate with leadership skills. Key Terms ACPE; CAPE; Continued Education; Employer Expectation; Guidelines; Leadership; Pharmacy; Standards Accreditation Council for Pharmacy Education (ACPE) The Accreditation Council for Pharmacy Education is responsible for the accreditation of pharmacy degree programs as well as providers of continuing pharmacy education.1 The ACPE began its educational accreditation services in 1932 and expanded its accreditation to include continuing education in 1975. The board of directors is represented by appointees from various prestigious pharmacy organizations including the American Association of Colleges of Pharmacy (AACP), the American Council on Education (ACE), the American Pharmacists Association (APhA) and the National Association of Boards of Pharmacy (NABP). The U.S. Department of Education has recognized ACPE as an educational accrediting body since 1952, and the Council for Higher Education Accreditation began recognizing ACPE in 2004. In the United States, state boards of pharmacy require that pharmacy licensure applicants have graduated from an ACPE accredited pharmacy degree program before attempting the North American Pharmacist Licensure Examination (NAPLEX ®) in order to practice.2 The mission of ACPE is, “To assure and advance excellence in education for the profession of pharmacy.” 1 In order to provide this assurance of excellence, ACPE establishes standards and criteria for colleges of pharmacy as well as continuing education providers. As the profession of pharmacy progresses, the ACPE guidelines and requirements are becoming more insistent that pharmacists are trained as skilled leaders throughout their education in order for the pharmacist workforce to be strengthened as a whole. On Feb. 2, 2015, ACPE released the updated 2016 “Accreditation Standards and Key Elements for the Professional Program in Pharmacy Leading to the Doctor of Pharmacy Degree.”

How Standards Are Created The accreditation standards released from ACPE reflect the expectations that colleges of pharmacy should meet and exceed in order to offer the Doctor of Pharmacy degree (PharmD).2 In order for a college of pharmacy to achieve and maintain accreditation, the degree program must meet ACPE’s standards, which also reflect the expectations from the U.S. Department of Education and state boards of pharmacy. Groups that are affected by educational outcomes of pharmacy degree programs provide their input to ACPE for the development of the standards.2,3 In January 2012, ACPE announced their intent to revise the PharmD standards to their stakeholders in order to receive their input. ACPE’s stakeholders include colleges that offer pharmacy programs, professional pharmacy organizations, student pharmacy organizations, as well as other accrediting bodies (e.g., U.S. Department of Education).2,4 The ACPE then led a Consensus Conference on Advancing Quality in Pharmacy Education and invited 90 participants—half from pharmacy practice and half from pharmacy education. The ACPE conducted a survey from the participants in order to focus on specific issues that concern the future needs of patients. This conference addressed the issue of interprofessional health care education, deducing that universities must work to incorporate interprofessional learning among health care degrees in order to improve the workforce, patient access to care and overall patient safety. Competency requirements were also addressed, focusing on learning gaps in the areas of proper medication use and prescription drug abuse. The information assessed during this conference provided a strong influence for the 2016 ACPE Standards. What is New in the 2016 ACPE Standards? There are several distinguished differences between the 2016 ACPE Standards and the previous 2007 Standards.2 First, the format has changed so that there are two documents for consideration—“Standards” and “Guidance.” The “Standards” document includes the key elements of the new standards as well as information about required documentation for these standards to be implemented. The “Guidance” document consists of suggested strategies and was created in order to assist colleges with enhancing the quality of educational programs.3 The philosophy and emphasis of the 2016 Standards are also different than the past standards.2 The 2016 Standards are now focusing more on the development of the students’ competencies, the ways in which educational bodies assess their students’ knowledge, the expertise of students’ skills, as well

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Changing Roles in Leadership for Today’s Pharmacist —A Look Into the New ACPE Draft Leadership Standards

as the advancement of students’ professionalism through their studies and interprofessional education. The importance of assessment, or improving the quality of the pharmacy education, has also enhanced focus for the 2016 Standards. These new standards also reiterate that colleges may use methods other than what is suggested in the ACPE 2016 Guidelines to improve their education as long as the Standards are being met.2, 3 In addition to the different educational approaches of the 2016 Standards, the organization of the “Standards” and “Guidance” documents, including the writing style, were changed in order to provide simpler clarifications for accredited institutions. Another important aspect of the differences between the 2007 and the 2016 Standards is rooted in the development of the 2013 Educational Outcomes from the Center for the Advancement of Pharmacy Education (CAPE).5 This guide for educational outcomes is developed by AACP, one of the representing organizations on ACPE’s Board of Directors, providing an influential connection between the CAPE guidelines and the ACPE Standards. “Domain 4” of the 2013 CAPE guidelines focuses on “Personal and Professional Development” in the pharmacist. This development is centered on self-awareness, leadership, innovation, entrepreneurship and professionalism. The suggested educational outcomes provide a solid basis for academic pharmacy programs to incorporate leadership outcomes into their curricula in order to build more experienced leaders and the incorporation of the ideas of the CAPE outcomes into ACPE’s new Standards.

Pharmacy Employer Expectations in Regard to Educational Accreditation In order to assess the proficiency to which the 2007 accreditation standards prepared recent PharmD graduates for practice, ACPE created a task force that examined employer expectations for new graduates in 2012.6 This task force was in partnership with other professional pharmacy groups such as the American Society of Health-System Pharmacists (ASHP), the National Community Pharmacy Association (NCPA), the National Association of Chain Drug Stores Foundation (NACDSF) and the Academy of Managed Care Pharmacy (AMCP). The ASHP targeted employers that hire graduates for entry-level positions in health systems or in postgraduate year one (PGY1) residency programs. Both the NCPA and NACDSF surveyed managers in the community setting and assessed responses from independent and chain pharmacies. The overall goals of the task force were to compile a comprehensive list of the expected competencies from employers in multiple pharmacy practice settings, evaluate if the current standards prepared new graduates to meet these competencies in their first pharmacy job after graduation and to discover what areas in the standards needed improvement in order to better meet employer expectations. Overall the task force identified 25 separate entry-level competencies expected by hiring employers in both the health care system and community pharmacy practice settings.6 The task force concluded that most of the competencies were addressed in the accreditation standards. Some areas that were identified as needing improvement for future standards

included communication skills, professionalism and leadership cultivation. Communication skills encompass both verbal and written proficiency to effectively communicate with patients and other medical professionals. There needs to be a level of empathy and compassion when dealing with all patients and expertise when communicating with patients. This is particularly important in the community setting, because an assessment for health literacy is imperative to make sure patients are able to properly care for themselves. Professionalism needs to be instilled in students so they can work in an interdisciplinary team of medical professionals to provide optimal patient care. Leadership skills will allow students to create objective goals for themselves and other medical professional team members in practice. With the proper communication and professionalism skills new graduates will be able to delegate, manage and motivate fellow colleagues to accomplish common goals and manage conflict between coworkers effectively. Context of Leadership in the Profession In 2004, ASHP conducted a survey of community and hospital pharmacy managers asking about job satisfaction, job retention and job recruitment for pharmacy management positions.7 The survey had a 31 percent response rate, which was low, but is beneficial to start establishing trends within the pharmacy job market. It showed that those in leadership positions were not likely to stay at their job after 10 years, due to retirement or moving onto another position, and they did not have a pharmacist successor in mind to take over when they would leave. The reasons for not having a replacement in mind came from a lack of leadership-qualified pharmacists on staff to fill the positions. They cited that pharmacists on staff or new graduates lacked experience in leadership roles and would benefit from having mentors in the work or school settings as well as leadership clerkship experiences prior to graduation. The authors predicted that because there was a shortage of qualified pharmacy leaders, there was a possibility that pharmacy management positions would be taken by nonpharmacists to fill this gap in the next five to 10 years. These findings supported the belief that there would be a pharmacy leadership crisis in the next five to 10 years. In 2011, ASHP issued a statement saying that taking on leadership roles in the practice setting is a professional obligation for all pharmacists, not just those in management and executive positions.8 All practicing pharmacists have the responsibility to ensure safe and optimal medication use and patient care methods while working in collaboration with other health care professionals. The publication also indicates that leadership practices should be fostered at all levels of pharmacy education and urges pharmacy schools and preceptors to integrate leadership education throughout the pharmacy curriculum.8 The goal is to create a mindset in pharmacists and pharmacy students that goes beyond just the managerial duties of completing tasks in a timely and cost efficient manner. To drive the profession forward, leadership qualities must be ingrained in students to make them question current practices and always strive to improve themselves, their colleagues and the pharmacy profession as

The Pharmacy And Wellness Review Summer 2015 Volume 6, Issue 3

Changing Roles in Leadership for Today’s Pharmacist —A Look Into the New ACPE Draft Leadership Standards

a whole.9 If leadership practices and ideologies are taught throughout the pharmacy curricula, new graduates will have the proper mindset and skills to effectively manage and become a leader in any position, not just in management. 8 This will solve the leadership shift problem and will guarantee that pharmacy management positions will stay with pharmacists. Leadership Expectations and the 2016 ACPE Standards There is an employer expectation that recent PharmD graduates will have a basic understanding of leadership skills when entering the workforce upon graduation. The skills expected include confidence in pharmacy knowledge, ability to define team objectives, set measurable workplace goals, implement employee delegation of tasks and provide effective conflict management. For the 2007 accreditation standards, the recommendation from the taskforce was to include the wording “delegate tasks, articulate objectives and measure/report performance” in future versions of the accreditation standards.6 For the newly released 2016 ACPE standards, “leadership cultivation” is a measurable objective under the personal and professional development standard. The overall outcome for leadership is for a student to “demonstrate responsibility for creating and achieving shared goals, regardless of position.”2 This defined and measurable outcome for leadership is new in the accreditation standards for 2016. The addition addresses the needed improvement for new graduates to “define team objectives, set measurable workplace goals, [and] delegate tasks” in the workplace setting. With the new leadership objective in the accreditation standards, a student will have the skills to work as a member of a health care team and provide quality medication counseling and medical care to patients. Recent graduates will also have an attitude that fosters continuous self-improvement in daily work practices and have the ability to motivate other employees to continuously self-improve to provide patients with the best possible care.2,6

Leadership

al positions. Through the guidance of the 2013 CAPE Outcomes as well as input from pharmacists and educational providers, the development of the new 2016 ACPE Standards and Guidelines Documents will establish greater expectations of leadership skills in today’s pharmacy graduates. Overall, leadership responsibilities need to be assumed by all pharmacists, regardless of position, to move the profession forward. References 1. Accreditation Council for Pharmacy Education [Internet]. Chicago (IL): Accreditation Council for Pharmacy Education; 2015 [cited 2015 Feb]. Available from: www.acpe-accredit.org/default.asp. 2. Accreditation Council for Pharmacy Education [Internet]. Chicago (IL): Accreditation Council for Pharmacy Education; 2015. Accreditation standards and key elements for the professional program in pharmacy leading to doctor of pharmacy degree: “standards 2016” [updated 2015 Feb 2; cited 2015 Feb]. Available from: www.acpe-accredit.org/ standards/default.asp. 3. Accreditation Council for Pharmacy Education [Internet]. Chicago (IL): Accreditation Council for Pharmacy Education; 2015. Guidance for the accreditation standards and key elements for the professional program in pharmacy leading to the doctor of pharmacy degree: “guidance for standards 2016” [updated 2015 Feb 2; cited 2015 Feb]. Available from: www.acpe-accredit.org/standards/default.asp. 4. Zellmer WA, Vlasses PH, Beardsley RS. Charting accreditation’s future: summary of the ACPE consensus conference on advancing quality in pharmacy education. Am J Pharm Educ. 2013 Apr 12;77(3): 1-10. 5. Medina M, et al. Center for the Advancement of Pharmacy Education (CAPE) Educational Outcomes 2013. Am J Pharm Educ. 2013 Oct 14; 77 (8):1-10. 6. Vlasses PH, Patel N, Rouse MJ, et al. Charting accreditations future employer expectations of new pharmacy graduates: implications for the pharmacy degree accreditation standards. Am J Pharm Educ. 2013;77 (3): 1-10. 7. White SJ. Will there be a pharmacy leadership crisis? An ASHP foundation scholar-in-residence report. Am J Health-Syst Pharm. 2005;62:84855. 8. American Society of Health-System Pharmacists. ASHP statement on leadership as a professional obligation. Am J Health-Syst Pharm. 2011;68:2293-5. 9. White SJ. Are you a manager or a leader? Am J Health-Syst Pharm. 2011;68:1206. The authors have no conflict of interest or funding support to disclose.

At Ohio Northern University’s Raabe College of Pharmacy, leadership cultivation is being implemented within all levels of the curriculum. Extra classes and activities that highlight leadership are provided to enhance the curricular basics. One additional leadership class is Contemporary Pharmacy Practice, where pharmacists from a variety of practice settings come in to talk about their careers and the choices that led them to their current job. Most of these professionals have held positions in national pharmacy practice organizations throughout their career. They stress the importance of getting involved in the profession to show to other medical professionals and patients the significance of what a pharmacist provides on a daily basis. Conclusion Leadership skills are an important aspect in job proficiency and satisfaction in the pharmacy profession. In the past, leadership qualities were cultivated on the job as opposed to being taught in pharmacy school. As a pharmacy leadership shortage was detected, there was a shift to push leadership education into the curricula prior to graduation in order to create a workforce with the skills needed to cover manageriSummer 2015 Volume 6, Issue 3 The Pharmacy And Wellness Review

The Pharmacy and Wellness Review Contributing Student Writers and Staff

The Ohio Northern Pharmacy and Wellness (PAW) Review is a student-run organization whose vision is to provide a professional, educational and relevant journal for both practicing and student pharmacists while further developing our own leadership, research skills and professional writing ability. The Review is published semiannually.

The Pharmacy And Wellness Review Summer 2015 Volume 6, Issue 3