Pharmacy and wellness Review January 2017

Drug Abuse Volume 7, Issue 2 Spring 2016

ISSN 2168-7382

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Latest Trends in the Heroin Epidemic and the Responsibility of the Pharmacist in Controlling Heroin Abuse CE Included Alexandra Herman, Cassandra Hacker, Emily Wells, Sabrina Hamman, Manoranjan D’Souza, M.D., Ph.D.

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Prevention and Treatment of Glucocorticoid-Induced Osteoporosis CE Included

Mackenzie DeVine, Anh Dao Le, Julie Puvogel, Victoria Cho, Michelle Musser, PharmD, BCPS

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Evaluating the Role of Fecal Microbiota Transplant in the Treatment of Clostridium Difficile Infection Anh Dao Le, Olivia Henton, Shane Bogusz, Brian Heilbronner, Jessica Hinson, PharmD

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Legislation Across the Nation and the Impact on Pharmacy Practice

Sabrina Hamman, Hannah Lamb, Jennifer Harklerode, Elizabeth Kramer, Steven Martin, BCPS, FCCP, FCCM

Legionnaires’ Disease, A Rising Occurrence in the United States

Jennifer Harklerode, Olivia Henton, Myranda Smith, Rebecca Worden, Andrew Roecker, Pharm D, BCPS

A Pharmacist’s Role in Educating on the Health Risks of Smoking During Pregnancy and Helping Patients with Smoking Cessation Alexandra Herman, Cassandra Hacker, Emily Wells, Brian Heilbronner, Brittany L. Long, PharmD, TTS

Ohio Northern University is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Editorial Board: Editor-in-Chief

Hannah Granger

Formatting Editor

Katherine Liu

Managing Editors

Christina Ciccone Joelle Farano

Website Editor

Sabrina Hamman

Lead Editors

Victoria Cho Brian Heilbronner Brendan Rasor Rebecca Worden

Faculty Advisors:

Mary Ellen Hethcox, BSPh, PharmD, BCPS Karen L. Kier, BSPh, Ph.D., BCPS, BCACP Natalie DiPietro Mager, PharmD, MPH

Layout

Darlene Bowers

Spring 2016 Volume 7, Issue 2 The Pharmacy And Wellness Review

Drug Abuse

Latest Trends in the Heroin Epidemic and the Responsibility of the Pharmacist in Controlling Heroin Abuse Alexandra Herman, Cassandra Hacker, Emily Wells, Sabrina Hamman, Manoranjan D’Souza, M.D., Ph.D.

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): 0048-0000-16-217-H01-P To complete the continuing education program and receive credit, please go to www.raabecollegeofpharmacy.org/PAW/.

Objectives After completion of this program, the reader should be able to: 1. Describe the mechanism of action and administration of naloxone.

2. Identify the signs and symptoms of opioid intoxication and overdose.

3. Recognize the emergency dispensing laws for naloxone.

4. Assess the risks and effects of the changing purity of heroin combined with fentanyl.

5. Define tolerance, cross-tolerance and incomplete cross-tolerance.

Abstract Over the last few years, there has been an exponential increase in morbidity and mortality associated with heroin abuse. The current rise in heroin abuse and overdose is attributed to widespread use and abuse of prescription opioids, which can produce significant euphoric effects in humans. In fact, reports suggest that heroin abusers initially become addicted to prescription opioids but subsequently switch to heroin because it is cheaper and more easily available than prescription opioids. Over the years, the purity of heroin available for illicit use has been on the decline. Smugglers and heroin vendors have started mixing heroin with other clandestinely prepared, potent, analgesic opioids such as fentanyl. Fentanyl is 30 to 50 times more potent than heroin, and the combination can be quite lethal to abusers due to the increased potency and effects on the body’s respiratory centers which may result in death. This review will mainly focus on some of the recent trends in heroin abuse and recent changes in laws with respect to dispensing and possession of naloxone, an effective antidote against heroin overdose. Finally, the role of the pharmacist in countering the current heroin epidemic by recognizing at-risk populations and providing the proper resources to addicts to prevent further heroin/opioid-related overdose fatalities will be discussed.

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Key Terms Analgesics; Blood-Brain Barrier; Controlled Substances; Criminals; Drug Overdose; Drug-Related Adverse Reactions; Drug-Related Side Effects; Euphoria; Fear; Fentanyl; Heroin; Lipids; Morphine; Naloxone; Narcotics; Opioid; Oxygen; Pharmaceutical Preparations; Pharmacists; Respiratory Center; Respiratory Rate; Solubility; Street Drugs Introduction Heroin is a highly addictive drug, and over the last decade the abuse of heroin has resulted in a sharp rise in heroin overdose deaths across the United States. The National Forensic Laboratory Information System (NFLIS) collects submissions from state and local forensic labs on any incidences that involve illicit drugs or legal drugs. From 2004 to 2014, heroin was consistently in the top five most commonly submitted drugs.1-11 Additionally, the rate of heroin use doubled from 2010 to 2012 compared to use between 2008 and 2010 alone. Importantly, the number of deaths per 10,000 in the Midwest region, which includes Ohio, nearly doubled between 2010 to 2012.12 The Drug Enforcement Agency (DEA) reports suggest a decrease in the purity of heroin available on the street. To counter this decrease in purity and enhance the potency of heroin, drug vendors and smugglers have started a trend of mixing/diluting heroin with illegally synthesized potent analgesics. One of the most common drugs added to heroin is the prescription opiate analgesic fentanyl. An increasing amount of fentanyl and its derivatives are being produced in clandestine laboratories, which are facilities that manufacture illegal drugs.13,14 Data from the NFLIS indicate that fentanyl and heroin showed an overall increase in the number of their respective NFLIS submissions from 2004 to 2014. From 2004 to 2013, fentanyl was submitted hundreds of times each year.1,10,12-19 However, from 2013 to 2014, fentanyl submissions quadrupled from 942 to 4,642 cases.2,11 Figures 1 and 2 show these trends for heroin and fentanyl submissions, respectively, over the last 10 years.3 The addition of fentanyl to heroin provides a much greater risk of toxicity to the drug abuser. The combination of heroin with fentanyl has been largely responsible for the rapid rise in heroin overdose fatalities.

The goal of this review is to discuss the history of heroin abuse over the decades and highlight some of the recent trends associated with heroin abuse. In addition, the pharmacologic effects of heroin and fentanyl, and the danger associated with their combination, will be described. Furthermore, the role of naloxone in reversing heroin intoxication, re-

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Latest Trends in the Heroin Epidemic and the Responsibility of the Pharmacist in Controlling Heroin Abuse

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Figure 1. Number of Annual Submissions Involving Heroin to NFLIS from Various State and Local Forensic Labs. 1-11

Figure 2. Number of Annual Submissions Involving Fentanyl to NFLIS from Various State and Local Forensic Labs. 1-11

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Latest Trends in the Heroin Epidemic and the Responsibility of the Pharmacist in Controlling Heroin Abuse

cent changes in the naloxone prescription law and the role of the from Mexico.20 Interestingly, the DEA has reported a decline pharmacist in countering the heroin epidemic will be discussed. in the purity of heroin over the last few years with an increase in price per milligram of heroin. The declining purity Heroin Addiction: An Historical Perspective and Chang- in heroin has initiated a dangerous trend among vendors and ing Trends smugglers of mixing (cutting) heroin with other drugs, such Heroin is chemically derived from the naturally occurring as fentanyl, to enhance its effects.13 Since fentanyl is a signifiopioid morphine, extracted from the opium poppy plant. 15 cantly more potent opioid than heroin and morphine, the risk Bayer originally introduced heroin to the market in 1898 as a of overdose and subsequent death significantly increases, cough suppressant and sedative due to its superior efficacy especially with an uneducated user.21 These fentanyl derivaover the standard morphine or codeine.16 However, by 1910, tives are “cut” or diluted into heroin in an attempt to expand it became clear that heroin had the potential to be extremely the quantity of the product for sale as well as shorten the addictive. Later in 1924, heroin production was banned by time to the “rush” or euphoria.13 Additionally, due to its high the U.S. Heroin Act. However, this also started the dawn of potency, fentanyl acts quickly and requires only a low volume heroin’s black-market manufacturing and abuse.17 Subse- to achieve a high. Together, these characteristics are economquent to this prohibition, the first major increase in heroin ically beneficial for the dealers of heroin. Yet the addition of abuse in the United States occurred during the 1960s. This fentanyl to heroin provides a much greater risk of toxicity to wave of heroin abuse correlated with the return of troops the drug abuser for several reasons including contamination from the Vietnam War, who started heavily abusing heroin in of the drug product itself and the unpredictable additive efVietnam. The most recent wave of heroin abuse started fects of the combination of these two opioids.22,23 In fact, around 2000, which was mainly perpetrated by the expansive knowing how much fentanyl to add to heroin is often guessabuse of opioid painkillers over the previous two decades. A work. Additionally, when the user receives the product, they large percentage of current heroin abusers actually start us- are unlikely to know how much of the drug is needed to ating prescription opioids first and then switch to heroin be- tain a high, which increases the chance of an overdose. cause it is cheaper and easier to obtain.18 Heroin and Fentanyl: Pharmacologic Mechanisms and There have been a number of new reports that suggest chang- Reward Pathway es in the trends of heroin abuse. Previously, heroin was typi- Two hydroxyl groups of morphine are replaced with less pocally abused by nonwhite populations living in urban lar acetyl groups in the heroin molecule, which is also known areas.18 Currently, heroin abuse has also spread to suburban as diacetylmorphine (Figure 3). This makes heroin more lipoand rural areas, predominantly among whites. In addition to philic than morphine, which allows it to cross the blood-brain the shift in location and race, there is also a shift seen in the barrier faster.24 After passing the blood-brain barrier, plasma mean age of heroin abusers. The median age of heroin abus- esterases de-acetylate heroin to monoacetylmorphine. Monoers has gone up from 16 years of age in the 1960s to 20 years acetylmorphine is then hydrolyzed to morphine, which proof age in the 1980s and now has increased to 23 years of age. duces its agonistic effects on opioid receptors, initiating the These changing trends suggest a wider, more atypical envi- sensation of euphoria. Heroin may be administered via nasal ronment in which heroin is being abused. inhalation, oral smoke inhalation or intravenous injection. 15 Although intravenous injection has the fastest onset of action, Changes in Purity of Heroin the drug rapidly produces euphoric effects by any administraDuring the wave of heroin abuse through the 1960s and tive technique. When injected intramuscularly, euphoria is 1980s, heroin was smuggled into the United States from attained after a few minutes, compared to the few seconds Southeast Asia, Afghanistan and Nigeria. Beginning in the taken by intravenous injection.25 If inhaled by smoking or 1990s through today, most of the heroin found in the United sniffing, euphoria arises after approximately 15 minutes. The States is imported from Mexico and South America.19 Current- initial euphoric high usually lasts 45 seconds to several ly, it is recognized that there are two distinct heroin markets minutes, but the general feeling of well-being continues three that dominate the United States. The East Coast of the United to five hours after administration depending on the level of States normally receives most of its heroin from South Ameri- drug potency or abuser tolerance.26 can countries, whereas the West Coast heavily imports heroin Figure 3. Chemical Structures of Morphine, Heroin and Fentanyl.23

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Fentanyl is a synthetic opioid that is frequently used in veterinary and human practice. It is also used in both the inpatient hospital and outpatient settings.20,27 Fentanyl has many derivatives which include alfentanil, sufentanil, remifentanil and carfentanil. These derivatives can be administered by injection, transdermal patch or transmucosal lozenge. 27 Typically, fentanyl or its derivatives are used as anesthetics adjunct to general anesthesia during surgery and analgesics for chronic pain relief or preoperative pain. Additionally, fentanyl is used to treat severe pain often associated with trauma, burns, orthopedic conditions and terminal illness; it also reduces cough and diarrhea.19 Fentanyl and other opioids are preferred in the clinical setting because they do not cause loss of consciousness, euphoria or sedation when used for analgesia.19,28 The benefits seen in patients that use fentanyl or its derivatives include, but are not limited to, the following: decreased amounts of adverse reactions, higher patient satisfaction, higher quality of life, improved compliance and a decreased need of rescue medications. Adverse drug reactions are usually only experienced when fentanyl is abused. 28 A review study done by Kornick et al. found that the benefits of using fentanyl as a prescription medication outweigh its potential risks.28 Fentanyl is estimated to be 30 to 50 times more potent than heroin and between 50 to 100 times more potent than morphine.19-21 This increased potency of fentanyl makes it lethal even at low doses.21 The lethal dose of fentanyl is estimated to be 2 mg in humans.27 Due to the low lethal levels of fentanyl, it is very easy for a patient or a drug abuser to overdose on this medication. As it is often mixed with other drugs to produce a more powerful and dangerous street drug, there is an increased incidence of drug overdose with fentanyl use.20 The actions of morphine, heroin, fentanyl and other opioid analgesics are mediated primarily by binding to the mu opioid receptors in the neurons of the brain, spinal cord and gastrointestinal tract.23,29 These mu opioid receptors are G proteins coupled to adenylyl cyclase. Binding of the opioid to these receptors inhibits the production of adenylyl cyclase, blocking calcium ion channels and opening potassium ion channels in the neuron to inhibit neurotransmitter release. 30 The euphoric effects of opioids, including heroin, are mediated by mesolimbic dopaminergic neurons, which originate from the ventral tegmental area in the midbrain. 31 The activity of these dopaminergic neurons are regulated by inhibitory gamma-amino-butyric acid (GABA) neurons. When an opioid such as morphine acts on the mu opioid receptor, the result is the inhibition of GABA release at synapses thus decreasing GABA’s inhibitory effect on dopaminergic neurons. Without GABA-mediated inhibition, dopamine release is uninhibited at dopaminergic neuron terminals in areas of the brain associated with brain reward, such as the nucleus accumbens, producing a sensation of euphoria.

Mu opioid receptor agonists cause a variety of other physiological reactions including respiratory depression, slowing of gastrointestinal movement causing constipation and bradycardia.29 The most life-threatening of effects is depression of

Drug Abuse

the respiratory centers, which are located in the medulla of the brain stem. A reduction in glutamate-induced excitation decreases respiratory activity, which leads to a decreased sensitivity to changes in oxygen and carbon dioxide levels. 29,32 Decreased sensitivity to levels of these gases results in hypoventilation causing hypoxia in tissues and ultimately leading to brain and subsequent organ shutdown and death in an overdose situation. If an overdose is survived, the prolonged lack of oxygen to the brain may cause severe brain damage.

When opioids are combined, the effects may be additive or synergistic.23 When morphine is combined with fentanyl, the analgesic effect is increased from that of either drug alone by at least twofold. In one study, morphine combined with fentanyl increased analgesia in mice from 10 percent with only morphine, and 15 percent with only fentanyl, to 30 percent when combined. The increased effects from combining opioids have highly unpredictable effects in vivo due to its illegal production and, therefore, cause severe increases in fatalities due to overdose.33 Opioid Tolerance, Cross-tolerance and Incomplete Crosstolerance Chronic use of opioids leads to tolerance, meaning that an increasingly higher dose is necessary to have the same effects as previous exposures.34 With repeated activation of the mu opioid receptors, as in heroin or fentanyl abuse, the mu opioid receptors either undergo desensitization, downregulation or receptor internalization. Losing opioid receptors due to these three pathways decreases the number of receptors available to cause a response. This phenomenon is called tolerance.31 As a consequence, using the same dose of an opioid (e.g., heroin) will no longer produce the same euphoria. Additionally, tolerance can develop through any route of administration of an opioid.

In addition to tolerance, opioid abuse can be complicated by issues of cross-tolerance and incomplete cross-tolerance.23 Cross-tolerance is the state of being tolerant to different chemicals or drugs that act on the same receptor. All opioids acting via the mu opioid receptors exhibit cross-tolerance to each other at varying degrees. Incomplete cross-tolerance occurs when tolerance to one drug is developed, but another drug that acts on the same receptor does not develop tolerance and produces normal effects. This second drug that the body is not yet tolerant to can be used at a much smaller dose, which may be useful in minimizing side effects. However, the risk for deadly overdose greatly increases. Due to the unpredictable nature of incomplete cross-tolerance of opioids, the risk of overdose is increased when two different opioids are coadministered that act on the same receptor.

For example, consider the coadministration of morphine and methadone which both act on the mu receptor. A person tolerant to morphine would need a significantly higher dose of morphine compared to a drug-naive individual to produce an analgesic effect. In contrast, the person would still be responsive to a normal dose of methadone due to incomplete crosstolerance. Use of methadone doses equivalent to high

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morphine doses would cause an overdose in this particular patient. As heroin and fentanyl both act on the mu opioid receptor, incomplete cross-tolerance is a possible consequence of using the two together and can increase incidences of overdose.

Mortality Due to Heroin Overdose Between 2000 and 2013, the incidences of heroin overdose and death increased across the United States.20 A recent study of 28 states (AL, AZ, CO, FL, IL, IN, IA, KS, KY, MA, MI, MN, MO, MT, NE, NV, NH, NM, NY, NC, OH, OK, OR, RI, SC, UT, VA, WA) confirmed that the rate of heroin use increased from 2008 to 2012, with the rate doubling between 2010 and

Figure 4. The Number of Heroin Overdose Deaths Based on Gender.12

Figure 5. The Number of Heroin Overdose Deaths Based on Race/Ethnicity.12

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2012. Overall, the data from the 28 states analyzed in this study encompassed 56 percent of the population of the United States and indicated that there is a growing problem with heroin mortality in the country.12 Importantly, the largest number of deaths from heroin overdose was seen in two different populations: males and whites. Figures 4 through 7 depict various trends in heroin mortality per 100,000 people from 2008 to 2012.12 Reversal of Heroin Intoxication/Overdose with Naloxone Symptoms of heroin intoxication are grouped into what is known as the “opioid triad.�35 The triad of symptoms includes pinpoint pupils, unconsciousness and respiratory de-

Figure 6. The Number of Heroin Overdose Deaths Based on Age.12

Figure 7. The Number of Heroin Overdose Deaths Based on Geographical Location in the United States.12

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pression (Figure 8), which is defined as less than 12 breaths per minute. Naloxone (NarcanÂŽ), an opioid-receptor antagonist, has the highest affinity for the mu opioid receptor. 36 It acts as an effective antidote to opioid overdoses, thus reversing the effects of opioid drugs such as fentanyl and heroin.

Naloxone has many forms of administration including intranasal inhalation, intramuscular (IM) injection, intravenous (IV) injection undiluted by IV push, IV continuous injection diluted in 5 percent dextrose in water (D5W) or normal saline (NS) 4 to 8 mcg/mL, or subcutaneously (SC) into the thigh.37 Intranasal administration of naloxone has several advantages including low risk of exposure to blood because there is no needle, fast administration, rapid onset of action, requires little training for administrator and is extremely effective.38,39 Figure 8. The Opioid Triad of Intoxication (Opioid Overdose Symptoms).35 Pinpoint Pupils

Unconsciousness

Respiratory Depression

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ry of nonmedical opioid use, receiving high-dose opioid prescriptions, receiving the first prescription for an opioid substance, receiving buprenorphine treatment for addiction, on opioid prescriptions with respiratory illnesses, with limited access to emergency medical services or by patient request. 42 Additionally, as health care professionals, pharmacists and prescribers are considered to be part of the at-risk community for abuse because of easy access to prescription drugs, especially opioids. It is estimated that 10 to 15 percent of health care professionals are addicted to drugs or alcohol.

As of 2014, over 150,000 people in the United States are trained and have received naloxone kits. Those involved with the training have already reported having a positive impact on over 26,000 overdoses nationwide.43 The kits come in two formulations: intranasal and intramuscular. The intranasal kit includes two naloxone 2 mg/2 ml prefilled syringes and two atomizers, while the intramuscular kit includes two naloxone 0.4 mg/ml vials and two intramuscular syringes. Both of the kits contain step-by-step instructions for responding to an opioid overdose and directions for naloxone administration.

The kits are to be stored at room temperature and protected from light; kits cannot be stored in places that are susceptible to seasonal temperature changes, such as a vehicle, in order to maintain effectiveness. Each kit has a shelf life between 12 and 18 months, and syringes should not be filled until the drug is needed. Each intramuscular kit costs roughly $44 and intranasal kits cost around $40, which is fairly inexpensive compared to other means of medical treatment that would be involved if naloxone was not received in an overdose situation. It is estimated that annual medical costs resulting from opioid overdose reach $72 billion.43-45 Although these kits are available to first medical response teams, depending on state laws, bystanders, family/friends of drug abusers, and pharmacies are also permitted to possess naloxone kits and distribute them. The laws regarding who is allowed to possess naloxone across the country, and which states have legislature providing immunity to individuals seeking treatment or providing treatment, is shown in Figure 9.43,46

Naloxone begins to have effects on the body in two to five minutes depending on the route of administration and has a 30 to 90 minute duration of action. Administrators of the drug should remain with the patient for the 30 to 90 minute period in the event that readministration is required.40 According to the algorithms for Advanced Cardiac Life Support (ACLS) protocols, the initial dose ranges from 0.4 to 2 mg/mL and is given every two to three minutes until the desired outcome is reached to treat opioid overdoses.41 Up to 10 mg is given as a total dose because the mechanism of action is short-lived, and repeated doses may be required depending on the opioid drug being antagonized. Doses should be repeatedly given until breathing has increased from none to Dispensing Laws for Naloxone minimal breathing. There is no tolerance buildup or abuse As of July 22, 2015, section 4729.44 of the Ohio Revised Code potential for naloxone. and rule 4729-5-39 of the Ohio Administrative Code authorizes a pharmacist or pharmacy intern, under the direct Side effects of naloxone when reversing opioid use include supervision of a pharmacist, to dispense naloxone without a nausea, vomiting, sweating and tachycardia.36,37,41 As nalox- prescription to the following in accordance with a physicianone does not have any drug-drug interactions and is safe for approved protocol: (1) An individual who there is reason to pregnant women, it is fairly safe to give when an opioid over- believe is experiencing or at risk of experiencing an opioiddose is suspected but not confirmed. If there is no opiate ago- related overdose; (2) A family member, friend, or other pernist present in the body, naloxone will have no effect on the son in a position to assist an individual who there is reason to body, thus no harm would occur if a patient was misdiag- believe is at risk of experiencing an opioid-related overdose; nosed with an opioid overdose and given naloxone. When an or (3) A peace officer as defined in section 2921.51 of the Reopioid overdose is suspected, emergency medical services vised Code.47 should be contacted immediately after a witness administers naloxone (or in concurrence if there is another witness avail- These new amendments come with little to no negative efable to do so) to have the best chance for the patient survival. fects and are extremely inexpensive. Even while inexpensive, the amendments also save health care dollars in the treatCandidates to be considered for naloxone treatment include ment aspect. It has been estimated that annually overdose patients with a history of opioid overdose, a suspected histo- fatalities cost about 21.5 million.48 Spring 2016 Volume 7, Issue 2 The Pharmacy And Wellness Review

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Latest Trends in the Heroin Epidemic and the Responsibility of the Pharmacist in Controlling Heroin Abuse

Figure 9. The Naloxone Dispensing Laws According to State Practice.43,46 States in blue are those with naloxone access and drug overdose Good Samaritan laws. States in green are those with naloxone access laws only. States in yellow are those without either law.

In the past, prescribers have been concerned about “third party prescribing” liability; third party prescribing means the prescription is written for a patient who has not been evaluated by a prescribing order (a standing order). Additionally, witnesses to overdose situations may not want to call for medical assistance in fear of legal punishment. Those witnesses, who do realize the need for naloxone distribution and have the antidote on hand, may choose not to distribute it because of liability concern myths (i.e., witness thinks he/she will be prosecuted for administering incorrectly). Initial evidence from the state of Washington, which amended its law in 2010, is positive with 88 percent of surveyed drug users indicating that they would be more likely to summon emergency personnel during an overdose as a result of the legal change.43 Because of these major concerns and fears, the new dispensing laws have aimed to displace those fears and establish grounds for saving the lives of the victims.

The new dispensing laws focus on two goals: 1. The first goal is “Good Samaritan” dispensing, which encourages witnesses of an overdose incident to come forward and get help for the victim without fear of being arrested for illicit drug possession. According to the National Conference of State Legislatures, the so-called “Good Samaritan” laws regarding drug overdoses fall into two primary categories.43 The first encourages calling 911 to seek medical assistance for yourself or

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someone experiencing an overdose by providing criminal immunity for both the person in need and the person who sought help. “New Mexico became the first state to amend its laws to encourage Good Samaritans to summon aid in the event of an overdose. As of June 22, 2016, thirty-five other states and the District of Columbia” follow the Good Samaritan law.43,46 The second goal provides varying levels of criminal or civil immunity for those involved with the prescription, possession or emergency administration of the naloxone to reverse the effects of an overdose.46 After the clarification of legal immunity for those reporting an overdose, several states began to make moves to incorporate new laws to protect those reporting the overdose. Additionally, prescribers would not be held liable for writing naloxone prescriptions for patients they did not personally evaluate.43 This goal strives to provide wider use and prescribing of naloxone. It will allow prescribers to confidently prescribe naloxone without fear of legal repercussion. Depending on the state the pharmacist and patient is living in, the laws for administration will vary.

For example, in Ohio, House Bill 170 (passed on March 11, 2014) removed civil liability for prescribers, allowed for third party prescriptions, removed civil liability for lay administration, removed criminal liability for prescribers and lay administration and allowed lay administration to practice unauthorized practice of medi-

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cine.47,49 This means that, in a given emergency situation of opioid overdose, actions taken by witnesses and health care professionals are not prosecutable, thus encouraging each participant involved to do what is best to save the victim’s life. Currently, Ohio does not have a state program created and does waive criminal liability for possession of naloxone without a prescription. Laws specific to each state are shown in Figure 9.43,46

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pharmacists to distribute naloxone with less liability concerns in emergency situations. Pharmacists have a responsibility to be informed on the latest dispensing laws of naloxone in their state of practice in the event of an emergency overdose situation. Additionally, being knowledgeable about the signs and symptoms of heroin overdose and identifying at-risk patient populations will allow lifesaving interventions to be made available in a timely manner to prevent fatal heroin overdoses.

Ohio offers an educational program called Project DAWN, which is a community-based education program that distrib- References utes naloxone for opioid overdose cases. Participants in the 1. National Forensic Laboratory Information System 2012 Annual Report.

Springfield (VA): US Department of Justice Drug Enforcement Adminprogram are given intranasal naloxone when appropriate and istration Office of Diversion Control; 2013 Sep. Available from: receive educational training on the signs and symptoms of an www.deadiversion.usdoj.gov/nflis/2012annual_rpt.pdf.

2. National Forensic Laboratory Information System 2013 Annual Report. overdose and how to administer naloxone.50 Role of the Pharmacist The pharmacist's role in protecting patients from an opioid overdose is imperative. Pharmacists are involved in the prevention of overdoses by researching patient history for the use of analgesics, especially opioids, using the Ohio Automated Rx Reporting System (OARRS), or state equivalent reporting system accordingly, and evaluating the patient’s potential for opioid abuse. By identifying patients and health care professionals at risk for overdoses, pharmacists can potentially prevent overdoses before they occur. Additionally, they can identify certain groups of patients with an increased risk of addiction to opioids, such as those with major depressive disorder, bipolar disorder, anxiety disorders, etc.49

To help prevent overdoses and addiction, pharmacists should counsel patients on the use of opioids and the potential for addiction at the start of a new prescription and with every refill on the medication. If the patient is having a family member or friend pick up the prescription for them, the pharmacist should counsel the individual picking up the medication, and provide hard copy medication guides to give to the patient to explain the main concerns and counseling points. It is also the responsibility of the pharmacist to be informed on the most recent state laws for distributing naloxone in their location of practice. This information can be found online at the Network for Public Health. Pharmacists should know the symptoms for abuse and overdose and know how to administer naloxone in an emergency situation. The main focus of the pharmacist should be to provide information regarding postoverdose treatment as well as guidance in recovering from an addiction. In the state of Ohio, pharmacists can refer patients to Project DAWN locations in order to receive communitybased encouragement, education and training on how to cope with and avoid overdoses. 50

3.

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6.

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9.

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Conclusion Overdoses as a result of heroin and other opioid medications kill thousands of patients annually. The dangerous trend of mixing clandestinely-prepared fentanyl derivatives with her- 14. oin has further increased the incidence of heroin overdose.

These deaths can be prevented with lifesaving medication naloxone along with the timely summoning of emergency responders. Amended dispensing laws for naloxone allow 15.

Springfield (VA): US Department of Justice Drug Enforcement Administration Office of Diversion Control; 2014 Aug. Available from: www.deadiversion.usdoj.gov/nflis/NFLIS2013AR.pdf.

National Forensic Laboratory Information System 2014 Annual Report.

Springfield (VA): US Department of Justice Drug Enforcement Administration Office of Diversion Control; 2015 Sep. Available from: www.deadiversion.usdoj.gov/nflis/NFLIS2014AR.pdf.

National Forensic Laboratory Information System 2011 Annual Report.

Springfield (VA): US Department of Justice Drug Enforcement Administration Office of Diversion Control; 2012 Sep. Available from: www.deadiversion.usdoj.gov/nflis/2011annual_rpt.pdf.

National Forensic Laboratory Information System 2010 Annual Report.

Springfield (VA): US Department of Justice Drug Enforcement Administration Office of Diversion Control; 2011 Sep. Available from: www.deadiversion.usdoj.gov/nflis/2010annual_rpt.pdf.

National Forensic Laboratory Information System 2009 Annual Report.

Springfield (VA): US Department of Justice Drug Enforcement Administration Office of Diversion Control; 2010 Aug. Available from: www.deadiversion.usdoj.gov/nflis/2009annual_rpt.pdf.

National Forensic Laboratory Information System 2008 Annual Report.

Springfield (VA): US Department of Justice Drug Enforcement Administration Office of Diversion Control; 2009 Jul. Available from: www.deadiversion.usdoj.gov/nflis/2008annual_rpt.pdf.

National Forensic Laboratory Information System 2007 Annual Report.

Springfield (VA): US Department of Justice Drug Enforcement Administration Office of Diversion Control; 2008 Jun. Available from: www.deadiversion.usdoj.gov/nflis/2007_annual_rpt.pdf.

National Forensic Laboratory Information System 2006 Annual Report.

Springfield (VA): US Department of Justice Drug Enforcement Administration Office of Diversion Control; 2007 Aug. Available from: www.deadiversion.usdoj.gov/nflis/2006_annual_rpt.pdf.

National Forensic Laboratory Information System 2005 Annual Report.

Springfield (VA): US Department of Justice Drug Enforcement Administration Office of Diversion Control; 2006 Aug. Available from: www.deadiversion.usdoj.gov/nflis/2005annual_rpt.pdf.

National Forensic Laboratory Information System 2004 Annual Report.

Springfield (VA): US Department of Justice Drug Enforcement Administration Office of Diversion Control; 2005 May. Available from: www.deadiversion.usdoj.gov/nflis/2004annual_rpt.pdf.

Rudd R, Paulozzi L, Bauer M, Burleson R, Carlson R, Dao D, et. al. Increases in heroin overdose deaths – 28 States 2010 to 2012. Morbidity and Mortality Weekly Report [Internet]. 2014 Oct 3 [cited 2015 Nov 8];63(39): 849-853. Available from: www.cdc.gov/mmwr/pdf/wk/ mm6339.pdf.

NPR [Internet]. How the prescription painkiller fentanyl became a street drug; 2015 Aug 26 [updated 2015 Aug 28; cited 2015 Sept]; [about 3 screens]. Available from: www.npr.org/sections/healthshots/2015/08/26/434867357/how-the-prescription-painkiller-fenta nyl-became-a-street-drug.

National Alliance for Drug Endangered Children [Internet]. Westminster (CO): US Department of Justice; c2015. Clandestine Methamphetamine Labs Frequently Asked Questions; [cited 2015 Nov 8]; [2 pages].

Available from: www.nationaldec.org/goopages/pages_downloadgal lery/downloadget.php?filename=17188.pdf.

National Institute on Drug Abuse [Internet]. DrugFacts: heroin;[updated 2014 October; cited 2015 September 6]; [about 4 screens]. Available

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Drug Abuse

Latest Trends in the Heroin Epidemic and the Responsibility of the Pharmacist in Controlling Heroin Abuse

from: www.drugabuse.gov/publications/drugfacts/heroin.

16. Hasztafi S. The history of heroin. Acta Pharm Hung. 2001 Aug; 71(2): 233-42.

17. The National Alliance of Advocates for Buprenorphine Treatment [Internet]. Farmington (CT). Laws; [updated 29 Oct 2013; cited 27 Nov 2015]; [about 1 screen]. Available from: www.naabt.org/laws.cfm.

18. Cicero TJ, Ellis MS, Surratt HL, Kurtz SP. The changing face of heroin use in the United States a retrospective analysis of the past 50 years.

JAMA Psychiatry. 2014 Jul;71(7): 821-826.

19. Williams R, Erickson T. Emergency diagnosis of opioid intoxication. Lab Med. 2000 Jun;31(6):334-342.

20. Hempstead K, Yildirim E. Supply side response to declining heroin purity: Fentanyl Overdose Episode in New Jersey. Health Econ. 2013 Jun;23:688-705.

21. National Council on Alcoholism and Drug Dependence [Internet]. New York (NY): National Council on Alcoholism and Drug Dependence.

DEA issues alert on fentanyl-laced heroin as overdose deaths surge nationwide; 2015 Mar 21 [cited 2015 Sept]; [about 1 screen].

Available from: ncadd.org/blogs/in-the-news/entry/dea-issues-alerton-fentanyl-laced-heroin-as-overdose-deaths-surge-nationwide.

22. Street versions of opioids more potent and dangerous. CMAJ. 2013 Sept 3; 185(12): 1027.

23. Pasternak G. Preclinical pharmacology and opioid combinations. Pain Med. 6456 Mar 5; 57(S5): S8-S11.

24. Poisindex managements [Internet]. Truven Health Analytics. Heroin-medical review officer information; [updated 2013 Feb 4; cited 2015 Sept]; [about 23 screens]. Available from: www.micromedexsolu tions.com/.

25. AddictionBlog.org [Internet]. How does heroin work?; 2012 Nov 30 [cited 2015 Sept]; [about 3 screens]. Available from: drug.addiction blog.org/how-does-heroin-work/.

26. Centre for Addiction and Mental Health [Internet]. 2009. Do you know...heroin; [cited 2015 Nov 2]; [about 4 screens]. Available from: www.camh.ca/en/education/about/camh_publications/Documents/ Flat_PDFs/dyk_heroin.pdf.

27. European Monitoring Centre for Drugs and Drug Addiction [Internet].

Lisbon (Portugal); European Monitoring Centre for Drugs and Drug Addiction; c1995-2015. Fentanyl Drug Profile; [updated 2015 Jan 8; cited 2015 Nov 8]; [about 9 screens]. Available from: www.emcdda. europa.eu/publications/drug-profiles/fentanyl.

28. Kornick CA, Santiago-Palma J, Moryl N, Payne R, Obbens E. Benefit-risk assessment of the transdermal fentanyl for the treatment of chronic pain. Drug Safety. 2003;26(13):951-973.

29. White J, Irvine R. Mechanisms of fatal opioid overdose. Br J Addict.

1999; 94(7): 961-72.

30. Al-Hasani R, Bruchas M. Molecular mechanisms of opioid receptordependent signaling and behavior. Anesthesiology. 2011 Dec; 115(6): 1363-81.

31. National Institute on Drug Abuse [Internet]. The neurobiology of drug addiction; [updated 2007 Jan; cited 2015 September 6]; [about 4 screens]. Available from: www.drugabuse.gov/publications/teachingpackets/neurobiology-drug-addiction/section-iii-action-heroin-morph ine/4-opiates-binding-to-opiate-rece.

32. Bianchi A, Denavit-Saubie M, Champagnat J. Central control of breathing in mammals; neuronal circuitry, membrane properties, and neurotransmitters. Physiol Rev. 1995 Jan; 75(1): 1.

33. Fitzsimmons E. Pennsylvania deaths of 22 linked to batch of heroin.

The New York Times (late ed.). 2014 Jan 28; Sect. A: 1 (col. 0).

34. Dumas E, Pollack G. Opioid tolerance development: a pharmacokinetic/ pharmacodynamic perspective. AAPS J. 2008 Dec; 10(4): 537-51.

35. Management of substance abuse: Information sheet on opioid overdose. [Internet] World Health Organization 2014 November. [Cited 2016 Nov 7]. Available from: www.who.int/substance_abuse/infor mation-sheet/en/.

36. Naloxone. Drug Facts and Comparisons. Drug Facts and Comparisons 4.0 [Internet]. 2015. Clinical Drug Information, LLC. [cited 2015 Nov 5].

Available from: online.factsandcomparisons.com/.

37. Clinical Pharmacology [Internet] Tampa, FL: Gold Standard Inc. 2015.

Naloxone; [cited 2015 Nov 5]. Available from: 0-www.clinicalpharm acology-ip.com.

38. Vermont Department of Health. Statewide opioid Antagonist Community Access Program Intranasal Naloxone Administration Training Module. [cited 2015 Nov 5]. Available from: healthvermont.gov/adap/ treatment/naloxone/documents/naloxone_pilot_intranasal_admin_pre

10

sentation.pdf.

39. Mulligan S. ADAPT Pharma. Nasal Naloxone (Product Under development) [Internet] 2015. [cited 2015 Nov 5]. Available from: www.fda. gov/downloads/Drugs/NewsEvents/UCM454813.pdf.

40. College of Psychiatric and Neurologic Pharmacists. Lincoln, NE. Naloxone access: a practical guideline for pharmacists. [cited 2015 Nov 5].

Available from: cpnp.org/_docs/guideline/naloxone/naloxone-access. pdf.

41. Naloxone. Lexicomp. [Internet] Hudson, OH: 2015. [cited 2015 Nov 5].

Available from: 0-online.lexi.com.

42. University of Kentucky College of Pharmacy. Protocol to initiate dispensing of naloxone for opioid overdose prevention and response. [cited 2015 Nov 5] Available from: pharmacy.ky.gov/Documents/Sam ple%20Naloxone%20Protocol%20and%20Education%20Sheets.pdf.

43. Davis C, Chang S, Carr D. Legal interventions to reduce overdose mortality: Naloxone access and good samaritan laws [Internet]. [Cited 2016 Nov 7] Available from: www.networkforphl.org/_asset/qz5pvn/ network-naloxone-10-4.pdf.

44. Behavioral Health Coordinating Committee. Department of Health & Human Services USA. Washington DC. Addressing prescription drug abuse in the United States. 2012. [cited 2015 Nov 5]. Available from: www.cdc.gov/drugoverdose/pdf/hhs_prescription_drug_abuse_report _09.2013.pdf.

45. Med Page Today. [Internet] Nasal naloxone price set to jump. 2015/ [cited 2015 Nov 5]. Available from: www.medpagetoday.com/Psychi atry/Addictions/48829.

46. National Conference of State Legislatures. Drug Overdose Immunity “Good Samaritan� Laws. 2016 August. [cited 2016 Nov 7] www. ncsl.org/research/civil-and-criminal-justice/drug-overdose-immunitygood-samaritan-laws.aspx.

47. Schierholt S, Kasich J. State of Ohio Board of Pharmacy. [Internet] Columbus, OH. Dispensing of naloxone by pharmacists and pharmacy interns without a prescription. 2015. [cited 2015 Nov 5]. Available from: pharmacy.ohio.gov/Documents/Pubs/Naloxone/Pharmacist/Gui dance%20Document%20-%20Dispensing%20of%20Naloxone%20wit hout%20a%20Prescription.pdf.

48. Florence CS, Zhou C, Luo F, Xu L. The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013.

Med Care. 2016 Oct 1;54(10):901-6.

49. Massatti R, Kasich J, Plouk T. Ohio Mental Health and Addiction Services. Columbus, OH. [Internet] Naloxone (Narcan) Administration in Ohio 2003-2012. [cited 2015 Nov 5]. Available from: mha.ohio.gov/ Portals/0/assets/Research/Reports/2013-no2-naloxone-epidemiologi cal%20report.pdf.

50. "Project DAWN (Deaths Avoided with Naloxone)." Project DAWN (Deaths Avoided with Naloxone). Ohio Department of Health, 58 Sept.

2015. Web. 27 Nov. 2015. Available from: www.healthy.ohio.gov/vipp/ drug/ProjectDAWN.aspx.

The authors have no conflict of interest or funding support to disclose.

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Latest Trends in the Heroin Epidemic and the Responsibility of the Pharmacist in Controlling Heroin Abuse

Drug Abuse

Assessment Questions 1.

Which of the following corresponds to the concept of incomplete cross-tolerance?

A. Higher dose of same drug is necessary to achieve same high.

B. Physical reaction is the same for two different drugs that act on the same receptor.

C. Tolerance to one drug is developed, but another drug that acts on the same receptor produces normal effects.

D. Drugs acting on different receptors produce the same effect.

2.

Due to the high potency of fentanyl, it requires a low volume to achieve a high. This is not economically beneficial to the dealers of heroin.

A. True B. False

3.

Addition of fentanyl to heroin enhances heroin’s effect of respiratory depression.

A. True B. False

4.

No matter the route of heroin administration, euphoria is achieved quickly. The initial euphoric high lasts ________, but the general feeling of well-being lasts _________.

A. 45 seconds to several minutes, 3 to 5 hours B. 30 minutes to 1 hour, 8 to 12 hours C. 1 to 2 hours, 18 to 24 hours D. 15 seconds, 8 to 12 hours

5.

Naloxone begins to have effects on the body in _______ minutes depending on the route of administration, and _____minute duration of action.

A. 10-15; 45-60 B. 2-5; 30-90 C. 1-2; 60-90 D. 2-5; 60-90

6.

Which of the following is not a symptom of the Opioid Triad of Intoxication?

A. Respiratory depression B. Unconsciousness C. Pinpoint pupils D. Tachycardia

7.

According to new law amendments, some states provide varying levels of criminal or civil immunity for those involved with the prescription, possession, or emergency administration of naloxone and/or criminal immunity for both the victim and the witness when seeking help by reporting an overdose.

A. True B. False

8.

According to the algorithms for Advanced Cardiac Life Support (ACLS) protocols, the initial dose of naloxone ranges from ______ and is given every ______until the desired outcome is reached to treat opiate overdoses.

A. 0.4-2 mg/mL; 2-3 minutes B. 2-10 mg/mL; 2-3 minutes C. 0.4-2 mg/mL; 10-12 minutes D. 2-10 mg/mL; 10-12 minutes

9.

What is the name of the educational program in Ohio that offers a community-based education and naloxone distribution center for overdose cases?

A. Good Samaritan Outreach B. OARRS C. Project DAWN D. DSM 5

10. In 2012 the ______ United States had the highest number of heroin overdoses, and in 2012 the _____ United States had the lowest number of heroin overdoses.

A. midwestern; southern B. northeastern; western C. northeastern; southern D. southern; midwestern

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 12/2/2019.

To complete the continuing education program and receive credit, please go to 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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Drug Abuse Endocrine

Prevention and Treatment of Glucocorticoid-Induced Osteoporosis Mackenzie DeVine, Anh Dao Le, Julie Puvogel, Victoria Cho, Michelle Musser, PharmD, BCPS

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): 0048-0000-16-218-H01-P To complete the continuing education program and receive credit, please go to www.raabecollegeofpharmacy.org/PAW/.

Objectives After completion of this program, the reader should be able to: 1. Identify the characteristics, pathophysiology and prevalence of osteoporosis.

2. Recognize patients at risk for or suffering from glucocorticoid-induced osteoporosis.

3. Define the mechanism, efficacy and safety of alendronate, risedronate, zoledronic acid and teriparatide.

4. Identify appropriate treatment plans based on the FRAX score, risk level and glucocorticoid therapy of the patient.

5. Recognize the unique advantages of individual therapies and apply them to patient cases.

6. Describe the role of a pharmacist in preventing and managing glucocorticoid-induced osteoporosis.

Abstract Osteoporosis is a disease state resulting in decreased bone mineral density (BMD) and increased risk of fracture, specifically of the vertebrae, spine and hip. Risk factors and high risk populations for developing osteoporosis include low BMD, long-term glucocorticoid therapy, genetics, diet, postmenopausal women and patients with inflammatory or chronic disease states. A variety of signaling pathways involving hormones, cytokines and other signaling molecules are involved in bone formation and are affected by long-term glucocorticoid therapy, leading to the development of glucocorticoid-induced osteoporosis (GIO).

There are a variety of drugs that work efficaciously to prevent and treat GIO. Alendronate is a potent bisphosphonate that has shown efficacy in increasing BMD and decreasing bone turnover. Risedronate, another potent bisphosphonate, has demonstrated similar effects in patients suffering from GIO and has been observed to decrease fractures. Zoledronic acid is another bisphosphonate option that has proven efficacy and noninferiority to oral bisphosphonates in GIO, but it is unique in that it is given intravenously once a year. Additionally, teriparatide is a recombinant human parathyroid hor-

12

mone (PTH) which is a newer therapy for the treatment of GIO and is beginning to replace older therapies such as testosterone and estrogen. The once daily administration of teriparatide induces bone formation, which allows for increase in bone mass thus reducing the risk of vertebral and nonvertebral fractures. Furthermore, calcium and vitamin D are usually seen as prophylaxis and adjunctive therapy. At the initiation of therapy, pharmacists should recommend bone density tests to evaluate if medication is appropriate for the patient. Subsequent action includes patient education and monitoring of initiated therapy and disease progression.

Key Terms Alendronate; Bone Density; Bone Remodeling; Chronic Disease; Osteoblasts; Osteogenesis; Osteoporosis; Parathyroid Hormone; Risedronate Sodium; Risk Factors; Teriparatide; Vitamin D Introduction to Osteoporosis Osteoporosis is characterized by the presentation of low bone density which may be caused by a variety of factors.1 Clinically, osteoporosis affects the normal daily activities and quality of life of patients who suffer from this disease. Quality of life is affected through the increased risk of fracture in areas such as the hip, vertebrae and wrist. These complications can ultimately lead to significant morbidity and mortality. Common risk factors for osteoporosis include low bone mineral density (BMD), long-term glucocorticoid therapy and diet. Populations most affected by osteoporosis include postmenopausal women, patients with inflammatory and chronic diseases and patients currently taking long-term glucocorticoid therapy.2 Symptoms of osteoporosis most commonly include an increase in fractures (specifically of the vertebrae, spine and hip) and bone loss detected through BMD testing.

The pathophysiology of osteoporosis is a complex process involving a variety of cells. It is suggested that bone remodeling plays a large role in the pathophysiology of osteoporosis.3 The processes of bone resorption and deposition, collectively termed bone remodeling, are dependent upon the activity of osteoclasts and osteoblasts. Osteoclasts transport protons to the extracellular space resulting in a lowering of pH and, therefore, dissolving bone mineral. Osteoblasts deposit bone mineral, although their mechanism is still not fully understood. These cells communicate to regulate bone remodeling.

Hormones also play a large role in the regulation of osteoblasts and osteoclasts and are necessary for bone maintenance and development. In osteoporosis, complex interactions among cytokines, hormones, pH, osteoblasts and osteoclasts cause osteoblasts to release signaling molecules that induce osteoclasts to dissolve bone. This ultimately

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leads to decreased BMD and development and progression of osteoporosis.

In a global longitudinal study of regional differences in the treatment of osteoporosis, several gaps in treatment became evident. In the United States alone, only 52 percent of patients who reported prior fractures of the hip or spine received treatment with an anti-osteoporotic medication.1 Of patients diagnosed with osteoporosis, only 62 percent receive treatment. Although this seems low, compared to other countries women in the United States are three times more likely to be treated for osteoporosis.

Pharmacology of Glucocorticoid-Induced Osteoporosis The mechanisms in which glucocorticoids affect the bone to induce osteoporosis are complex, multifaceted and still not completely understood (Figure 1). One of the known pathways involved in glucocorticoid-induced osteoporosis (GIO) is the Wingless-type mouse mammary tumor virus integration site family member (Wnt) signal pathway which has a role in osteogenesis and the differentiation of osteoblasts. 4,5 Researchers have examined an antagonist of this pathway, dickkopf-1 (Dkk-1). By testing cultured human osteoblasts, Ohnaka and colleagues found that when given dexamethasone there was an increased expression of Dkk-1 in the osteoblast through the activation of transcription of the Dkk1 promoter by glucocorticoids. Because the glucocorticoids upregulate expression of Dkk-1, they ultimately antagonize the Wnt signaling pathway, interfering with osteoblast signaling for bone formation. A study conducted by Hayashi and colleagues looked at the expression of certain mRNA proteins in an osteoblastic precursor cell line when affected by dexamethasone.6 This study showed an increase in a different Wnt signal inhibitor, axin-2, along with an increased expression in bone morphogenetic protein (BMP) antagonists, follistatin, and Dan. Similar to the Wnt pathway, BMP stimulates osteogenesis and osteoblast differentiation in bone. Howev-

Drug Abuse Endocrine

er, the expression of follistatin and Dan suppresses proper osteoblast function. There was also a decrease in Runx2, a known downstream protein of the BMP pathway, providing additional evidence that dexamethasone inhibits the pathway.

Glucocorticoids also increase the apoptosis of osteoblasts and osteocytes while decreasing the production of osteoclasts.7 A study conducted by Weinstein and colleagues showed mice in the high-dose prednisolone group (2.1 mg/ kg/day) had a significant increase in osteoblast apoptosis in the vertebral cancellous bone compared to controls (2.03 +/- 0.34 vs. 0.66 +/- 0.07 percent, P < 0.05). Apoptotic osteocytes were also found in cortical bone sections taken from the femora, in contrast with the absence of apoptotic osteocytes in the control group.

The newest research suggests that glucocorticoids may cause osteoporosis by a different mechanism by activating the local renin-angiotensin system in bone.8 In a study by Yongtao and colleagues, rabbits were treated with dexamethasone alone or with perindopril, an angiotensin-converting enzyme (ACE) inhibitor. The study found that several genes and proteins including the sclerostin (SOST) gene, the receptor activator of nuclear factor-KB ligand (RANKL) to osteoprotegerin (OPG) ratio, and Runx2 were influenced. The SOST gene is responsible for the production of sclerostin, which antagonizes the Wnt pathway. The RANKL/OPG ratio increases osteoclastogenesis (higher ratio levels mean more osteoclastic genes found in mRNA). When treated with dexamethasone alone, SOST and RANKL/OPG levels were increased, but in the dexamethasone plus perindopril group, SOST and RANKL/OPG were significantly lower compared to the dexamethasone alone group. Runx2 was decreased when given with dexamethasone alone, but it was increased when given with perindopril. This coincides with the results from the aforementioned study by Hayashi and colleagues. The effects

Figure 1. Summary of Glucocorticoid Effects on Bone. 4,6,7,8

The increases in Wnt and BMP antagonists interfere with osteoblast signaling ultimately inhibiting osteogenesis.

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Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

of the glucocorticoid were reversed when given an ACE inhibitor. Therefore, the study concluded that the local reninangiotensin system on bone plays a role in GIO, and further studies are needed to fully understand this mechanism.

Pharmacologic Treatments for Osteoporosis Bisphosphonates Bisphosphonates have shown promise as effective therapy in GIO because of the ability of this drug class to inhibit the resorption of bone while having minimal side effects, thus making therapy more desirable for the patient.9 Bisphosphonates work to increase BMD by inhibiting bone resorption and the activity of osteoclasts. Although there are many bisphosphonates, three are particularly recommended by the American College of Rheumatology for the treatment of GIO: alendronate, risedronate and zoledronic acid.10 Alendronate Alendronate is a potent second-generation bisphosphonate.9 Alendronate has a high affinity for bone mineral and is taken up into bone during osteoclast resorption. The drug inhibits the enzyme farnesyl pyrophosphate synthase which is an enzyme involved in the mevalonic acid pathway. 11 The mevalonic acid pathway affects the production of isoprenoids essential for the modification of small guanosine triphosphate (GTP) binding proteins. By inhibiting this pathway, alendronate restricts osteoclast survival. It has also demonstrated effectiveness in increasing BMD of the hip and spine as well

as decreasing the incidence of fractures in these areas, along with the forearm, in postmenopausal women who suffer from osteoporosis.12 The American College of Rheumatology’s guidelines for alendronate therapy suggests determining the patient’s risk category based on their Fracture Risk Assessment Tool (FRAX) score.10 The FRAX is a questionnaire tool used to assess a patient’s risk of fracture within the next 10 years in patients who are not being treated and are between the ages of 40 years and 90 years.13 It can be used with or without knowledge of the individual patient’s BMD in low, medium and high risk patients. Additionally, there is a strong level of evidence for the efficacy and use of alendronate in therapy.

Please refer to Table 1 for specific recommendations. At all risk levels, patient monitoring is recommended. The pharmacist should monitor for additional fractures, modifiable patient risk factors for osteoporosis, patient adherence to therapy and changes in BMD.10 If glucocorticoid therapy is discontinued alendronate may also be discontinued.

Typically, alendronate is dosed once daily, twice weekly or once weekly. Each regimen has shown near equivalent efficacy in increasing BMD in the hip, neck, trochanter and entire body.9 It is recommended as a once daily regimen in patients with GIO receiving systemic steroids. Typically, patients are given 5 mg by mouth daily. In women who are postmenopausal not taking any type of estrogen replacement therapy,

Table 1. Recommendations for Therapeutic Use in Glucocorticoid-Induced Osteoporosis.10

Glucocorticoid Therapy

Low Risk Patient (FRAX < 10% for 10 year major osteoporosis fracture)

Medium Risk Patient (FRAX 10-20% for 10 year major osteoporosis fracture)

High Risk Patient (FRAX >20% for 10 year major osteoporosis fracture)

< 5 mg/day for < 1 month

Alendronate Risedronate Zoledronic Acid

> 5 mg/day for < 1 month

Alendronate Risedronate Zoledronic Acid Teriparatide

Any dose for 1-3 months

Alendronate Risedronate Zoledronic Acid

< 7.5 mg/day for ≥ 3 months

> 7.5 mg/day for ≥ 3 months

Alendronate Risedronate Zoledronic Acid

Alendronate Risedronate

Alendronate Risedronate Zoledronic Acid Teriparatide

Alendronate Risedronate Zoledronic Acid

Alendronate Risedronate Zoledronic Acid Teriparatide

These recommendations are from the American College of Rheumatology and apply to postmenopausal women and men over the age of 50 years.

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10 mg by mouth daily is recommended. Patients should remain sitting upright for at least 30 minutes after taking each dose to avoid esophageal irritation. Bone mineral density should also be measured at baseline, six months and 12 months. Due to the potential for increased risk of osteonecrosis of the jaw, patients on glucocorticoids should be advised to have dental exams prior to initiation of bisphosphonates like alendronate. Patients should also have their renal function and serum calcium levels checked before initiation. If the creatinine clearance is less than 35 mL/min, alendronate should not be started. Furthermore, because alendronate decreases serum calcium levels, hypocalcemia should be corrected before starting therapy, and calcium levels should be monitored throughout therapy. This medication should be used with caution in patients suffering from certain gastrointestinal (GI) and esophageal diseases such as esophagitis, gastritis and gastroesophageal reflux disease due to the increased risk of esophageal irritation associated with this therapy. The geriatric population is at increased risk for these reactions and should be monitored for any sign of GI reactions. Also, this medication is specifically contraindicated in patients with an increased risk of aspiration or delay of emptying of the esophagus. Lastly, therapy should be discontinued if the patient develops any signs of dysphasia or retrosternal pain.

In a study conducted by Saag and colleagues, researchers found that alendronate increased BMD in patients currently taking glucocorticoid therapy.12 The main goal of the study was to examine the mean percent change in lumbar-spine bone density from baseline to week 48 between the groups receiving different doses of alendronate therapy and placebo.

Secondary outcomes measured bone density changes in the hip along with new fracture incidence of the vertebrae and bone turnover markers. The study was a double-blind, randomized, placebo-controlled, multicountry trial. Two different doses of alendronate were studied in men and women ranging from 17 to 83 years of age without significant differences in baseline characteristics. Patients had been receiving at least 7.5 mg of prednisone daily or an equivalent glucocorticoid therapy for underlying chronic diseases. They were then further divided based on the duration of their glucocorticoid therapy (four months, four to 12 months and more than 12 months).

The study included 477 patients who were randomly assigned to receive 5 mg or 10 mg alendronate or matching placebo daily.12 The patients were seen at baseline, four, 12, 24, 36 and 48 weeks where researchers reviewed their therapy usage diary. At baseline and every 12 weeks, BMD of the hip, lumbar area of the spine and whole body were quantified and analyzed. Studies were evaluated using intention-totreat standards. Results were analyzed using the step-down Tukey trend test which adjusted for multiplicity.

After 48 weeks of therapy, patients receiving 5 mg and 10 mg of alendronate saw a significant increase (p < 0.001) in the BMD of the neck, trochanter and lumbar spine.12 Only 45 percent of the patients in the placebo group saw an increase in

Drug Abuse Endocrine

the lumbar spine BMD as compared to 80 percent in the treatment group (mostly seen in postmenopausal women).

Whole body BMD significantly increased in the treatment group on 10 mg of alendronate therapy. Similar side effects were experienced among groups such as headache, musculoskeletal pain and upper respiratory infection. Patients receiving 10 mg of alendronate reported increased GI adverse events.

This study concluded that alendronate was efficacious in increasing the BMD in patients with GIO regardless of duration of glucocorticoid therapy.12 Additionally, bone turnover was decreased as a result of this therapy.

Risedronate Risedronate, one of the most potent bisphosphonates, acts by inhibiting the resorption of bone but does not affect mineralization.14 The action of risedronate is based on its affinity for the component of bone matrix hydroxyapatite.15 It acts as an analogue of isoprenoid diphosphate lipids, therefore inhibiting farnesyl pyrophosphate, a key enzyme associated with the mevalonate pathway. By inhibiting the key enzyme in osteoclasts that is essential for the synthesis of isoprenoid lipids, posttranslational modification of small GTPase proteins is inhibited. As a result, osteoclast activity is inhibited, and bone resorption and turnover are reduced. Also, postmenopausal women have seen a net gain in bone mass with treatment of risedronate.16 The American College of Rheumatologyâ&#x20AC;&#x2122;s guidelines for risedronate therapy are evaluated in the same manner as alendronate.10 Please refer to Table 1 for recommendations on initiation of treatment of risedronate based on FRAX score and glucocorticoid therapy. At all risk levels, patient monitoring is recommended. Additionally, risedronate has a strong level of evidence in low, medium and high risk patients.

Risedronate is typically dosed once daily, once weekly, once monthly or twice monthly depending on the condition.14 For GIO, it is a recommended dosing of 5 mg orally daily before breakfast in an immediate-release tablet. Patients should remain sitting upright for at least 30 minutes after receiving each dose to avoid esophageal irritation. This drug is contraindicated in patients with hypocalcemia or abnormalities of mineral or bone metabolism such as chronic kidney disease and certain thyroid disorders. It has been shown to cause skin reactions such as rash and induce acute bronchospasms in patients with hypersensitivities to phosphonate or aspirinsensitive asthma. Similar to alendronate, risedronate should not be used in patients unable to remain sitting upright for 30 minutes after receiving a dose of medication or those who have esophageal malfunctions. Monitoring should occur for symptoms of esophageal reactions, dysphasia or retrosternal pain.

In a multicenter, double-blind, placebo-controlled, parallelgroup study conducted by Reid and colleagues, researchers aimed to assess the efficacy and safety of risedronate in pa-

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Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

tients taking high dose, long-term glucocorticoid therapy.16 Patient tolerability of this therapy was also assessed. Male and female patients between the ages of 18 years and 85 years were enrolled from 23 study centers and had been receiving at least 7.5 mg of glucocorticoid therapy for a minimum of six months. A total of 290 patients were enrolled (109 men and 181 women), and 14 percent of the women were premenopausal. Patients were divided into three groups: men, premenopausal women who were either sterile or using some kind of contraceptive and women who were postmenopausal for a year or more. Patients were then randomized to receive placebo, 2.5 mg risedronate or 5 mg risedronate daily for one year. Baseline demographics and characteristics were comparable among treatment groups.

Patients were required to take the medication with 240 ml of water 30 to 60 minutes before breakfast on an empty stomach and to remain upright for at least one hour. Additionally, patients received vitamin D and calcium supplementation.

The study had 90 percent power to detect a difference in BMD with an alpha level of 0.05 and standard deviation of 5 percent.

The BMD of the lumbar spine, neck, trochanter and forearm were measured at baseline, six months and 12 months.16 Vertebral fractures were also assessed at baseline and 12 months. Physical examination of the patients was conducted at six months and 12 months, and laboratory tests were completed at baseline, one month, three months, six months and 12 months. After 12 months of treatment, risedronate demonstrated significant differences in BMD of the lumbar spine (p < 0.001), femoral neck (p < 0.004) and trochanter (p < 0.001). Patients receiving the 5 mg dose of risedronate saw an increase in BMD by 2.9 percent in the lumbar spine, 1.8 percent in the femoral neck and 2.4 percent in the trochanter. In patients receiving 2.5 mg of risedronate, there was a small increase in spinal BMD which was not significant when compared to the placebo group. In the radius, BMD was maintained in patients receiving 5 mg risedronate, while there was a loss of BMD in the placebo group. A further subgroup analysis of patients receiving 5 mg risedronate demonstrated that 5 mg therapy, relative to placebo, increased the BMD at all sites in both men and postmenopausal women. Due to the small population of premenopausal women in the study, their results were not considered significant. Risedronate 5 mg therapy was also shown to increase BMD in patients with underlying chronic disease (rheumatoid arthritis, lung disease). Although these results were not statistically significant, there was a positive correlation.

Nearly 15 percent of patients in the placebo group experienced fractures, while only 5 percent of the patients in the treatment group experienced fractures, at 12 months. 16 A reduction of 70 percent in fractures of the vertebrae, as compared to placebo, was calculated for both risedronate groups.

Significance was found overall in the lumbar spine, femoral neck and femoral trochanter in both the 2.5 mg and 5 mg treatment groups (p < 0.001, p < 0.004, p < 0.010, respectively). Also, reported adverse events were similar among treat-

16

ment and placebo groups. The treatment groups receiving 5 mg risedronate reported a higher incidence of back pain and arthralgia when compared to placebo. However, these side effects, along with other GI symptoms such as abdominal pain and gastritis, were mild and not considered relevant. Gastrointestinal side effects were reported but were similar among treatment and placebo groups; none being reported as severe.

Overall, Reid and colleagues showed that in patients on high doses of long-term glucocorticoid therapy, 5 mg of risedronate significantly increases BMD while dosing of 2.5 mg is less effective.16 Additionally, fractures were reduced in the treatment groups as compared to the placebo group. There was a significant increase (3 percent) in BMD of the lumbar spine after 12 months of therapy with 5 mg risedronate, in addition to a significant increase in BMD of the trochanter and femoral neck. Risedronate was also well tolerated in the study and can be recommended in the studied patient population.

Zoledronic Acid (ReclastÂŽ) Parenteral Therapy Zoledronic acid is a bisphosphonate that is unique in its administration and frequency. It targets farnesyl pyrophosphate synthase in osteoclasts located in areas of high bone turnover.17 The drug only needs to be administered intravenously once a year because of its high affinity for mineralized bone. This schedule is appealing for prescribers with patients that have compliance issues.

The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) group performed a year long, randomized, double-blind, double-dummy, noninferiority study comparing zoledronic acid with risedronate.18 Both genders aged 18 to 85 years could participate in the study.

The main goal of the study was to prove that zoledronic acid 5 mg intravenously is noninferior to oral risedronate 5 mg daily when looking at percentage change from baseline in BMD of the lumbar spine (primary outcome), total hip, femoral neck, trochanter and distal radius (secondary outcomes) after 12 months. Bone turnover markers and adverse events were also compared and assessed. All patients in the study were required to take vitamin D and calcium before the trial began and throughout the trial. The groups were randomized in a one to one ratio into either the zoledronic acid group or the risedronate group and also into either a treatment or prevention group based on the initiation of glucocorticoid therapy (less than three months was considered prevention and greater than three months was considered treatment).

The trial confirmed that zoledronic acid is noninferior to risedronate in the treatment and prevention of GIO. The HORIZON group concluded that after 12 months zoledronic acid increased lumbar spine BMD in prevention and treatment when assessed at all test areas of the body with the exception of the prevention of GIO of the distal radius. Perhaps more importantly, when the BMD of the lumbar spine was tested at six months it was significantly higher than the risedronate group. This is significant because patients can start to see GIO within a few months of glucocorticoid thera-

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Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

py. Therefore, the faster a drug can begin showing considerable effects of GIO prevention or treatment, the better.

In the HORIZON study, zoledronic acid did have significantly higher occurrence of adverse events as compared to risedronate.18 The study found within the first three days after the infusion of zoledronic acid, flu-like illnesses and pyrexia were reported; however, after that time period elapsed, reporting of adverse events was similar between the groups. A review article discussing the management of common adverse events associated with intravenous bisphosphonates found flu-like illnesses to be frequently reported but transient in duration.19 The most severe adverse event reported for both groups was worsening of rheumatoid arthritis, and the main difference was seen in the higher reporting of pyrexia in the patients receiving zoledronic acid.18 The administration of acetaminophen immediately following the infusion of zoledronic acid is suggested to reduce frequency or duration of pyrexia, myalgia, arthralgia and headache within the first three days.17 The HORIZON study convinced the American College of Rheumatology to include zoledronic acid in their 2010 recommendations for the prevention and treatment of GIO.10 The recommendations according to FRAX score can be found in Table 1. Because the FRAX score can only be used in postmenopausal patients or men over 50 years of age, there are also recommendations for premenopausal women and men less than 50 years of age that have a history of fragility fracture. Zoledronic acid is recommended if taking at least 7.5 mg of prednisone for one to three months and of nonchildbearing potential. If at least three months of glucocorticoid therapy are expected for those with a history of fragility fractures and of nonchildbearing potential, zoledronic acid is a recommendation for any dose. Zoledronic acid is not recommended for women of childbearing potential. All of the recommendations provided were level B evidence, meaning that the data came from a single, randomized, controlled trial or nonrandomized study.

The absolute contraindications for zoledronic acid therapy include hypocalcemia (unless adequately treated), a creatinine clearance less than 35 mL/min or evidence of acute renal impairment, pregnancy, and hypersensitivity to any component in zoledronic acid.17 Patient warnings include osteonecrosis of the jaw, atypical femoral fractures, musculoskeletal pain and bronchoconstriction in aspirin-sensitive patients.

While these are very rare side effects, patients should receive appropriate education about these possible occurrences and what to do if they occur. Zoledronic acid should be considered in patients that have compliance problems and could be considered a first-line option for many patients as evidenced by a survey at the end of the HORIZON study.18 The survey asked patients to comment on their preferences of route of administration regarding convenience, satisfaction and willingness to use long term. Most patients reported in the survey that they favored the intravenous preparation over the oral for convenience and satisfaction and stated they were willing to take the intravenous preparation.

Drug Abuse Endocrine

Teriparatide Glucocorticoid therapy induces bone loss by inhibiting osteoblast formation and activating osteoblast apoptosis.20 Teriparatide is a recombinant human parathyroid hormone (PTH), which is a newer therapy for the treatment of GIO, and replaces older therapies such as testosterone and estrogen.10 The administration of teriparatide once daily induces bone formation, which allows for an increase in bone mass thus reducing the risk of vertebral and nonvertebral fractures.20 Please refer to Table 1 for the American College of Rheumatology’s guidelines for recommendations of the therapeutic usage of teriparatide based on FRAX score and glucocorticoid therapy.10 Similar to the previously mentioned medications, patient monitoring is recommended during usage. In addition to the recommendations above, for premenopausal women who have childbearing potential along with a fragility fracture, teriparatide is recommended if the patient is on glucocorticoids (dose of 7.5 mg or more of prednisone) for more than three months. For men below 50 years of age, teriparatide is recommended if glucocorticoid usage is longer than three months and if a fragility fracture exists. Currently, the use of teriparatide therapy for GIO is only approved for at most 24 months of therapy.21 The effectiveness of the teriparatide was studied in a randomized, double-blind, controlled trial conducted by Saag and colleagues.20 Teriparatide was compared with alendronate in 428 females and males who were diagnosed with established glucocorticoid-induced osteoporosis. These patients were defined as patients diagnosed with osteoporosis and were on a glucocorticoid therapy for at least three months.

Two hundred fourteen patients were randomly assigned to either receive 20 mcg of subcutaneous injectable teriparatide once daily with an oral placebo or 10 mg of alendronate once daily orally with an injectable placebo. Patients also received 1000 mg calcium carbonate and vitamin D daily. There were no significant differences between the patients in the two study groups when baseline characteristics were accounted.

The study was conducted for 18 months. The main focus of the study was to measure the change in BMD of the lumbar spine from baseline to 18 months. Additional outcomes assessed included changes in BMD at the total hip, markers of bone turnover, and the time to fluctuations in BMD, occurrence of fractures, and safety.

It was found that the mean BMD in the lumbar spine improved more in the teriparatide group than in the alendronate group (teriparatide: 7.2 ± 0.7 percent and alendronate: 3.4 ± 0.7 percent, P < 0.001). There was a significant difference (P < 0.001) between the groups six months into the study. At 18 months, the measured difference from baseline for teriparatide was 3.8 ± 0.6 percent but only 2.4 ± 0.6 percent for alendronate. When analyzing markers of bone turnover, N-terminal propeptide of type I collagen served as an indicator of bone formation. C-telopeptide of type I collagen

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Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

served as an indicator of resorption. Both of these markers increased 69.8 percent and 44.8 percent measuring from baseline, respectively. Alendronate showed a decrease in markers followed by constant suppressed levels. The teriparatide group also had fewer new vertebral fractures than in the alendronate group showing a 0.6 percent occurrence in the teriparatide group and 6.1 percent occurrence in the alendronate group while P = 0.004. It was shown that there were more nonvertebral fractures for patients who received teriparatide. However, the occurrence of nonvertebral fractures did not show a big difference with 5.6 percent occurrence in the teriparatide group versus 3.7 percent in the alendronate group with P=0.36.

Osteoporosis patients have a lowered ability to convert 25-hydroxyvitamin D [25(OH)D] to 1,25 dihydroxyvitamin D [1,25(OH)2D], which is the active form.22 Cosman and colleagues found that with doses greater than 7.5 mg per day, teriparatide increased renal activity in order to promote the conversion of vitamin D. The increased vitamin D conversion to its active form allows for an increased calcium absorption in the GI tract, renal conservation of calcium, skeletal calcium release and increase in serum calcium concentrations. This is supported by the study conducted by Saag and colleagues which showed that, similar to the 18 month study, the 36 month study showed teriparatide patients with elevated serum calcium levels 21 percent compared to only 7 percent in alendronate patients.23 Adverse events of teriparatide use reported include nausea, insomnia, pharyngitis, viral infection, headache, dizziness and injection site reactions.20 Three patients experienced hyperuricemia and one patient experienced gout in the teriparatide group, but these adverse events did not occur in the alendronate group.

Patients with osteoporosis and elevated risk for fracture showed more improvement in BMD while receiving teriparatide when compared to patients who received alendronate.20 Since BMD increased more with the usage of teriparatide therapy in GIO, it is associated with a higher volumetric BMD than alendronate.

Although teriparatide use should not exceed 24 months, a 36 month follow-up study by Saag and colleagues was conducted and found that patients treated with teriparatide showed greater increases in BMD of the lumbar spine (11 percent versus 5.3 percent) and fewer new vertebral fractures than subjects treated with alendronate.23 Calcium and Vitamin D Clinicians have often struggled to find the correct place for calcium and vitamin D in the treatment of osteoporosis. A double-blind, parallel-group study, performed by Sambrook and colleagues, randomized patients on corticosteroids into three groups: group 1 took calcitriol, salmon calcitonin nasal spray, and elemental calcium; group 2 took the same but had a placebo nasal spray; group 3 took calcium and placebos of the calcitriol and calcitonin.24 The study looked at the effects

18

of the therapies on BMD while on corticosteroids. They found that calcium plus calcitriol, with or without calcitonin, prevented bone loss from the lumbar spine. The study also looked at the femoral neck and the distal radius, but none of the treatment groups prevented bone loss in these locations.

Sambrook and colleagues also did a later study that was randomized and open label.25 This study compared calcitriol, vitamin D (ergocalciferol) plus calcium and alendronate plus calcium. Bone mineral density of the lumbar spine was measured every six months from baseline for two years, and femoral neck and total body were also measured as secondary end points of the study. Results from the study indicated that alendronate plus calcium was superior to the other treatments in the study. This was especially noticeable in the initial bone loss phase.

Because drugs that work more efficaciously in the prevention and treatment of GIO are now considered first-line, calcium and vitamin D are usually seen as adjunctive therapy.10 In studies that deal with the treatment of GIO, most often the patients in the treatment groups are also receiving some type of calcium and vitamin D supplementation.12,18 Prevention of GIO All patients on glucocorticoids should engage in weightbearing exercise like running or lifting to stimulate bone remodeling.10 Regardless of the strength or duration of glucocorticoid therapy, patients should receive 1200 to 1500 mg/day of calcium (diet or supplement) in addition to 800 to 1000 IU/day of vitamin D. All of the aforementioned drugs can be initiated with the start of glucocorticoid therapy as either prevention or treatment. See Table 2 for dosage recommendations.

The Pharmacistâ&#x20AC;&#x2122;s Role It is estimated that more than 1 million people in the United States alone are on long-term glucocorticoid therapy.26 This type of therapy elevates patients to a higher risk of osteoporosis and fractures. Most of the adverse events of the glucocorticoids occur during the first six months of therapy.

Patients on long-term glucocorticoid therapy require education and monitoring.26 Pharmacists are readily available to help counsel these patients as they have the most knowledge about medications. These two factors make pharmacists, especially community pharmacists, prime candidates to assist patients who have or are at risk for GIO. Through counseling and education, pharmacists can increase patient awareness of potential risks of long-term use of glucocorticoids.27 They can inform patients that cigarette smoking, excessive alcohol intake, an inactive lifestyle and hypogonadism can increase their risk for developing GIO. McDonough and colleagues conducted a randomized control design where 15 community pharmacies were randomized to either the control group (which provided usual patient care) or the treatment group (which provided patients with education about the risks of GIO).27 The treatment group re-

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Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

Drug Abuse Endocrine

Table 2: Dosing for Prevention of Glucocorticoid-Induced Osteoporosis.9,10,14,17 Drug

Route

Dose

Frequency

Alendronate

Oral

5 mg / 35 mg

Daily/Weekly

Risedronate

Oral

5 mg / 35 mg

Daily/Weekly

Intravenous

5 mg

Annually

Subcutaneous

20 mcg

Daily

Zoledronic Acid

Teriparatide

ceived education via pamphlets. The pharmacists monitored patient drug therapies and looked for potential drug-related issues. Osteoporosis risk factors were then collected through patient surveys after nine months. Variables such as using calcium supplements, discussion of GIO risk, discussion of bone density tests, reported inactivity and reported low calcium diets were compared between the two groups. There was only a significant difference between the two groups when the frequency of patients taking a calcium supplement was analyzed: control group (-6.9 percent) and the treatment group (17.1 percent) with P < 0.05. This study shows that community pharmacists are able to increase vitamin supplementation for patients on glucocorticoid therapy.

Additionally, pharmacists can help identify high-risk patients before glucocorticoid therapy starts and, as a result, educate patients about their risk for GIO, recommend a BMD test and potentially collaborate with a physician to initiate therapy to prevent GIO occurrence.26, 28 It is recommended that patients start therapy on the lowest dose of glucocorticoids for the shortest length of therapy to minimize GIO risk. Patients beginning glucocorticoid therapy that will last longer than three months should be advised to have the following tests: fall risk assessment, baseline dual x-ray absorptiometry, serum 25-hydroxyvitamin D level, baseline height, assessment of prevalent fragility fractures and radiographic imaging of spine or vertebra.10 Patients should also consider appropriate lifestyle changes such as weight-bearing activities and exercise, fall prevention, smoking cessation and avoidance of excessive alcohol consumption (> two drinks/day). Furthermore, pharmacists should counsel patients on medication usage, calcium and vitamin D supplementation and the importance of adherence.10,28 For patients who have been taking glucocorticoids for longer than three months, pharmacists should advise patients to consult their doctors about periodically receiving serial bone mineral density testing, assessments for incident fragility fracture, osteoporosis medication compliance, annual serum 25-hydroxyvitamin D measurements and height measurements to monitor for GIO.10

When reviewing patient profiles, pharmacists should be alert for red flags in regard to glucocorticoid therapy and GIO.27 They should watch for medications that may interact with glucocorticoids such as thyroid hormone supplements and anticonvulsants. Additionally, pharmacists should check profiles or ask patients on glucocorticoids if they are also taking recommended calcium and vitamin D supplementation.

Also, pharmacists can determine when a drug holiday is necessary by analyzing therapy duration of past therapy and patient risk factors. A drug holiday is a break in therapy designed to reduce the risks of long-term glucocorticoid treatment.26 Patients on drug holiday should be monitored; presenting an ideal role for the pharmacist. If the BMD decreases significantly, or if occurrence of fractures takes place, therapy should resume. If a patient is on an osteoporosis treatment holiday, the pharmacist can create an action plan and follow up with the patient every one to two years. Pharmacists can also reassess a patientâ&#x20AC;&#x2122;s risk of fracture by utilizing FRAX to help identify when it would be appropriate to start or end a drug holiday.

Pharmacists can prevent and treat GIO via monitoring, educating patients on lifestyle and diet alterations, and providing therapeutic management.26 Community pharmacists readily interact with physicians, allowing for initiation of a management process to reduce GIO. Utilizing these methods will allow for better therapeutic outcomes with interprofessional work between the pharmacist and physician along with communication with patient.

Conclusion Osteoporosis is characterized by the presentation of low bone density influenced by individualized factors. The disease has also been shown to occur in the vast majority of patients on long-term glucocorticoid therapy. The development of GIO poses negative effects on the patient by hindering their ability to complete daily activities and lowering their quality of life through the increased risk of fracture in areas such as the hip, vertebrae and wrist. Prevention of GIO by utilizing nonpharmacologic measures such as weight-bearing

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Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

exercises like running or lifting to stimulate bone remodeling is recommended with any glucocorticoid therapy.

The same medications used for prevention are also used for treatment of GIO. Medication therapy options most frequently recommended to treat GIO consist of bisphosphonates, including alendronate oral therapy, risedronate oral therapy or zoledronic acid parenteral therapy. The most recent addition to the guidelines is teriparatide, a subcutaneous injectable therapy. Recommendations are made based on the patientâ&#x20AC;&#x2122;s FRAX score and glucocorticoid treatment plan and are individualized to best fit the patientâ&#x20AC;&#x2122;s lifestyle. The concurrent use of supplements such as calcium and vitamin D is beneficial to help build up BMD. Both supplements have been found to significantly improve BMD and lower fracture risk in patients.

Although therapeutic outcomes depend on patient compliance, the pharmacist can play an important role in glucocorticoid therapy. Pharmacists should counsel and assess the appropriateness of each medication to prevent GIO. After therapy is initiated, pharmacists should be involved in monitoring the wellness of the patient and evaluating if additional therapy is necessary.

References 1. Diez-Perez A, Hooven FH, Adachi JD, Adami S, Anderson FA, Boonen S, et al. Regional differences in treatment for osteoporosis. The Global Longitudinal Study of Osteoporosis in Women (GLOW). Bone. 2011 Sep;49(3):493-498.

2. Lekamwasam S, Adachi JD, Agnusdei D, Bilezikian J, Boonen S, Borgstrom F, et al. A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporosis Int. 2012 Sep;23(9):2257-2276.

3. International Osteoporosis Foundation [Internet]. Switzerland: International Osteoporosis Foundation; c2015. Pathophysiology: biological causes of osteoporosis [cited 2015 Nov 3]. Available from: www.iofbonehealth.org/pathophysiology-biological-causes-osteoporo sis.

4. Ohnaka K, Taniguchi H, Kawate H, Nawata H, Takayanagi R. Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis. Biochem Biophy Res Commun. 2004;318:259-264.

5. Atlas of genetics and cytogenetics in oncology and haematology [Internet]. Oslo (NO); 2003 Apr. The WNT signaling pathway and its role in human solid tumors; [cited 2015 Nov 5]; [about 12 screens].

Available from: atlasgeneticsoncology.org//Deep/WNTSignPathID20 042.html.

6. Hayashi K, Yamaguchi T, Yano S, Kanazawa I, Yamauchi M, Yamamoto M, Sugimoto T. BMP/Wnt antagonists are upregulated by dexamethasone in osteoblasts and reversed by alendronate and PTH: potential therapeutic targets for glucocorticoid-induced osteoporosis. 2009;379: 261-266.

7. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: potential mechanisms of their deleterious effects on bone. J Clin Invest. 1998 Jul;102:274-282.

8. Yongtao Z, Kunzheng W, Jingjing Z, Hu S, Jianqiang K, Ruiyu L, Chunsheng W. Glucocorticoids activate the local renin-angiotensin system in bone: possible mechanism for glucocorticoid-induced osteoporosis. Endocrine. 2014;47:598-608.

9. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Alendronate; [updated 2015 Jun 16; cited 2015 Oct 1]; [3 pages]. Available from: www.clinicalpharmacology-ip.com/Forms/drugoptions.aspx?cp num=13&n=Alendronate&t=0.

10. Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, et al.

American college of rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.

20

Arthritis Care Res. 2010 Nov;62 (11): 1515-1526.

11. Drug Bank [Internet]. Alberta (CA): Drug Bank. 2005. unique ID: DB00630, Alendronate; [updated 2014 Jan 17; cited 2015 Nov 30]; [about 3 screens]. Available from: www.drugbank.ca/drugs/DB00630.

12. Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaure S, et al. Alendronate for the prevention and treatment of glucocorticoidinduced osteoporosis. N Engl J Med. 1998 Jul;339(5):292-299.

13. American College of Rheumatology [Internet]. Atlanta (GA): American College of Rheumatology; c2015. Fracture Risk Assessment Tool (FRAX) [cited 2015 Nov 3]; [about 1 screen]. Available from: www.rheumatology.org/I-Am-A/Rheumatologist/Research/ClinicianResearchers/Fracture-Risk-Assessment-Tool-FRAX. 14. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Risedronate; [updated 2010 Oct 13; cited 2015 Oct 1]; [3 pages]. Available from: www.clinicalpharmacology-ip.com/Forms/drugoptions.aspx?cpnum= 2139&n=Risedronate&t=0.

15. Drug Bank [Internet]. Alberta (CA): Drug Bank. 2005. unique ID: DB00884, Risedronate; [updated 2013 Sep 16; cited 2015 Nov 30]; [about 3 screens]. Available from: www.drugbank.ca/drugs/DB00884.

16. Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S, et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial.

J Bone Miner Res. 2000;15(6):1006-13.

17. Reclast (zoledronic acid injection) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015 Jan. 18. Reid DM, Devogelaer J-P, Saag K, Roux C, Lau C-S, Reginster J-Y,et al.

Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicenter, double-blind, double-dummy, randomized controlled trial. Lancet.

2009;373:1253-63.

19. Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Onc. 2006 Jun;17:897-907.

20. Saag KG, Emkey R, Shane E, Boonen S, Marin F, Donley D, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007 Nov;357(20):2028-2039.

21. Dore RK. Long-term safety, efficacy, and patient acceptability of teriparatide in the management of glucocorticoid-induced osteoporosis.

Patient Prefer Adherence. 2013 May:7:435-446.

22. Cosman F, Dawson-Hughes B, Wan X, Krege J. Changes in vitamin D metabolites during teriparatide treatment. Bone.2012 Jun;50(6):13681371.

23. Saag KG, Zanchetta JR, Devogelaer J, Adler RA, Eastell R, See K, et al.

Effects of Teriparatide versus alendronate for treating glucocorticoidinduced osteoporosis. Arthritis Rheum. 2009 Nov;60(11):3346-3355.

24. Sambrook P, Birmingham J, Kelly P, Kempler S, Nguyen T, Pocock N, Eisman J. Prevention of corticosteroid osteoporosis:a comparison of calcium, calcitriol, and calcitonin. N Engl J Med. 1993 Jun;328(24): 1747-1752.

25. Sambrook PN, Kotowicz M, Nash P, Styles CB, Naganathan V, Henderson-Briffa KN, et al. Prevention and treatment of glucocorticoidinduced osteoporosis: a comparison of calcitriol, vitamin d plus calcium, and alendronate plus calcium. J Bone Miner Res. 2003;18 (5):919-924.

26. Menezes M. Role of the pharmacist in medication therapy management services in patients with osteoporosis. Clin Ther. 2015 Jul;34(7):15731586.

27. McDonough RP, Doucette WR, Kumbera P, Klepser DG. An evaluation of managing and educating patients on the risk of glucocorticoid-induced osteoporosis. Value in Health Reg Issues. 2005 Feb;8(1):24-31.

28. Elias MN, Burden AM, Cadarette SM. The impact of pharmacist interventions on osteoporosis management: a systematic review. Osteoporos Int. 2011 Jul;22:2587-2596.

The authors have no conflict of interest or funding support to disclose.

The Pharmacy And Wellness Review Spring 2016 Volume 7, Issue 2

Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

Drug Abuse Endocrine

Assessment Questions 1.

2.

3.

JD, a 65 year old female, is receiving prednisone 15 mg daily as maintenance therapy for autoimmune hepatitis.

JD’s FRAX score indicates she is at high risk for (glucocorticoid-induced) osteoporosis. Which of the following would be appropriate therapy for JD? A. Alendronate therapy.

B. Discontinuation of maintenance prednisone.

C. Calcium and vitamin D supplementation only.

D. No pharmacologic intervention is necessary at this time.

Patients taking glucocorticoid therapy for at least _____ have a significant increase in developing osteoporosis.

A. 1-2 months B. 4-8 months C. 3-6 months D. 1 year The pathophysiology of osteoporosis involves: A. Hormones B. Osteoclasts C. Osteoblasts D. All of the above

4.

What dose of risedronate has been shown to significantly increase bone mineral density in patients with GIO? A. 2 mg B. 5 mg C. 7.5 mg D. 12.5 mg

5.

JL’s doctor has identified him as a high-risk patient that needs to be started on therapy to prevent glucocorticoidinduced osteoporosis. His doctor knows that JL frequently misses appointments and never calls regarding refills for his hypertension medication. Which medication would you suggest for JL? A. Alendronate B. Zoledronic Acid C. Risedronate D. Calcium alone will show benefit.

6.

7.

Which of the following is a contraindication to zoledronic acid therapy?

A. Untreated hypocalcemia B. CrCl < 35 mL/min C. Pregnancy D. All of the above are contraindications to zoledronic acid therapy.

8.

What does teriparatide stimulate?

A. Osteoblast apoptosis B. Osteoclasts C. Osteoblastogenesis D. Glucocorticoid-induced Osteoporosis

9.

What is the usual dose of teriparatide for GIO patients?

A. Oral: 20 mg once daily B. Sublingual: 200 mcg once daily C. SubQ: 20 mcg once daily D. IM: 20 mcg once daily

10. Pharmacists should counsel on __________ and ___________ supplementation when a patient starts a glucocorticoid therapy for a duration longer than three months.

A. fish oil; St. John’s Wort B. vitamin C; calcium C. vitamin A; vitamin C D. vitamin D; vitamin A

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 12/2/2019.

To complete the continuing education program and receive credit, please go to 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.

The 2010 American College of Rheumatology guidelines recommend of calcium and ____ of vitamin D. A. 1200-1500 mg/day; 800-1000 IU/day B. 800-1000 IU/day; 1200-1500 mg/day C. 2200-2500 mg/day; 80-100 IU/day D. 80-100 IU/day; 2200-2500 mg/day

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Drug Abuse Gastroenterology

Evaluating the Role of Fecal Microbiota Transplant in the Treatment of Clostridium Difficile Infection Anh Dao Le, Olivia Henton, Shane Bogusz, Brian Heilbronner, Jessica Hinson, PharmD

Abstract Fecal microbiota transplant (FMT) therapy is an increasingly prevalent treatment option for Clostridium difficile infection (CDI). Clostridium difficile infection is an aggressive and potentially fatal disease state, and antibiotic therapy often fails to resolve the disease state effectively. Clostridium difficile infection occurs most commonly subsequent to the use of antimicrobial agents that disrupt the natural bacterial flora of the gastrointestinal (GI) tract. Since disease state pathophysiology operates in this way, researchers have experimented with ways to restore GI flora to a natural state in which nonpathogenic bacteria can proliferate. Probiotic agents do not impose an acute enough response to recreate typical GI tract flora, which has led to experimentation with direct supplementation of GI bacteria, thus underlying the purpose of FMT therapy.

Presently, FMT has demonstrated unparalleled efficacy in resolving CDI and is poised to become first-line therapy as the body of evidence supporting its use continues to grow. This review examines the mechanism of action for FMT therapy and evaluates the results of clinical trials that have tested FMT therapy. Finally, the potential role for pharmacists in the management of patients with CDI will be discussed. Research has supported both the expanded use of FMT therapy in CDI and the establishment of standard practices for administering FMT therapy in hospitals treating larger numbers of CDI patients.

Furthermore, additional clinical trials that could supplement existing support for FMT therapy are currently recruiting patients.

Key Terms Clostridium Difficile; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Metronidazole; tcdA protein; toxB protein; Vancomycin Background The gastrointestinal (GI) tract comprises more than 500 species of intestinal microbiota, serving the functions of protection, structural support and metabolism to maintain homeostasis.1 Antibiotics are utilized to treat infectious diseases states; however, long-term use of antibiotics poses the risk of causing digestive adverse effects such as cramping, gas or diarrhea, due to nonselective eradication of bacteria and protective intestinal microbiota.2 Overutilization of antibiotics may also increase the risk of Clostridium difficile infection (CDI).1 Clostridium difficile infection is caused by Clostridium difficile (C. difficile), a gram positive, rod-shaped, sporeforming bacteria that is transmitted via the fecal-oral route through direct and indirect contact. Subsequent to their inadvertent ingestion, C. difficile spores survive gastric acid and proceed to the small intestine where they colonize and rapidly proliferate under anaerobic conditions. Proliferation and

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subsequent CDI may be further exacerbated by the coadministration of antibiotics, which additionally displace and eradicate the homeostatic functions of normal GI flora.

The infectious symptomatology of C. difficile originates from the bacterial spore which releases specific toxins, Toxin A and Toxin B, that progress to GI cells.1,2 Toxin A is an enterotoxin which alters GI mucosal epithelium cell permeability, allowing fluid secretion, whereas Toxin B is a cytotoxin that induces mucosal inflammation in the colon. The inflammation causes increased GI permeability and motility, which allows more granulocytes and fluid in the GI tract, resulting in antibiotic-induced diarrhea. Alterations in cellular function and structure from the toxins also initiate cellular response and apoptosis, further damaging the GI tract.

According to the guidelines for diagnosis, treatment and prevention of C. difficile infections, diagnostic testing for confirmation of CDI should occur prior to treatment for patients who do not present strong pre-test suspicion for CDI.3 Diagnostic techniques include testing the suspected patientâ&#x20AC;&#x2122;s stool using laboratory tests and diagnostic imaging, the most common of which include toxin enzyme immunoassays, toxigenic cultures, nucleic acid amplification tests and the C. difficile cytotoxin neutralization assay.4 GI structural remodeling can be observed by diagnostic colonoscopy and computed tomography of the abdomen and pelvis.

The recommended first-line treatment for mild CDI is metronidazole 500 mg three times daily for 10 to 14 days.3 If resolution of symptoms does not occur within five to seven days, oral vancomycin 125 mg four times daily for 10 days should be administered. Patients who experience recurrence of CDI within eight weeks of therapy are classified as having recurrent infection (RCDI), and approximately 20 percent of CDI patients in mid-pharmacologic therapy for CDI treatment experience a recurrence of the infection within six months of therapy. For patients with RCDI, treatment with metronidazole or a vancomycin pulse regimen (every two to three day dosing) is initially recommended. Fecal microbiota transplant (FMT) is then recommended after three recurrences of infection within six months after discontinuing therapy. The use of FMT is to establish normal GI flora composition, metabolism and upregulate immune responses in the mucosa.

Fecal microbiota transplant is used due to its safety, efficacy and perceived cost-effectiveness.

Fecal Microbiota Transplant: Treatment Procedure, Efficacy and Safety Fecal microbiota transplant is a procedure during which stool from a healthy patient is infused into a patient with

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RCDI. The rationale behind the treatment is based on RCDI and the loss of homeostasis of GI flora, and the stool from healthy patients can reintroduce normal flora to reestablish homeostasis.4 The procedure calls for a stool sample from a healthy donor to be prepared with normal saline and administered into the GI tract of the patient with CDI. 5 Patients should be placed in the right lateral recumbent position and hold this position throughout the implantation in order to facilitate the optimum permanence of the fecal solution into the colon. The procedure lasts about 10 minutes. The tube is then removed, but patients are monitored during recovery for approximately two hours.

Various methods of FMT administration exist, including nasogastric tube, naso-duodenal tube, colonoscopy, oral fecal capsules and self-administered enemas.5 The most common and advantageous route is via colonoscopy due to its ability to spread the stool throughout the length of the colon extensively. Accessing the colon also allows the physician to observe abnormalities in the colon. This route has yielded 86 percent to 100 percent successful outcomes.

Given the limited understanding of the short-term and longterm effects of FMT, there are only a few studies that have investigated the potential effects of transplanted microbiota on recipient patients. In one cohort study by Song and colleagues at the University of Maryland’s School of Medicine, 14 RCDI patients underwent FMT along with their respective healthy donor as subjects.6 The fecal specimens of both populations were analyzed before FMT, as well as one week and one year post-FMT to determine if the recipient’s recovered intestinal microbiota would mirror that of the donor’s after an extended period of time. Patients recovered symptomatically within two to three days of undergoing FMT and were classified as asymptomatic based upon resolution of diarrhea.

The fecal specimens of RCDI patients collected prior to FMT displayed low diversity in microbial species when compared to the samples given by healthy donors. The species present in each sample were determined using rarefaction analysis of operational taxonomic units, a method that utilizes DNA to determine the presence of types of species. One week after FMT, patients displayed an increase in microbial species, determined using Shannon diversity index calculations, a set of calculations used to determine how proportional a multiple species are in a given environment. Furthermore, the study discovered that species diversity and species richness remained constant over time: fecal specimens collected one year after FMT illustrated constant Shannon diversity scores.

More specifically, recipient microbiota not only increased in diversity but also matched the composition of the donor in most patient cases. However, multiple subjects did experience a transient return to a microbiota composition that resembled the patient’s pre-FMT specimen collection. Despite this regression on a microbial level, all patients experienced a resolution of symptoms. One patient relapsed one month after the initial FMT following antibiotic treatment for a urinary tract infection but underwent a second, successful FMT. This data suggests that asymptomatic patients are still more susceptible to a C. difficile infection than healthy individuals fol-

Drug Abuse Gastroenterology

lowing administration of antibiotics despite an evolved microbiota. This study supported FMT for treatment of C. difficile infections presenting evidence that FMT treatment improved the microbiota composition of RCDI patients.

Another cohort study that investigated a similar parameter was conducted by researchers of Wright State School of Medicine.7 Three RCDI patients received fecal matter from the same healthy donor and fecal specimens were collected from the three subjects as well as the donor prior to the FMT procedure. Specimens subsequently were collected from patients on days three and seven following the treatment and throughout a four month post-FMT period. Similar to the results found by Song and colleagues, all three patients experienced a resolution of symptoms characteristic to a C. difficile infection only days after FMT. Two of the three patients reported to have a firm bowel movement on day three following the FMT procedure. The same two patients remained free of infection for approximately two years following FMT; the third patient, who also suffered from ulcerative colitis, experienced an infection of C. difficile 1.5 years following treatment after taking antibiotics for an unrelated urinary tract infection. Specimens obtained from patients prior to FMT illustrated low species diversity. The composition of the healthy donor was diverse, and the abundance of organisms was even with regard to each species. The study found a pattern in the type of species that existed in patients pre-FMT compared to that found in the donor. The three recipients had specimens containing high levels of organisms belonging to the classes gammaproteobacteria and bacilli. These microbial classes are able to withstand the presence of oxygen as C. difficile infections often lead to an infiltration of reactive oxygen species. In contrast, the study reported that the donor’s fecal matter were dominated by bacteria in Clostridia, Actinobacteria, Erysipelotrichi and Bacteroidia, classes that typically comprise the GI tract of a healthy human. Following FMT, the three patients displayed an increase in bacteria from classes Bacteroidia and Clostridia which remained stable over the four month period following treatment. The patients’ preFMT fecal compositions were reportedly variable and distinct from each other. Following FMT, however, the three subjects’ samples paralleled the donor sample. This study concluded that the composition of the subjects’ microbiota prior to FMT did not affect the outcome or microbial makeup following treatment and confirmed the efficacy of FMT on a long-term basis. This finding provides clinical significance in the outcome of FMT; the change in microbial makeup parallels the patients’ reduction of symptoms, including diarrhea.

Comparison of Fecal Microbiota Transplant, Antibiotics and Combination Therapy in Treating Clostridium Difficile Infection Several studies and randomized control trials have evaluated the efficacy of FMT in comparison to traditional pharmacologic treatment modalities, specifically comparing FMT alone or as an adjunct therapy with antibiotics to antibiotic monotherapy. 5,8,9 Catholic University School of Medicine conducted an open-label, randomized clinical trial comparing the thera-

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pies of FMT via colonoscopy in patients with recurrent CDI versus pharmacologic vancomycin therapy.5 Twenty patients diagnosed with C. difficile were treated with 125 mg vancomycin tablets four times a day for three days, followed by one or more infusions of feces until the conclusion of 10 weeks. Nineteen patients were treated with 125 mg vancomycin four times a day for 10 days, followed by pulse therapy of 125 to 500 mg/day every two to three days for at least three weeks. Results showed 18 of the 20 patients treated by FMT with vancomycin short term pretreatment no longer suffered from diarrhea. Only five of the 19 patients treated with vancomycin alone (P < 0.0001) were treated successfully. The researchers concluded that FMT via colonoscopy is more effective than vancomycin therapy in treatment of CDI.

Another randomized, control trial compared traditional antibiotic use with FMT. Els van Nood and colleagues conducted a study using duodenal infusion of feces versus a typical 14 day vancomycin treatment for CDI.8 Three dependent groups in the trial were included: patients who were given an initial vancomycin regimen of 500 mg orally four times a day for a duration of four days then underwent a bowel lavage, followed by infusion fecal; patients who were given the standard vancomycin regimen followed by bowel lavage; and patients who were just given the standard vancomycin regimen. Patients were randomly assigned to one of these groups with the primary end point of curing RCDI with absence of relapse within 10 weeks. Sixteen patients were in the infusion group and 13 patients (81 percent) met the primary end point. The remaining three patients who did not show resolution underwent a second infusion, and two patients had successful resolution (P < 0.001). The group that received the bowel lavage had three successful resolutions within 13 patients (23 percent). The group that only received standard vancomycin regimen yielded four successful resolutions out of 13 patients (31 percent). Researchers concluded that infusion donor feces is more efficacious in comparison to vancomycin in RCDI treatment.

Researchers of the Harvard School of Public Health conducted a retrospective review of the long-term effects of multiple FMT treatments in patients with RCDI.9 The review involved 94 RCDI patients total; 45 subjects were cured (defined as having not experienced diarrhea incidents for six consecutive months) after one single FMT treatment. The remaining patients received multiple FMTs, the highest number of which was 10 FMTs. Patients receiving multiple FMTs were given antibiotics between each treatment which resulted in a 5.3 percent increase in the resolution rate; thus, the subsequent treatment was more successful. Patients considered cured following FMT were reported to be free of C. difficile infection for an additional period of six to 24 months. The study resulted in an absence of adverse events as a result of FMT therapy. The authors reported a 92 percent cure rate among patients who underwent FMT with additional antibiotic therapy. Researchers concluded that FMT is an effective treatment for RCDI not resolved by antibiotic therapy and is safe when completed multiple times on a single patient.

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The Role of the Pharmacist in FMT: Post-treatment and Prevention of Recurrent Clostridium Difficile Infection Despite the impressive reported cure rates of C. difficile infections treated with FMT, there remains a major risk of disease recurrence. A retrospective study that surveyed CDI patients treated with FMT found that diarrhea recurred in 29 percent of patients, although the time window for recurrence was three years in some documented cases.10 Of the 22 total patients with documented recurrent diarrhea, seven (32 percent) experienced self-limited diarrhea, thus not attributable to recurrent CDI. The significant risk of disease recurrence therefore presents an opportunity and obligation for medical professionals to provide patient education to CDI patients upon their release from institutional care. In the outpatient setting, pharmacists have an opportunity to counsel patients recovering from CDI by distinguishing between nonpathogenic self-limiting diarrhea and diarrhea associated with CDI recurrence, which requires rehospitalization. Specifically, CDI-related diarrhea is associated with a foul smelling, watery nature as well as fever and abdominal pain.11 Another opportunity for pharmacists to help in the prevention of CDI involves promoting antibiotic stewardship and appropriate adherence to antibiotic regimens. Alternative antibiotic therapies should be considered in patients prescribed antibiotics with high rates of causing CDI. Antibiotics considered to be highest risk for causing CDI include ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, ceftriaxone, cefotaxime, ceftazidime and cefixime.12 When conducting medication reviews, pharmacists should be mindful of the use of high-risk antibiotics in both patients with previous CDI and patients belonging to general demographics with increased risk of CDI. Several patient groups that may warrant additional attention for CDI prevention include patients in hospitals with ongoing CDI outbreaks, geriatric patients, those taking multiple different antibiotics in a brief window of time and patients admitted for an unrelated infection.13 A 2014 meta-analysis of antibiotic stewardship programs and CDI risk found a relative risk for CDI of 0.48 for patients who participated in such a program.14 Antibiotic stewardship is a valuable intervention that, when implemented appropriately, can prevent thousands of cases of CDI every year.

Researchers have investigated the use of proton pump inhibitors (PPIs) alongside high-risk antibiotics and found that PPI use represents a significant risk factor for CDI with a relative risk of 2.2 (95 percent CI: 1.52-3.23; p = 0.0001).12 This retrospective cohort study by Gordon and colleagues assessed how CDI incidence in a population of U.S. veterans was related to PPI use. Although the 20,944 patient medical records included only 111 documented cases of CDI, sufficient statistical significance demonstrated a clear additional risk with PPI use in patients receiving antibiotics known to increase CDI susceptibility. Further, Gordon and colleagues reaffirmed the high-risk status of the antibiotics investigated, particularly clindamycin and ciprofloxacin, which were most likely to produce CDI. With this in mind, pharmacists should seek to identify patients taking both PPIs and high-risk antibiotics and attempt a therapeutic substitution when possible. Since

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certain PPIs are available over-the-counter, the patientâ&#x20AC;&#x2122;s physician may not be aware of this medication use. Pharmacists should counsel patients taking PPIs for extended periods of time, and should remain vigilant for cases of patients on high-risk antibiotics taking either prescribed or over-thecounter PPIs.11 Conclusion Fecal microbiota transplant exerts its therapeutic action by restoring intestinal nonpathogenic bacteria to produce a state more closely resembling the GI flora of the fecal matter donor. Preliminary research suggests a superiority of FMT over antibiotic therapy in treatment of C. difficile infection.

Though comparative trials between the two therapies are limited in scope and number, FMT produced disease state resolution in 81 percent and 90 percent of patients, while antibiotic therapy attained such success in only 26 percent and 23 percent of patients, respectively.8 When the two therapies were combined, with intermittent antibiotics administered between multiple FMTs, a synergistic effect was produced by the combination therapy with a successful treatment rate of 92 percent. Additional trials are currently recruiting patients to increase the strength of the evidence supporting increased use of FMT in treating CDI, but the direction of preliminary research indicates that FMT is a safe, effective treatment with superiority to antibiotics alone.

Drug Abuse Gastroenterology

and Clostridium difficile infection: reducing risk. MEDSURG Nursing.

2015 Dec;4-6.

12. Gordon D, Young LR, Reddy S, Bergman C, Young JD. Incidence of Clostridium difficile infection in patients receiving high-risk antibiotics with or without a proton pump inhibitor. J Hosp Infect. 2016 Feb;92 (2):173-7.

13. Reacher M, Verlander NQ, Roddick I, Trundle C, Brown N, Farrington M, Jones P. Excess mortality attributable to Clostridium difficile and risk factors for infection in an historic cohort of hospitalized patients followed up in the United Kingdom Death Register. PLoS One. 2016 March;11(3):1-24.

14. Feazel LM, Malhotra A, Perencevich EN, Kaboli P, Diekema DJ, Schweizer ML. Effect of antibiotic stewardship programmes on Clostridium difficile incidence: a systematic review and meta-analysis. J Antimicrob Chemother. 2014;69:1748-1754.

The authors have no conflict of interest or funding support to disclose.

References 1. Boyle ML, Ruth-Sahd LA, Zhou Z. Fecal microbiota transplant to treat recurrent clostridium difficile infections. Crit Care Nurse. 2015 Apr;35 (2):51-64.

2. Gens KD, Elshaboury RH, Holt JS. Fecal microbiota transplantation and emerging treatments for clostridium difficile infection. J Pharm Pract.

2013 Jan 21;26(5):498-505.

3. Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, et al. Guidelines for diagnosis, treatment, and prevention of clostridium difficile infections. Am J Gastroenterol. 2013 Feb 26;108(4):477-498.

4. Brandt LJ. American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection. Am J Gastroenterol. 2012 Dec 6;108 (2):177-185.

5. Cammarota G, Masucci L, Ianiro G, Bibbo S, Dinoi G, Costamagna G, et al. Randomised clinical trial: Faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent clostridium difficile infection. Aliment Pharmacol Ther. 2015 Mar 1;41(9):835-843.

6. Song Y, Garg S, Girotra M, Maddox C, von Rosenvinge EC, Dutta A, et al.

Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection. PLoS One. 2013 Nov 26;8(11):1-11.

7. Shankar V, Hamilton MJ, Khoruts A, Kilburn A, Unno T, Paliy O, Sadowsky MJ. Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation. Microbiome. 2014 Apr 2; 2 (13): 1-10.

8. Van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of feces for recurrent clostridium difficile.

N Engl J Med. 2013 Jan 31; 368(22):2143-45.

9. Lee CH, Belanger JE, Kassam Z, Smieja M, Higgins D, Broukhanski G, Kim PT. The outcome and long-term follow up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema. Eur J Clin Microbiol Infect Dis. 2014 Mar 14;33:1425-28.

10. Brandt LJ, Aroniadis OC, Mellow M, Kanatzar A, Kelly C, Park T, et al.

Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012 Jul;107(7):1079-87.

11. Frary JA, Winsett RP. The association between proton pump inhibitors

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Drug Abuse Legislation

Legislation Across the Nation and the Impact on Pharmacy Practice Sabrina Hamman, Hannah Lamb, Jennifer Harklerode, Elizabeth Kramer, Steven Martin, PharmD

Abstract Pharmacy legislation is constantly being updated, giving pharmacists a larger role in the health care field. In the past 20 years, pharmacists have seen expansions to legislation involving contraceptive authority, medical marijuana, vaccines and provider status. There is a greater pharmacist impact from legislation passed on the state level in comparison to the national level. As a result, pharmacists have different opportunities to provide new and advanced services to patients based on the state in which they are practicing.

Comparing these various laws across the nation allows the profession to determine which sections of the law are problematic and which sections are important to help advance the profession. This information can then be used to shape new and improved laws in other states and extend these services to benefit more patients across the country.

Key Terms Contraception; Immunization; Legislation; Medical Marijuana; Pharmacists; Pharmacy Introduction A shortage of up to 20,000 primary care physicians is expected by the year 2020 due to the Affordable Care Act (ACA) as well as the aging population.1 Due to this projection, it is becoming vital for other health care professionals to provide basic primary care services that were otherwise reserved for physicians. Although the increasing number of certified nurse practitioners and physician assistants has benefitted the health system, there is still a high demand for additional primary care resources. This primary care shortage along with the education and knowledge base of doctoral pharmacists are possible reasons why the scope of pharmacy practice continues to broaden in many states. In an effort to increase patient access to care, new legislation has been enacted to build upon the pharmacistâ&#x20AC;&#x2122;s immunization certification and increase involvement in contraceptive prescribing and medical marijuana dispensing. Additionally, pharmacists are advocating for provider status, meaning that their services would be included under Medicare Part B coverage. If such legislation would pass, new payer models would develop to sustain available services such as medication therapy management (MTM) and create incentives to provide additional primary health services.

Provider Status Pharmacists have a unique skill set that could greatly benefit a health care team.2 Medication nonadherence and uncontrolled chronic disease states can lead to excess or unnecessary hospital stays, which are easily avoidable if the right patient education is provided. Pharmacists are able to pro-

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vide the proper patient counseling on medications, disease state management and the prevention of diseases. This ability would be a great asset to the health care team. Pharmacist involvement has been shown in studies and practice-based experience to improve patient outcomes, increase patient satisfaction rates and reduce the overall cost of health care.

Pharmacists have the potential to play a much larger health care role in the United States.3 Currently, the U.S. health care system faces challenges with the increasing need for health care access, the demanding quality of this care and excessive costs. In 2002, the Medicare Payment Advisory Commission (MedPAC) stated there was increasing evidence that pharmacists taking a more active role in managing drug treatment could reduce costs and improve the quality of patient care.

Since then, the profession has progressed, but there are still many opportunities for pharmacists to become more involved and become recognized health care providers.

The House of Representatives bill H.R. 592 and Senate bill S. 314 are two important federal bills introduced into Congress during the 114th Congress that would amend the Social Security Act, specifically Medicare Part B, to allow pharmacists to receive compensation for their services in medically underserved areas.4,5 Pharmacists would receive reimbursement at a rate of 80 to 85 percent of what a physician providing the service would receive. These bills have continued to gain support from legislatures, but face opposition due to the initial costs of providing the service. The initial costs are because of pharmacists billing for their time. Evidence is needed to show that there is a long-term, overall reduction in cost to the health care system due to decreased admission rates, physician visits and better patient outcomes.

A literature review done by Ponniah and colleagues looked at seven studies evaluating outpatient and post-discharge pharmacy servicesâ&#x20AC;&#x2122; impact on patients with heart failure.6 Six of the seven studies found positive outcomes for patients such as decreases in readmission rates, mortality and greater compliance with medication regimens. Another study did not show a difference between the control group and interventional group.13 This review demonstrated the importance of pharmacist involvement in the continuity of care. The expansion of these types of services could lead to better care and outcomes for patients.

Without provider status recognition and a payment model for pharmacist services, such as pharmacist-initiated smoking cessation therapy, contraceptive services or diabetic shoe fittings, providing them may not be sustainable and, thus, they become less accessible to patients.2 Having reimburse-

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ment in place would incentivize employers to provide these services, which would increase access to care. Pharmacists would be given the chance to innovate and create new practice models to better serve patients and improve the quality of care and patient outcomes.

Provider Status in Ohio In Ohio, a recent project has produced data showing the benefit of pharmacist intervention in patients with diabetes and hypertension.14 With the help of a grant from the Centers for Disease Control and Prevention (CDC), in 2014 three federally qualified health centers (FQHCs) in Ohio partnered with the Ohio Department of Health (ODH) in order to test the outcomes of pharmacists providing medication therapy management (MTM) to patients with diabetes and hypertension.

The FQHCs monitored patient A1C and blood pressure before and after the MTM services were provided to analyze the benefit of extra pharmacist intervention.

The data from over 500 patients in a six month period showed an increase in diabetes control from 0 to 44.8 percent and hypertension control from 0 to 68.6 percent. 14 This project will continue by adding more FQHC sites and some primary care physician practices. Hopefully, showing the benefit of these MTM services will increase payer support for them in the future.

Pharmacists and Contraceptive Authority The Problem According to Santelli and colleagues, unintended pregnancies are defined as being either unwanted or mistimed. 15 In 2012, 40 percent of all pregnancies worldwide were considered unintended, despite the wide variety of available contraceptives.16 Unintended pregnancies have been associated with poor health, financial and social outcomes for both mothers and children, creating a worldwide disparity in this population. In the United States, it is estimated that 82 percent of all teenage pregnancies are unintended. 17 While the rate of teenage pregnancy in the United States has been declining in recent years, the country still has the highest rate among other similarly developed countries.

Access to care, societal stigmas, socioeconomic imbalance and sexual behavior are all expected to be reasons for this statistical gap.

Unintended pregnancies in the United States have the highest rates among 18 to 24 year olds, minorities and low education and/or low income women which costs the U.S. health care system a significant amount of money.18 According to the Guttmacher Institute, $21 billion was spent in 2010 on unintended pregnancies nationwide. However, many methods have been shown to help reduce this cost. One method is family planning. Women who used contraceptives correctly only accounted for 5 percent of total unintended pregnancies. Therefore, increasing access to contraceptive methods has the potential to decrease the rate of unintended pregnancies in the United States and would most likely reduce public expenditures over time.

Drug Abuse Legislation

Current Legislative Actions Currently in order to obtain contraception, most women must visit a physician or go to a women’s health clinic.19 This can be difficult for many reasons: women may not be able to get time off from work, physicians may not have immediate openings to see the patient or a patient may lack the insurance needed to see a physician. Visiting a pharmacist may alleviate these complications since pharmacists are one of the most accessible health care professionals. In fact, 93 percent of people in the United States live within five miles of a community pharmacy.20 In order to help improve access to contraceptive care in their respective states, California and Oregon recently passed laws allowing pharmacists to prescribe hormonal contraceptives.21,22 Tennessee’s senate bill S.B. 1677 with similar provisions has also been recently passed.23 While California passed the law earlier than Oregon, Oregon is the first state to implement it as of Jan. 1, 2016.

The Oregon law, house bill (H.B.) 2879, allows pharmacists who have taken a board-approved training course to prescribe hormonal contraception in the form of an oral tablet or patch to a patient over 18 years of age or patients under 18 years of age with previous evidence of a prescription from a health care practitioner.24 Before the pharmacist prescribes, they are required to have the patient complete a selfscreening risk assessment tool, which includes questions about a patient’s sexual and medical history.25 This selfscreening risk assessment tool then helps the pharmacist decide whether or not a patient is eligible for pharmacistinitiated contraception or if the patient should be referred for further evaluation by a primary health care provider or a woman’s health care provider.26 If the pharmacist determines contraception is appropriate, the pharmacist must then refer the patient to a primary health care provider and provide a summary of the initial visit. This is done in order to promote communication between the patient and their health care providers, help them find a health care provider if they do not have one and promote additional routine health screenings. Furthermore, the pharmacist cannot continue to prescribe the medication if the patient does not have a clinical visit with a health care provider within three years of the first prescription.24 A clinical visit is defined as a consultation addressing appropriate women’s health screenings and contraception by a health care provider other than a pharmacist.21 See Figure 1 and Figure 2.25,26 In addition to the passing of H.B. 2879, Oregon has also passed H.B. 3343. This law requires insurance companies to allow patients to receive a 12-month supply of a birth control medication or device.27 This law will also help with women’s access to contraceptive care regardless of who provided the prescription. Allowing a patient to receive all 12 months at once may improve adherence which may lead to better outcomes for the patient.28 This expanded access is not expected to decrease women’s likelihood of receiving regular preventive care screenings.29 Support and Opposition There is controversy regarding a pharmacist’s ability to pro-

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Figure 1 . Hormonal Contraceptive Self-Screening Questionnaire.

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Figure 2 . Standard Procedures Algorithm for Oregon Pharmacist Prescribing of Contraceptives.

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vide this service with adequate monitoring and follow up and if this is the best way to improve access for women.19,30,31 The American College of Obstetricians and Gynecologists (ACOG) released a statement claiming that while they approve of allowing pharmacists to prescribe birth control, they still ultimately want contraception available over-the-counter (OTC).31 Although many providers support pharmacist-initiated contraception, some have argued that pharmacists are still another barrier for women to go through to receive contraceptives.19,32 Rafie and colleagues evaluated provider opinions on prescription-only, pharmacist-initiated, behind the counter versus OTC contraceptives.32 The investigators in the study surveyed 614 health care providers from different areas around the United States on various topics surrounding birth control access. The study found that 74 percent of providers supported pharmacist-initiated access for the pill, patch and vaginal ring. The study also found that while 45 percent supported behind the counter access, 28 percent of providers supported OTC availability of the same dosage forms. There have been studies conducted that have shown that women can accurately screen themselves for eligibility for birth control if given the right tool.33,34 However, this may leave the patient with limited monitoring by a health care professional. Insurance companies also may not pay for OTC contraceptives. This would be an additional barrier for women.

While pharmacist-initiated contraceptives would significantly improve access for patients, providers have the concern that too few pharmacies would participate in the service, constituting a barrier to patient access.32 Without proper reimbursement models for pharmacist services, it may be hard to justify the extra training required along with the time needed for pharmacists to provide these services. Legislation is needed to address this issue.

Pharmacist Qualification In order to become a pharmacist, one must complete at least six years of training after high school in order to obtain a Doctor of Pharmacy (PharmD) degree.3 During this training, pharmacists learn pathophysiology, pharmacotherapy and disease state management, as well as a variety of other skills such as preventive screenings, point-of-care testing and basic physical examination. Pharmacists are medication experts and are able to manage possible drug interactions with birth control and interpret screening results to determine the appropriateness of contraceptive therapy.35 Studies have shown that pharmacist-initiated contraception is safe and effective.35 Gardner and colleagues conducted a study that examined 214 women ages 18 years to 44 years who consulted pharmacists for contraceptive care. Over half the participants reported having a provider they regularly saw for primary care. Most patients participated in the study due to the convenience of having a pharmacist-prescribed contraceptive. In addition, many patients stated that they did not want to receive a pelvic exam before initiating contraceptives.

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Before the prescription was provided, patients completed a screening tool to determine if they were able to use hormonal contraceptives safely along with a blood pressure check and weight check.35 Pharmacists then consulted with patients on their eligibility to receive pharmacist-initiated contraceptives. Patients had to have a blood pressure of less than 140/90 mmHg and a weight less than 200 pounds in order to be eligible for pharmacist-initiated contraception. If patients did not meet these criteria, they were referred to a family planning clinic for further evaluation. Patients that were eligible then received a prescription and were required to return to the pharmacy again after three months for a second blood pressure and weight check. In addition, phone interviews were conducted at one month, six months and 12 months by the study interviewers to assess patient satisfaction with their interactions and hormonal contraceptive choice.

At the 12 month interview, 70 percent of eligible participants reported continued use of their contraception.35 Of these, 98.6 percent (123 out of 127) of women reported that they would feel comfortable continuing to receive contraception from a pharmacist. Some patients were lost due to lack of follow up, occurrence of adverse events and dissatisfaction with their prescribed contraceptive method. There were limitations to this study due to conservative prescribing requirements for patient eligibility. In addition, women under the age of 18 years were not included and, due to the lack of insurance reimbursement, many patients had to pay out-ofpocket for the cost of these services. Therefore, many lowincome women could not afford to participate in the study.

However, it was advantageous for uninsured women to enroll since pharmacist services in general were much less expensive than physician services. While there may be limitations, this study helped show effectiveness of pharmacistinitiated contraception.

Pharmacists remain a largely untapped resource for contraceptive services across the nation. With the implementation of new laws in Oregon and California, more data may become available over time to show the benefit of the expansion of pharmacist services. Depending on the outcomes, other states may follow suit. This could be a new area of practice for pharmacists to play a role in womenâ&#x20AC;&#x2122;s health and improve access to care.

Legalization of Medical Marijuana The legalization of marijuana, or cannabis, is not a new debate and has been an upcoming issue in recent years. The question of legalizing marijuana for medical or recreational use or both is an issue that presses current legislation. One of the reasons for the push to legalize medical marijuana is due to its pharmacologic effects and the potential medical benefits it can provide to patients. Marijuana has at least 460 active chemicals and 60 different cannabinoids (CBD), with δ-9-tetrahydrocannabinol (THC) being the predominant cannabinoid that is responsible for the pharmacologic effects by binding to either of the two receptor subtypes.36,37 The cannabinoid-1 receptors (CB1) are located predominantly in the

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central nervous system including the cortex, hippocampus, basal ganglia, cerebellum and spinal cord. The cannabinoid-2 receptors (CB2) are located mostly in the peripheral tissues on cells responsible for an immune response.

Many chronic disease states may benefit from the use of medical marijuana including multiple sclerosis, pain syndromes and glaucoma.36 It can also help alleviate nausea and vomiting associated with chemotherapy treatment, as well as reduce weight loss due to the disease progression of cancer or HIV. While there are various studies that demonstrate the efficacy of this product for a wide variety of disease states,37-42 many of these studies are case studies or trials with small sample sizes and caution should be taken when interpreting these results for an entire population of patients.

Mahmoud ElSohly, Ph.D., research professor at the University of Mississippi School of Pharmacy and director of the University of Mississippi Marijuana Project brings up another concern with medical marijuana dosing.43 The University of Mississippi has the only federally funded marijuana research program in the country and has yet to determine the appropriate dose, frequency or duration of treatment for the use of marijuana in any disease state. This lack of data can pose problems when trying to provide marijuana as a mode of treatment.

Pharmacist Role and Reactions Many pharmacists are concerned with the state-level legalization of medical marijuana in fear that it might jeopardize their license and career since it is still illegal to distribute this drug under federal law.43 Others have expressed concern

Drug Abuse Legislation

because they feel that they do not have the proper education and training to be dispensing medical marijuana to their patients. Providing proper education to pharmacists will be key to helping them feel more confident with dispensing this product. Dispensing medical marijuana would allow pharmacists to expand their title as a drug and medication expert by helping to monitor patient use to ensure the drug is being used in a safe and effective manner. According to the American Pharmacists Association (APhA) 2015 report from the house of delegates, the policy pertaining to the role of pharmacists when caring for patients using cannabis contains five key aspects. The APhA supports furthering clinical research to establish the clinical efficacy and safety of the use of cannabis, encourage further health care provider education and advocate that pharmacists collect and document all patient information regarding cannabis use. This policy also supports the role of the pharmacist to dispense cannabis to patients when it is scientifically supported and the proper laws are in place while countering pharmacists from becoming a provider of cannabis for recreational purposes.

There are many drugs and disease states that have potential interactions with medical marijuana.36 A pharmacist can have a large impact on patient safety by checking for any drug-drug or drug-disease interactions while also monitoring the patient closely for any adverse reactions.

Current State Versus Federal Legislation The legalization of marijuana for medical purposes was accomplished by individual states passing their own legislation to remove the criminal actions taken against a patient for possession of the drug. However, federally, the Controlled Substances Act (CSA) classifies marijuana as a Schedule I

Table 1. Medical Marijuana and Drug Interactions.36,44-48 Drug Opioids

Possible Interactions Cross-tolerance, mutual potentiation of effect

Benzodiazepines Muscle relaxants Lithium Opioids Alcohol

Excessive CNS depression Drowsiness

Anticholinergics Alpha-agonists

Tachycardia Exacerbate hypertension

Naltrexone

Increased effects of euphoria

Disulfiram

Hypomanic episodes

Sildenafil

Myocardial infarctions

Fluoxetine

Mania

Tricyclic antidepressants

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Table 2. Medical Marijuana and Disease State Interactions.36,49-54 Disease State HIV Diabetes Lupus Rheumatoid arthritis Cancer Organ transplantation Schizophrenia Psychosis Bipolar disorder Depression Eating disorders Cardiovascular disease

Possible Interactions

Increased health risk due to increased immunosuppressive properties

Exacerbation of respective psychiatric disorder Four times as likely to develop depression Increased hallucinations, delusions and violent behavior

Increased risk of effects (stroke, myocardial infarction)

COPD Asthma Tuberculosis

Increased risk with long-term marijuana use

Vertigo

Increased dizziness Complications with diagnosis and treatment

Diabetes Obesity

Significant, undesirable weight gain

Pregnancy

Impaired fetus development Structural and neurobehavioral defects in the fetus

which defines it as a drug that has a high potential for abuse, no acceptable medical use and a lack of accepted safety when using this drug under medical supervision.55 When state and federal laws conflict, the stricter law is typically enforced, meaning that all possession of marijuana for medical purposes, regardless if legal in the state, is still illegal. However, only 1 percent of convictions that involve marijuana are federal cases, making it highly unlikely for a patient to be federally convicted for using medical marijuana.56 Current and Future Legislation As of April 2016, there are four states along with the District of Columbia that have legalized the use of both medicinal and recreational marijuana, as depicted in Figure 3. 57,58 An additional 20 states have legalized marijuana strictly for medical use, and another 17 states have passed limited access marijuana product laws which allow for the use of products with low THC and high CBD levels for selected medical purposes.

Each of these states is unique in the laws that they have passed in regard to the legal implications for the use of marijuana. Adoption of legislation related to marijuana use and distribution is occurring rapidly and several changes may be in place by the time of this publication. The information used to populate Figure 3 was obtained from two sites that are updated regularly.57,58 These sites may be accessed for more up-to-date information.

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California California was the first state to legalize the use of medical marijuana with Proposition 215, also known as the Compassionate Use Act of 1996.57,59 The Compassionate Use Act was passed to allow medical marijuana to be prescribed to patients with any disease state that may benefit from its use.59 This law also ensures that prescribing physicians and patients using marijuana for medical purposes will not be subject to criminal punishment. Seven years later, the state of California passed SB 420. This additional law allowed for better identification of patients and their primary caregivers in order to eliminate unnecessary arrests, enforcement of uniform enactment of the laws by different counties across the state and further enhanced patient access to medical marijuana.60 Since California was the first state to pass medical marijuana laws, it provides a legislative model for other states. Some proposed changes for future states include strictly defining the disease states that patients may have in order to have access to medical marijuana and limiting the number of dispensaries.61 This will ensure that medical marijuana use is only for patients who have disease states where proven benefits of its use exist. Placing restrictions on the number of dispensaries will help ensure the highest quality and standards for marijuana products while limiting the risk of illegal dispensing.

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Connecticut In April 2012, Connecticut passed HB 5389 to allow for the use of medical marijuana.62 This legislation is similar to California; however, there are some differences in how the legislation was phrased. First, the law states that a person is eligible to use marijuana for a medical purpose if they have a “debilitating medical condition.” These conditions include cancer, glaucoma, HIV/AIDS, posttraumatic stress disorder, Parkinson's disease, multiple sclerosis, damage to the nervous tissue of the spinal cord, epilepsy, cachexia, wasting syndrome and Crohn's disease. Additionally, if a person with a different condition feels like he or she could benefit from medical marijuana treatment, it must be approved by the Department of Consumer Protection (DCP). This specific wording excludes marijuana use in the treatment of other diseases that is managed efficiently by other prescription medications.

One aspect that is unique to Connecticut law is that only a licensed pharmacist is eligible to apply for and receive a dispensary license. This may have helped the bill pass, as it provides more medically driven regulation for patients.63 As of June 2015, there are six dispensaries in Connecticut, with four owned by pharmacists. Connecticut legislation provides new opportunities for pharmacists to exercise both their entrepreneurial skill set by owning dispensaries and utilizing their clinical skills in selecting and dosing the right product for the patient.

Patient certification from a prescriber that states that the patient has a chronic disease constituting medical marijuana use is also included in HB 5389.62 This certification must be a DCP-prescribed form with the physician’s signature and date and is valid for up to one year. HB 5389 also limits the number of dispensaries in the state. The DCP commissioner determines the number of dispensaries needed to meet the needs of patients that qualify to receive medical marijuana.

Mississippi In April of 2014, Mississippi signed HB 1231, or Harper Grace’s Law.64 This legislation allowed patients with debilitating epileptic conditions and their caregivers to have possession of marijuana extracts, oils or resins containing more than 15 percent of CBD and no more than 0.5 percent THC. While this law is beneficial to those with epileptic conditions, access to this product is very limited. The National Center for

Additionally, legalizing medicinal marijuana in this state led to the Connecticut Prescription Monitoring and Reporting System in which both pharmacists and physicians have access.63 This law will protect patients, caregivers, physicians and dispensaries from criminal action for the possession or use of medical marijuana within the scope of its legislation.62

Figure 3. Marijuana Laws by State.57,58

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Natural Products Research at the University of Mississippi is the only location that can produce this oil. Furthermore, the Department of Pharmacy Services at the University of Mississippi Medical Center is the only place that can dispense the product. While Mississippi is the only state with federal privileges to produce marijuana products, it still prohibits distribution to patients, as well as the actual use of the drug, despite state legislation. On Feb. 8, 2016, HB 1360 and SB 2358 were introduced in an effort to legalize medical marijuana in the state of Mississippi.65 Both pieces of legislation, however, died in committee later that month.

Ohio Ohio has recently joined other states in the passage of a medical marijuana bill. In November 2015, Issue 3: The Ohio Marijuana Legalization Initiative, was on the ballot.66 Issue 3 proposed the legalization of the production and sale of both medical and recreational marijuana and included provisions for a monopoly for only select individuals to participate. This would have allowed persons over the age of 21 years to possess up to one ounce of marijuana for recreational use and grant anyone with medical certificate permission for medical use. However, nearly 64 percent of Ohioans voted against Issue 3. The state General Assembly subsequently passed HB 523 and, in June 2016, the governor signed this legislation to allow for medical marijuana only.57,66,67 At this time, it has not yet become operational.

The two main differences between the original proposed legislation and the current legislation is HB 523 does not allow for the home growing of marijuana and does not require employers to allow employees to use medical marijuana.57,68,69 Immunization Laws Pharmacist Impact on Disease Prevention Pharmacists have the potential to make a drastic impact on disease prevention by being involved with providing vaccinations across the country.70 A study conducted by Goad and colleagues found that 30 percent of vaccinations given at a community pharmacy during the 11 month study period were provided during off-clinic hours.71 These hours consisted of weekday evenings, weekends and federal holidays when a physicianâ&#x20AC;&#x2122;s office, where patients would traditionally receive a vaccine, is closed. This time period was exceptionally popular with younger, working-aged, healthy adults. With a pharmacistâ&#x20AC;&#x2122;s ability to administer vaccinations, community pharmacies are able to create new opportunities to increase the low immunization rates that are observed in the adult and adolescent age groups. This can be done by expanding access and convenience to vaccinations to better suit the lifestyles of this age group. Additionally, it has been found that the immunization rates, specifically for the influenza vaccine, in states that allow pharmacists to administer vaccines is higher than in states that do not allow this.72 With this trend, it is suggested that pharmacists are not pulling patient populations away from medical centers but are instead bringing in new populations to receive vaccinations. Regarding the benefits of immunizations, it has been shown that vaccinations specifically against influenza lead to a reduction in the rates

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of hospitalization and deaths from influenza related complications when compared to unvaccinated groups.73 This is especially true in elderly populations. Additionally, a cost benefit model was created by Duncan and colleagues to show the overall savings related to the implementation of a vaccination program within a company.74 It was found that if a company was to have at least 50 percent of employees vaccinated at a pharmacy, there would be an employer cost savings of $49 per vaccination.

Increasing both the accessibility to pharmacists who are already able to vaccinate, as well as the types of vaccinations pharmacists are able to administer, will allow for increased rates of disease prevention. This will also lead to a decreased overall cost to the health care system. In order for legislation to be drafted and passed across the country, more detailed studies are needed to solidify the benefits of pharmacists administering vaccinations.

CDC Recommendations As of January 2015, pharmacists were able to administer any Centers for Disease Control and Prevention Advisory Committee for Immunization Practices (CDC ACIP) approved vaccine in 45 states, excluding New Hampshire, Florida, New York, West Virginia and Wyoming.75 Ohio was added to this list in March 2015. Age restrictions, as well as prescription protocols, vary from state to state for each CDC ACIP vaccination.

Vaccinations currently recommended by the CDC for adults aged 19 years or older are shown in Figure 4.76 If a patient is younger than 19 years of age, or has any other medical conditions, consult a physician before administering any vaccinations.

Vaccine Legislation Across the United States Immunization laws and regulations greatly vary between states across the nation. In many of these states, a prescription is required to receive a vaccine from a pharmacist.75 The state of New Hampshire has a more limited scope of immunization laws than states that require a prescription. On Aug. 26, 2011, Senate Bill 93 expanded the vaccines a pharmacist could administer and the qualifications needed in the state.77 Currently, pharmacists can administer the influenza, pneumococcal, and varicella zoster vaccines. They must then notify the patientâ&#x20AC;&#x2122;s primary care provider, when asked by the patient, after administering the pneumococcal and/or varicella zoster vaccines. Pharmacists also must hold a current license and have completed training specific to the vaccination being administered.

Additionally, pharmacists in all 52 states and territories of the United States have the authority to administer the pneumococcal part B vaccine and the zoster vaccine.75 Other vaccines, such as tetanus-diphtheria or tetanus-diphtheriapertussis (Td/Tdap), human papillomavirus (HPV) and meningococcal, can be administered by pharmacists in most circumstances, but a few states still pose restrictions (Table 3).

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Figure 4. CDC Recommended Vaccinations for Adults 19 years of age or older — 2016.76 VACCINE

AGE

DOSE

Influenza

≥ 19 years

1 dose annually

Tetanus, diphtheria, pertussis (Td/ Tdap)

≥ 19 years

Substitute Tdap for Td once, then Td booster every 10 years

Varicella

≥ 19 years

2 doses

Human papillomavirus (HPV)

19-26 years (females) 19-21 years (males) 22-26 years (males with a risk factor)

3 doses

Zoster

≥ 60 years

1 dose

Measles, mumps, rubella (MMR)

19 years – anyone born after 1956

1 or 2 doses depending on indication

Pneumococcal 13-valent conjugate (PCV13)

19 – 65 years with risk factors ≥ 65 years

1 dose

19 – 65 years with risk factors

1 or 2 doses based on indication

≥ 65 years

1 dose

Hepatitis A

≥ 19 years with risk factors

2 or 3 doses depending on vaccine

Hepatitis B

≥ 19 years with risk factors

3 doses

Meningococcal 4-valent conjugate (MenACWY) or polysaccharide (MPSV4)

≥ 19 years with risk factors

1 or more doses depending on indication

Meningococcal B (MenB)

≥ 19 years with risk factors

2 or 3 doses depending on vaccine

Haemophilus influenza type B

≥ 19 years with risk factors

1 or 3 doses depending on indication

Pneumococcal 23-valent polysaccharide (PPSV23)

Table 3: States and Territories Where Pharmacists Cannot Administer Various Vacccines.75

Vaccine

U.S. States/Territories Where Pharmacists Cannot Administer Specific Vaccines

Tetanus-Diphtheria or Tetanus-DiphtheriaPertussis (Td/Tdap)

Florida, New Hampshire, New York

HPV vaccination

Florida, New Hampshire, New York, West Virginia

Meningococcal vaccine

New Hampshire, West Virginia

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Figure 5 was adapted from data collected by APhA. 75 The figure illustrates the number of states and territories in which a pharmacist can administer the listed vaccination, starting with an age within the listed range.

Pharmacy Profession Recommendations States with expanded immunization authority for pharmacists each have their own training requirements that must be completed. The American Society of Health-System Pharmacists (ASHP) suggests that a training program should include:70  Education on the at-risk patient populations as well as public health goals.  Vaccine safety.  Contraindications and precautions of vaccinations.  Stability and storage of vaccinations.  Drug interactions.  Vaccine dosing, including immunization schedules.  Proper dose preparation and injection technique.  Signs and symptoms of adverse reactions, reporting of these and emergency procedures.  Documentation and reporting to primary care provider and/or local health department.  Billing information.

Pharmacy interns are currently able to administer vaccinations in 44 states and territories based on state laws surveyed effective Jan. 11, 2014.75 In these states and territories, interns are required to complete a certificate training program as well as operate under the supervision of a trained pharmacist at all times. States and territories in which interns may not administer vaccines as of this writing are Florida, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Puerto Rico and South Carolina.

How Ohio Compares Currently in the state of Ohio, pharmacists and pharmacy interns working under the direct supervision of a pharmacist can administer any vaccination recommended by the CDC ACIP to individuals 13 years old and older without a prescription.78 Additionally, they can vaccinate patients 7 to 13 years old with a prescription. Influenza vaccinations can be given to those 7 years and older without a prescription. Before administering vaccinations, the pharmacist or pharmacy intern must successfully complete immunization training which aligns with the standards set forth by ASHP. As more states begin to follow suit and pass legislation to allow pharmacists to provide vaccinations, the country as a whole will be positively impacted and public health across the nation will likely improve.

Conclusion As legislation expanding the pharmacists’ scope of practice continues to be introduced on a state level, access to health care will continue to grow. Pharmacists are seeing expansions in their roles regarding contraceptive authority, dispensing of medical marijuana and providing immunizations.

This expansion helps pharmacists to accommodate the shortage of primary care physicians, resulting in better patient care. At a national level, provider status will help compensate pharmacists for some of the services they may already be providing, in addition to future patient care initiatives. With progressive legislative initiatives, pharmacists’ dynamic role in health care allows their knowledge and services to be more accessible to patients.

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Figure 5. Number of States and Territories with Vaccines Limited by Patient Age.75

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Legislation Across the Nation and the Impact on Pharmacy Practice

ceuticals International; 2006 May. 45. McLeod AL, McKenna CJ, Northridge DB. Myocardial infarction following the combined recreational use of Viagra and cannabis. Clin Cardiol.

2002; 25:133-134.

46. Stoll AL, Cole JO, Lukas SE. A case of mania as a result of fluoxetine marijuana interaction. J Clin Psychiatry. 1991;52:280-1.

47. Mannion V. Case report: adverse effects of taking tricyclic antidepressants and smoking marijuana. Can Fam Physician. 1999;45:2683-4.

48. Hillard JR, Vieweg WV. Marked sinus tachycardia resulting from the synergistic effects of marijuana and nortriptyline. Am J Psychiatry.

1983;140:626-7.

49. Smit F, Bolier L, Cuijpers P. Cannabis use and the risk of later schizophrenia: a review. Addiction. 2004;99:425-30.

50. Bovasso GB. Cannabis abuse as a risk factor for depressive symptoms.

Am J Psychiatry. 2001;158:2033-7.

51. Johns A. Psychiatric effects of cannabis. Br J Psychiatry. 2001;178:116122.

52. National Institute on Drug Abuse. Drug Facts: Marijuana. Available from: www.drugabuse.gov/publications/drugfacts/marijuana.

53. Moore BA, Augustson EM, Moser RP, Budney AJ. Respiratory effects of marijuana and tobacco use in a U.S. sample. J Gen Intern Med. 2005; 20:33-7.

54. Mathew RJ, Wilson WH, Davis R. Postural syncope after marijuana: a transcranial doppler study of the hemodynamics. Pharmacol Biochem Behav. 2003;75:309-18.

55. Controlled Substances Act, 21 § 812.

56. Okie S. Medical marijuana and the supreme court. N Engl J Med. 2005;353:648-651A. 57. National Conference of State Legislatures [Internet]. Denver (CO): National Conference of State Legislatures; 2016. State Medical Marijuana Laws; 2016 Jan 25;[cited 2016 Feb 20]; [about 17 screens]. Available from: www.ncsl.org/research/health/state-medical-marijuana-laws. aspx.

58. ProCon.org [Internet]. Santa Monica (CA): ProCon.org; 2016. 24 legal medical marijuana states and DC; [updated 2016 Mar 14; cited 2016 Apr 19]; [about 38 screens]. Available from: medicalmarijuana.pro con.org/view.resource.php?resourceID=000881.

59. Proposition 215, (Calif. 1996).

60. S.B. 420, (Calif. 2003).

61. Ludlum M, Ford D. Lessons from California’s compassionate use act.

Allied academics international conference. 2010 Apr 14-16; New Orleans, LA. 2010. p.22-26.

62. H.B. 5389, (Conn. 2012).

63. Bonner L. In Connecticut, medical cannabis must be dispensed by pharmacists. Pharmacy Today [Internet]. 2015 June 1. [Cited 2016 Feb 20]; [about 7 screens]. Available from: www.pharmacist.com/connecticutmedical-cannabis-must-be-dispensed-pharmacists.

64. Marijuana Policy Project. An Overview of “Harper Grace’s Law”: Mississippi CBD Extract-Only Medical Marijuana Law. 65. ProCon.org [Internet]. Santa Monica (CA): ProCon.org; 2016. 6 states considering medical marijuana legalization; [updated 2016 Apr 18, cited 2016 Apr 19]; [about 11 screens]. Available from: medicalmarijuana.procon.org/view.resource.php?resourceID=002481.

66. Hickey M. Ohio lawmakers officially join push for medical marijuana.

Newsnet5Cleveland [Internet]. 2016 Apr 14 [cited 2016 Apr 19];[about 8 screens]. Available from: www.newsnet5.com/news/state/ohiolawmakers-officially-join-push-for-medical-marijuana.

67. Borchard J. Ohio medical marijuana hearings being Tuesday: read the bill. Cleveland.com [Internet]. 2016 Apr 14 [cited 2016 Apr 19];[about 7 screens]. Available from: www.cleveland.com/open/index.ssf/2016/ 04/ohio_medical_marijuana_hearing.html#Bill.

68. Ballotpedia: The Encyclopedia of American Politics [Internet]. Middleton (WI): The Lucy Burns Institute; 2007. Ohio marijuana legalization initiative, Issue 3 (2015); [cited 2016 Feb 21]; [about 29 screens].

Available from: ballotpedia.org/Ohio_Marijuana_Legalization_Initiative, _Issue_3_%282015%29.

69. Marijuana Policy Project [Internet]. Washington D.C.: Marijuana Policy Project; c1995-2016. Make 2016 the year that Ohio improves marijuana policies; [updated 2016 Jan 27; cited 2016 Feb 21]; [about 12 screens]. Available from: www.mpp.org/states/ohio/.

70. American Society of Health-System Pharmacists. ASHP guidelines on the pharmacist’s role in immunization. Am J Health-Syst Pharm. 2003; 60:1371–7.

71. Goad JA, Taitel MS, Fensterheim LE, Cannon AE. Vaccinations administered during off-clinic hours at a national community pharmacy: impli-

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72.

73.

74.

75.

76.

77.

78.

cations for increasing patient access and convenience. Ann Fam Med. 2013 Sep/Oct;11(5): 429-436.

Steyer TE, Ragucci KR, Pearson WS, Mainous AG III. The role of pharmacists in the delivery of influenza vaccinations. Vaccine.

2004;22:1001-1006.

Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med. 1994 Sep 22;331(12):778784.

Duncan IG, Taitel MS, Zhang J, Kirkham HS. Planning influenza vaccination programs: a cost benefit model. Cost Eff Resour Alloc. 2012;10 (10):1-11.

American Pharmacists Association [Internet]. Washington (DC): American Pharmacists Association; c2016. Pharmacist Administered Vaccines; [updates 2015 Jan 31; cited 2016 Feb 22]; [about 17 screens].

Available from: www.pharmacist.com/sites/default/files/files/Pharma cist_IZ_Authority_1_31_15.pdf.

Centers for Disease Control and Prevention [Internet]. Atlanta (GA): U.S. Department of Health & Human Services. Recommended Adult Immunization Schedule-United States- 2016; [updated 2016 Feb; cited 2016 Apr 3]; [about 1 screen] Available from: www.cdc.gov/vaccines/ schedules/downloads/adult/adult-combined-schedule.pdf.

S.B. 93, (NH 2011). Available from: www.gencourt.state.nh.us/legisla tion/2011/SB0093.html.

Ohio. Gen. Laws ch. 4729.41 Adult immunizations. Available from: codes.ohio.gov/orc/4729.41.

The authors have no conflict of interest or funding support to disclose.

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Legionnaires’ Disease, A Rising Occurrence in the United States Jennifer Harklerode, Olivia Henton, Myranda Smith, Rebecca Worden, Andrew Roecker, PharmD ’00, Pharm D, BCPS

Abstract Legionella pneumophila, a microscopic bacterium usually responsible for a number of illnesses and fatalities, can eliminate a local population, a region or even a nation. In 1976, L. pneumophila was first discovered due to a number of cases presenting with pneumonia-like symptoms. These cases occurred in an isolated population attending an American Legion convention in Philadelphia, Pennsylvania, therefore lending to the name Legionella. Usually found in aquatic environments such as lakes, streams, cooling towers, air conditioning systems and hot tubs, its ability to thrive in artificial and natural environments makes it an ideal bacterium. L. pneumophila can be transmitted via inhaling aerosols that contain the pathogen. After inhalation, the alveolar macrophages phagocytize the pathogen which then serves as its host. Virulence factors such as lipopolysaccharides (LPS), are one way the pathogen causes infection, however it can also utilize heat shock protein and surface antigens. Usually with Legionnaires’ disease the physical symptoms consist of high fever, malaise, muscle aches, rigors, confusion, headache and diarrhea which categorizes this pathogen as causing an atypical pneumonia. Since L. pneumophila may be associated with travel-related infections, it is hard to track and isolate travel-associated incident clusters because the symptoms present themselves after returning from travel. In regard to diagnosis, this disease has five available techniques to confirm that the patient is in fact positive for L. pneumophila.

Programs such as the Environmental Legionella Isolation Techniques Evaluation Program (ELITE) have been started by the Centers for Disease Control and Prevention (CDC) in order to decrease outbreak incidences. Additionally, the current recommendations for the management of Legionnaires’ disease adapted from the CDC have been summarized into a flow chart which may help clinical decisions in the treatment of this disease.

Key Terms Centers for Disease Control and Prevention (U.S.); Disease Outbreaks; Legionella; Legionella Pneumophila; Legionellosis; Legionnaires’ Disease Introduction Legionnaires’ disease, or Legionellosis, was first identified in 1976 when an onslaught of pneumonia-like symptoms began in a group of individuals in attendance at an American Legion convention in Philadelphia.1 Since its first documented manifestation, Legionnaires’ disease has remained relatively dormant. Recently, however, the respiratory illness has returned to the spotlight as its abnormal instances of infection have been thoroughly covered by the news to alert the public. In July 2015, an outbreak of Legionnaires’ disease in the

South Bronx of New York occurred.2 Investigation of this recent outbreak has allowed scientists to trace the pathogen to its origin at the Opera House Hotel in the South Bronx. The same strain of bacteria responsible for the outbreak of Legionnaires’ disease was found on the cooling towers of the hotel. This was an overlooked location for disinfection and may be the reason behind the reoccurrence of the disease.

Potential sources of Legionnaires’ disease are often undetected until the disease manifests itself in symptomatic infected individuals. Furthermore, because patients present with fever, cough and diarrhea, symptoms that are common among many conditions, the disease presentation does not often provide a differential diagnosis.3 Laboratory diagnostics are utilized to confirm a case of Legionnaires’ disease. The condition is classified as a notifiable disease by the Centers for Disease Control and Prevention (CDC) and, therefore, is subject to CDC protocol and intervention in the instance of an outbreak. Finally, with a recent increase in Legionnaires’ disease, new policies have been set forth by the CDC to control as well as prevent future outbreaks.

Etiology/Transmission Legionella pneumophila is the causative agent of Legionnaires’ disease. The microbe is a small, rod-shaped, gramnegative, aerobic, intracellular bacterium.1 The variations in antigens that reside on the surface of the bacteria give rise to variations, or serogroups, of the microbe. Serogroup 1 is responsible for approximately 79 percent of infections in humans.4 Many diagnostic tools utilize the prevalence of serotype 1 as the primary source of infection to determine whether a patient has Legionnaires’ disease or another type of respiratory infection. L. pneumophila resides in natural, as well as artificial, aquatic environments such as lakes, streams, cooling towers and air conditioning systems.5 In a natural environment, the microbes reside as an intracellular parasite within protozoa.6 The microorganism thrives best in warm temperatures, at an optimal temperature of 35°C, and therefore it is prevalent in human synthesized water environments where this temperature is maintained.4 The opportunistic, waterborne pathogen is transmitted via inhalation of aerosols. The bacterium is able to contaminate an aerosol, become airborne and easily access the respiratory system of a potential host. Aerosols are commonly in the form of sprays or mists. For instance, transmission may occur while an individual is showering. This provides an opportunity for accidental inhalation. Likewise, an individual may become infected by inhaling contaminated water. It is also important to note that this particular pathogen is not transmitted from person to person. A droplet expelled from an infected individual in the form of a sneeze or cough will not transmit the

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pathogen. Therefore, contact with a patient infected by Legionnaires’ disease is not dangerous. Furthermore, most healthy people do not become infected with L. pneumophila after exposure. Risk factors include ages 50 years or older, current or former smokers, having a chronic lung disease, weakened immune system from diseases like cancer, diabetes, or kidney failure, and taking medications that suppress the immune system.7 The incidence of Legionnaires’ disease in the United States has increased greatly since 1998. This may be attributed to a rise in the number of individuals in close proximity to contaminated water sources that have not been properly sanitized.8 The increase, however, may also be due to greater access to diagnostic testing or an increase in the number of immunocompromised or at-risk individuals. This includes the elderly and those with weakened immune systems or an underlying illness.9 Pathophysiology Once inhaled, the pathogen is phagocytized by alveolar macrophages.10 Attachment and entrance into the immune cells is thought to be complement independent and facilitated by the presence of pili. The microbe possesses the ability to escape an immune response by preventing the formation of the phagolysosome utilizing a type 4 secretion system. Therefore, the immune function of the macrophage is disabled. The intracellular bacterium then replicates depending on iron levels and the success of its various virulence factors.

The virulence factors contributing to the body’s response to a L. pneumophila infection are key elements in the bacterium’s ability to enact an immune response. For example, lipopolysaccharide (LPS), heat-shock proteins as well as other surface proteins serve as antigens, which are common to all gram-negative bacteria.11 Lipopolysaccharide is an endotoxin that signals the macrophage to release different proinflammatory cytokines that produce an immune response.

The cytokines that trigger the inflammatory response include tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1).

T-lymphocytes target heat-shock proteins and produce antibodies in response to their presence to promote the immune response. Furthermore, fluid extravasation is a characteristic of this immune response. When the response is signaled within the lung, fluid can occupy the air spaces thus causing pneumonia in progressive cases of Legionnaires’ disease.

Finally, once the bacterium has completed its replication process, it can initiate apoptosis or necrosis of the macrophage.

New bacteria are then released to infect other cells of the immune system to further its infective process.

Signs/Symptoms L. pneumophila is classified as an atypical pneumonia. 12 Presented symptoms, radiograph or x-ray results, and response to certain antibiotics may differ from typical bacteria that cause pneumonia by Streptococcus pneumoniae. Physical symptoms that are commonly observed in patients include high fever, malaise, muscle aches, rigors, confusion, headache and diarrhea.12,13 These symptoms may be followed by a

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nonproductive cough and shortness of breath. Symptoms usually present two to 10 days following exposure to the bacteria. However, patients should still be monitored for two weeks following exposure. Legionnaires’ disease is also usually associated with hospital-acquired pneumonia and travel.

Association with travel has been reported during the incubation period for more than 20 percent of cases reported to the CDC.7 Symptoms often do not present until after the person has returned from traveling from the source of infection, which makes detection of travel-associated clusters difficult.

Diagnosis If an individual is suspected of having Legionnaires’ disease, confirmation should be made with diagnostic testing. There are five available techniques for the diagnosis of Legionnaires’ disease.7 A urine antigen assay along with a culture of respiratory secretions is the preferred diagnosis method because both tests are 100 percent specific. Urine antigen assay allows for rapid, same day results but only tests for L. pneumophilia serogroup 1. Respiratory cultures can take more than five days to provide a result but allow for comparison of clinical and environmental samples. Cultures may be affected by antibiotic therapies and must be obtained as soon as possible after a suspected diagnosis. Additionally, cultures detect all species and serogroups of the bacteria. The following chart adapted from the CDC classifies the advantages and disadvantages for each diagnostic test (Table 1).

After confirmation of Legionnaires’ disease, steps must be taken to find the source of infection and inform the proper officials. Figure 1 provides a breakdown of the steps to diagnose a case of Legionnaires’ disease.14 Recent Outbreaks The World Health Organization (WHO) defines a disease outbreak as an “occurrence of cases of disease in excess of what would normally be expected in a defined community, geographical area or season.”15 These occurrences may be confined to one area or may span entire countries while lasting anywhere from days to several years. The CDC mentions that when two or more L. pneumophila exposed individuals occur at the same time and place and become sick as a result, a Legionellosis outbreak has occurred.7 In 2008, there were eight confirmed cases of a Legionnaires’ disease outbreak at Saint Peter’s University Hospital in New Jersey, resulting in three fatalities.16-18 All those infected had other underlying diseases that made them more susceptible to the L. pneumophila that was traced back to the hospital's water system.

The Veteran Affairs Pittsburgh Healthcare System reported another L. pneumophila outbreak in October 2012.19 The CDC identified a total of 21 cases of Legionnaires’ disease in this outbreak. This total was broken down into five definite and 16 probable health care-associated cases. There were five fatalities resulting from this outbreak, all within 30 days of a positive diagnostic test.

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Table 1. Diagnostic Tests for Legionnaires’ Disease.12 Adapted from Centers for Disease Control and Prevention [Internet]. Atlanta (GA): U.S. Department of Health & Human Services. Atypical Pneumonia; [updated 2014 Feb 7; cited 2015 Nov 7]. Available from: www.cdc.gov/pneumonia/atypical/.

Test

Advantages

Culture



Urine Antigen

Disadvantages

 

Clinical and environmental isolates can be compared Detects all species and serogroups 100% specific

   

Technically difficult Slow (>5 days to grow) Sensitivity high dependent on technical skill May be affected by antibiotic treatment



Rapid (same day results)



Only 100% specific for L. pneumophilia serogroup 1 (Lp1)  Lp1 may account for up to 80% of cases Does not allow for molecular comparison to environmental isolates



Serology



Less affected by antibiotic treatment

 

Must have paired sera 5-10% of population has titer 1 > 256 (no discrimination between cases of Legionnaires’ disease and other causes of community-acquired pneumonia)



80-90% sensitive; 99% specific

Direct Fluorescent Antibody (DFA)





25-75% sensitive



Can be performed on pathologic specimens > 95% specific

Polymerase Chain Reaction (PCR)



Rapid



Assays vary by laboratory and are not FDAapproved

Figure 1. Process for Suspected Cases of Legionnaires’ Disease.14 Adapted f rom: Bartram J, Chartier Y, Lee JV, Bond K, Surman-Lee S. Legionella and the prevention of legionellosis [Internet]. World Health Organization; 2007. Figure 9-1 p.143 [cited 2015 Nov 7]. Available from: www.who.int/water_sanitation_health/emerging/legionella.pdf.

Suspect case of Legionnaires’ Disease

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One of the largest outbreaks occurred in July 2015 in the South Bronx in New York City.20 The source of contamination was found to be a cooling tower located on top of the Opera House Hotel. In this outbreak, 120 people were infected resulting in 12 deaths.

The most recent cases occurred in August 2015. The Illinois Department of Veterans’ Affairs announced eight confirmed cases with no related fatalities.21 In this same time period, an outbreak also occurred in the San Quentin State Prison located in California where there were six confirmed cases. 22 Furthermore, a woman died after diagnosis in University Hospitals Case Medical Center in Cleveland, Ohio. 23 A month later in Cleveland, Ohio, an employee at the NASA Glenn Research Center was diagnosed with Legionnaires’ disease. Although there was no direct CDC response in these cases, the respective state health departments were involved. However, in some situations the CDC protocols for treating L. pneumophila were used.23 Response from Centers for Disease Control and Prevention In response to numerous outbreaks of L. pneumophila, the CDC started the Environmental L. pneumophila Isolation Techniques Evaluation Program (ELITE). Its goal is to certify labs that are collecting and testing water samples for Legionella. However, even with the ELITE certification, a lab is not automatically certified to eliminate the bacteria from the water. The CDC recommends that every outbreak should be treated independent from other cases. 24

The CDC has kept a close eye on areas of natural disaster or warfare. These events lead to water systems becoming stagnant at room temperature. Since L. pneumophila bacterial growth thrives in temperatures of 35°C, these water systems become the ideal areas for Legionnaires’ disease. The CDC has teamed up with the American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE®) to compile guidelines for treating and eradicating affected water systems. The final report, “ASHRAE Guideline 12-2000– Minimizing the Risk of Legionellosis Associated with Building Water Systems,” has served as the standard to eradicate L. pneumophila in affected water systems.25, 26

Management of Disease Current general recommendations for the management of Legionnaires’ disease have been outlined in the flowchart in Figure 2.27 These include the early diagnosis, prompt treatment with appropriate antibiotics and management of any of the possible respiratory, renal or CNS complications. This is key in identifying and managing Legionnaires’ disease effectively to predict the best patient outcomes. Patients presenting with community-acquired pneumonia (CAP) should be tested for Legionnaires’ disease if they have failed a course of antibiotics for CAP, have severe symptoms requiring intensive care, are immunocompromised, are from an environment with a Legionella outbreak or have a travel history within two weeks of the onset of symptoms.

In cases of community-acquired pneumonia, the treatment guidelines are established via the Infectious Diseases Society of America and American Thoracic Society.28 These consensus guidelines provide information on the diagnosis, empirical therapy and focused management of both inpatient and outpatient situations. For patients who are in the ICU, recommendations for empiric antibiotics are a beta-lactam in addition to azithromycin or respiratory fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin). Once the L. pneumophila is confirmed, the beta-lactam is no longer needed. Most patients recover from fever within three to five days, but therapy is continued for 10 to 14 days (five to 10 days for azithromycin), based on clinical stability (Table 2). In immunocompromised patients, therapy may be continued for as long as 21 days.14 Conclusion Legionnaires’ disease management, treatment and eradication come to the spotlight when outbreaks occur. Recent outbreaks throughout the United States have prompted the scientific community to learn more about how to earlier identify and fight Legionnaires’ disease. With the use of programs like ELITE from the CDC and effective treatment protocols, health care professionals can effectively eradicate Legionnaires’ disease while providing the best care to their patients.

Figure 2. General Recommendations for Legionellosis Management.27

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Table 2. Criteria for Clinical Stability.28 Patients should have no more than one of the following before discontinuation of antibiotics:  Temperature ≤ 37.8° C  Heart rate ≤ 100 beats/min  Respiratory rate ≤ 24 breaths/min  Systolic blood pressure ≥ 90mm Hg  Arterial oxygen saturation 90% or pO2 60mm Hg on room air  Normal mental status

Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infec Dis. 2007;44(Suppl 2):S27-S72.

References 1. Brooks GF, Carroll KC, Butel JS, Morse SA, Mietzner TA. Jawetz. Melnick & Adelberg’s Medical Microbiology. 26th ed. New York, NY: McGrawHill; 2013. Chapter 22, Legionellae, Bartonella, and Unusual Bacterial Pathogens.

2. NYC Health: The New York City Department of Health and Mental Hygiene [Internet]. New York City, NY: NYC Health. Health Department Announces Source of Legionnaires’ Disease Outbreak in South Bronx, Declares Outbreak Over; 2015 August 20; [cited 8 November 2015]; [about 1 screen]. Available from: www1.nyc.gov/site/doh/about/ press/pr2015/pr034-15.page.

3. Yu VL, Pedro-Botet L, Lin YE. Harrison’s Principles of Internal Medicine.

19th ed. New York City, New York: The McGraw-Hill Companies; 2015.

Chapter 184, Legionella infections.

4. Fields BS, Benson RF, Besser RE. Legionella and Legionnaires’ disease: 25 years of investigation. Clin Microbiol Rev. 2002 July;15(3):506-526.

5. World Health Organization (WHO) [Internet]. Geneva, Switzerland: World Health Organization. Legionellosis; 2014 Nov. [cited 8 November 2015]. [about 5 screens]. Available from: www.who.int/media centre/factsheets/fs285/en/.

6. Fields BS. The molecular ecology of legionellae. Trends Microbiol. 1996 July;4(7):286-290.

7. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): Centers for Disease Control and Prevention. Legionella (Legionnaires’ Disease and Pontiac Fever); [updated 2015 Sep 1; cited 2015 Oct 8].

Available from: www.cdc.gov/legionella/index.html.

8. Centers for Disease Control and Prevention [Internet]. Atlanta, Georgia: Centers for Disease Control and Prevention. Legionella (legionnaires’ disease and pontiac fever) For Media; 28 Oct 2015 [cited 8 November 2015]. Available from: www.cdc.gov/legionella/qa-media.html.

9. Occupational Safety and Health Administration [Internet]. Washington DC: US Department of Labor. What is legionnaires’ disease? [about 10 screens]. Available from: www.osha.gov/dts/osta/otm/legionnaires/ disease_rec.html.

10. Swanson MS, Hammer BK. Legionella pneumophila pathogenesis: a fateful journey from amoebae to macrophages. Annu Rev Microbiol.

2000 Feb;54:567-613.

11. Friedman H, Yamamoto Y, Klein TW. Legionella pneumophila pathogenesis and immunity. Semin Pediatr Infect Dis. 2002 Oct;13(4):273279.

12. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): U.S. Department of Health & Human Services. Atypical Pneumonia; [updated 2014 Feb 7; cited 2015 Nov 7]. Available from: www.cdc.gov/ pneumonia/atypical/.

13. Tsau TF, Finn DR, Plikaytis BD, McCauley W, Martin SM, Fraser DW. Legionnaires’ disease: clinical features of the epidemic in Philadelphia (Abstract only). Ann Intern Med. 1979 Apr;90(4):509-517.

14. Bartram J, Chartier Y, Lee JV, Bond K, Surman-Lee S. Legionella and the prevention of legionellosis [Internet]. World Health Organization; 2007. Figure 9-1 p.143 [cited 2015 Nov 7]. Available from: www.who.int/water_sanitation_health/emerging/legionella.pdf.

15. World Health Organization [Internet]. Washington DC: World Health Organization. Disease outbreaks [cited 2015 Nov 7]; [about 1 screen].

Available from: www.who.int/topics/disease_outbreaks/en/.

16. Legionnaires’ outbreak at NJ hospital. ABC News [Internet]. 2008 Sep 23 [cited 2015 Oct 8]; [about 2 screens]. Available from: abclocal.go.com/story?section=news/local&id=6409266.

17. Epstein S. Seventh patient tests positive for Legionnaires’ disease. NJ Advance Media for NJ.com [Internet]. 2008 Sep 26 [cited 2015 Oct 8]; [about 3 screens]. Available from: www.nj.com/news/index.ssf/ 2008/09/seventh_patient_tests_positive.html.

18. Haydon T. A third patient dies of Legionnaires’ at New Brunswick Hospital. NJ Advance Media for NJ.com [Internet]. 2008 Oct 3 [cited 2015 Oct 8]; [about 1 screen]. Available from: www.nj.com/news/index. ssf/2008/10/a_third_patient_dies_of_legion.html.

19. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): Centers for Disease Control and Prevention. 2013 Feb 5. The CDC investigation of Legionnaires’ disease among patients at the VA Pittsburgh Healthcare System; [cited 2015 Oct 8]; [about 8 screens]. Available from: www.cdc.gov/washington/testimony/2013/t20130205.htm.

20. Hu W. Bronx Legionnaires’ outbreak is over, health officials say. The New York Times [Internet]. 2015 Aug 21 [cited 2015 Oct 8]; A22. Available from: www.nytimes.com/2015/08/21/nyregion/health-officialsdeclare-end-of-legionnaires-outbreak-in-the-bronx.html?_r=0.

21. Illinois Department of Public Health [Internet]. Illinois Department of Public Health. Respiratory illness at Illinois veterans’ home- Quincy; 2015 Aug 27 [cited 2015 Oct 8]; [about 1 screen]. Available from: www.dph.illinois.gov/news/respiratory-illness-illinois-veterans%E2% 80%99-home-quincy.

22. CDCR Today [Internet]. California Department of Corrections and Rehabilitation. San Quentin state prison legionnaires’ disease case update; 2015 Aug 30 [cited 2015 Oct 8]; [about 2 screens]. Available from: cdcrtoday.blogspot.com/2015/08/san-quentin-state-prison-legi onnaires.html.

23. Blackwell, Brandon. Brunswick woman dies of legionnaires' disease in Cleveland while New York grapples with outbreak. Cleveland.com.

Advance Digital, 2015 Aug 7. Web. 2015 Oct 8. Available from: www.cleveland.com/metro/index.ssf/2015/08/brunswick_woman_ dies_of_legion.html.

24. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): Centers for Disease Control and Prevention. 2015 Oct 28. Legionella (Legionnaires’ Disease and Pontiac Fever) Environmental Legionella Isolation Techniques Evaluation Program; [cited 2015 Oct 8]; [about 3 screens]. Available from: www.cdc.gov/legionella/elite.html.

25. Phin N, Parry-Ford F, Harrison T, Stagg HR, Zhang N, Kumar K, et al.

Epidemiology and clinical management of Legionnaires' disease. Lancet Infect Dis. 2014;14(10):1011-1021.

26. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): Centers for Disease Control and Prevention. Legionella (Legionnaires’ Disease and Pontiac Fever) For Clinicians; [updated 2015 Oct 28; cited 2015 Oct 15]. Available from: www.cdc.gov/legionella/clinicians.html.

27. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): Centers for Disease Control and Prevention. What Clinicians Need to Know about Legionnaires’ Disease. [updated 2016 May; cited 2016 Nov 9] Available from: www.cdc.gov/legionella/downloads/fs-legionellaclinicians.pdf.

28. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of communityacquired pneumonia in adults. Clin Infec Dis. 2007;44(Suppl 2):S27S72.

The authors have no conflict of interest or funding support to disclose.

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Drug Abuse Special Populations

A Pharmacist’s Role in Educating on the Health Risks of Smoking During Pregnancy and Helping Patients with Smoking Cessation Alexandra Herman, Cassandra Hacker, Emily Wells, Brian Heilbronner, Brittany L. Long, PharmD, TTS

Abstract While many people know smoking causes cancer, heart disease and other major health problems, smoking during pregnancy causes additional fetal health complications including birth defects, premature birth and infant death. Cigarettes contain carbon monoxide and nicotine, both of which can cause a decrease in oxygen delivery to the fetus’ developing tissues causing organs like the brain, lungs, kidneys and ears not to develop properly. If children are exposed to these toxins through secondhand smoke after birth, they are more likely to experience severe health problems such as ear infections, cataracts, lung cancer and heart disease. It is also known that nicotine is found in high concentrations in breast milk which allows it to be transferred to infants as they breastfeed. Approximately 15 to 20 percent of pregnant women smoke tobacco during pregnancy despite the strong public-health campaign over the last few decades. Because of the risks and potential negative pregnancy outcomes, pharmacists have the duty to assess the patient’s willingness to quit smoking (during and after pregnancy) and, if receptive, offer counseling and create a plan for cessation. Nonpharmacologic treatment is the best option for smoking cessation for women who are pregnant as it does not expose the fetus to any additional medications. The “5 R’s” are often used to influence any patient, including pregnant women, to consider quitting smoking and to provide them with the right direction to successfully quit. Nonpharmacologic options are the most important for pregnant patients as pharmacologic treatments have not been studied sufficiently to determine safety for the fetus.

Key Terms Breast Feeding; Carbon Monoxide; Fetus; Heart Disease; Nicotine; Parturition; Pharmacists; Pregnant Women; Premature Birth; Smoking; Smoking Cessation; Tobacco

Introduction The contribution of the pharmacist is key in facilitating smoking cessation interventions in the community setting.

Conveniently located in a retail setting, pharmacists are easily accessible to patients who seek counseling and follow-up consultation during smoking cessation. Pharmacists have a unique opportunity to counsel patients who are pregnant or are considering becoming pregnant on the risks of smoking during pregnancy as well as various treatment options for smoking cessation. Smoking during pregnancy can cause various health problems and risks for both the mother and the fetus including gestational bleeding, placental abruption, placenta previa miscarriage and preterm birth.1,2 Additionally, tobacco smoke contains many chemicals that are potentially toxic to fetal development. The most toxic include

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nicotine and carbon monoxide. Nonpharmacologic treatment using the “5 A’s” counseling technique is considered first-line in order to prevent pregnancy complications and potential birth defects.3 Health Risks of Smoking During Pregnancy Numerous health risks of smoking during pregnancy exist.

Many are linked to nicotine and carbon monoxide.1 Pharmacists can educate patients on the specific health risks linked to these chemicals. Specifically, nicotine has been shown to cross the placenta and enter fetal circulation in both active and passive smoking mothers resulting in an accumulation of nicotine in the fetal compartments as early as seven weeks gestation. The concentrations of nicotine in fetuses are known to be higher with longer lasting effects than the nicotine concentrations in the mothers. Evidence has shown nicotine concentrations are 15 percent higher in fetal circulation compared to the mother’s, while the amniotic fluid contains nicotine concentrations that are 88 percent higher than those in the mother’s plasma. These elevated concentrations of nicotine can cause vasoconstriction of the uteroplacental vasculature causing a decrease in the nutrients and oxygen reaching the fetus.2 Nicotine also causes alterations in cellular growth in the peripheral and central nervous systems of the fetus. Additionally, nicotine has been shown to suppress appetite which results in less maternal food intake and potential nutritional deprivation of the fetus. Ultimately, this causes a reduction in the energy supplied to the fetus which may deter its growth and development.

Similarly, carbon monoxide has been shown to cross the placenta and bind to the hemoglobin in fetal circulation, displacing oxygen, which limits the delivery of oxygen to the tissues and organs of the fetus resulting in hypoxic ischemia.1,2 The growth of the fetus during pregnancy depends on the oxygen and nutrition supply to help the tissues to continue to develop. Normally when fetal oxygen levels are low, a protective mechanism helps keep the brain supplied with oxygen. The chemicals from the cigarette can cause this protection mechanism to work incorrectly, reducing the exposure of the brain to oxygen, thus negatively impacting its growth and development. Specifically, the proposed mechanism is that nicotine increases the apoptosis of various structures in the brain including progenitor cells and postmitotic neurons. Considering the health concerns of carbon monoxide on fetal growth and development, research suggests that maternal smoking cessation early in pregnancy may support normal fetal head and brain and the prevention of volumetric changes associated with the brain including thinning of the frontal, parietal and temporal lobe which may take until adolescence to be manifested.1 Changes and abnormalities in brain structure

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can cause long-term effects on behavior including an increased risk of Attention Deficient Hyperactivity Disorder (ADHD).1,2 The fetuses of smoking mothers have an additionally increased risk of being born at a low birth weight, developing Sudden Infant Death Syndrome (SIDS) and being born with other respiratory diseases because nicotine exposure causes decreased airway size, resulting in a reduction in the overall growth of the lungs.2 The chemicals found in cigarettes may reduce kidney size leading to kidney malfunction later in life for the child. 2 Newborns were shown to be four times more responsive to sound stimuli than their nonexposed counterparts resulting in potential dysfunction in their ability to process auditory information and potentially leading to both impaired reading and language skills as they grow up.1 Even though children exposed to cigarette smoking are initially smaller than those not exposed to prenatal smoking, they are at a higher risk for developing obesity later in life which puts them at risk for comorbid conditions like cardiovascular disease or diabetes.2 Additional Health Risks: Secondhand Smoke and Smoking During Breastfeeding Following pregnancy, some women choose to breastfeed their infant. However those who smoke tend to have a smaller milk supply and usually stop breastfeeding their infants sooner than those who do not smoke.4 It is known that nicotine can easily be transferred into the breast milk in high levels, and the amount of nicotine transferred to the breast milk is 2.9 times the amount present in the mother’s blood plasma causing the infants to be exposed to nicotine every time they feed. This exposure to nicotine when feeding can cause shorter sleep times and altered sleep patterns especially if mothers smoke just prior to feeding their child.4,5 A study by Primo and colleagues demonstrated that when mothers smoked before breastfeeding their children only slept for 53.4 minutes whereas children whose mothers did not smoke before breastfeeding slept on average 84.5 minutes. 5 The infants who were exposed to nicotine when they breastfed experienced sleeping disorders. Additionally, the study showed if the mother smoked during pregnancy and lactation, the child had permanent destruction of the pancreatic β cells which caused them to have an impaired glucose tolerance. Based on the findings of these studies, it important that smoking mothers be counseled on all the harmful chemicals in tobacco smoke and their potential detrimental effects on pediatric health. While limited research is currently available on the impact of e-cigarettes, it is thought that e-cigarettes have similar risks to regular cigarettes because e-cigarettes still deliver the same level of nicotine to the mother. Furthermore, the nicotine is passed to the infant in the same way as from regular cigarettes.

Pharmacists can also educate patients on the additional fetal health risks of exposure to secondhand smoke and smoking during breastfeeding. Secondhand smoke is defined as smoke from a cigarette, pipe or a cigar that is inhaled by people in close proximity to the person smoking.6 Secondhand smoke is known to be dangerous and can cause mild symptoms in

DrugPopulations Abuse Special

children like a stuffy nose, headache, sore throat, eye irritation, tooth decay and hoarseness.7 These children can also experience more serious health problems like lung cancer, heart disease, cataracts, wheezing, coughing and ear infections. Studies show children who are exposed to secondhand smoke are more likely to become sick with diseases like the common cold, pneumonia or bronchitis and tend to be sick longer than normal which causes them to miss more school than children from nonsmoking families. If a child has preexisting asthma, secondhand smoke can trigger asthma attacks which may occur more frequently with an increased severity. If the asthma attack is severe enough, it could require hospitalization and may be life threatening for the child.7,8 Children who grow up in smoking households are also more likely to become smokers themselves.7 Smoking During Pregnancy: Patient Perceptions and Demographics Considering the known fetal and maternal health risks from smoking and secondhand smoke during pregnancy, understanding patient perceptions about smoking during pregnancy is of utmost importance for the pharmacist to initiate interventions for smoking cessation.9 Furthermore, understanding the demographics of pregnant patients who smoke can help better identify target populations for smoking cessation interventions. According to the American College of Nurse-Midwives, some potential misconceptions for smoking during pregnancy include:10  Smoking hasn’t seemed to have any impact on my health. I got pregnant without any difficulty.  I smoked during my last pregnancy and had a healthy baby, so this baby will be healthy, too.  There is nothing wrong with a small baby.  I am three months pregnant. There is no point in stopping smoking now. The damage is done.  Smoking relaxes me, and being relaxed is better for my baby.  Quitting smoking during pregnancy will be too stressful on my baby.  Smoking fewer cigarettes during pregnancy is good enough.  If I stop smoking, I’ll gain too much weight.  The only way to quit smoking is cold turkey.  I smoke, so I should not breastfeed my baby.

Approximately 15 to 20 percent of pregnant women smoke tobacco during pregnancy despite a strong public-health campaign over the last few decades.2 About 20 percent of pregnant smokers quit before their initial prenatal visit. Of women who smoke before pregnancy, 55 percent quit during their pregnancy, 40 percent of which relapse within six months after giving birth.11 It was reported that the number of pregnant smokers decreased in half from 1989 to 2000.

The federal government initiative “Healthy People 2020” has a goal to continue to decrease the number of pregnant smokers to nearly 2 percent.12 The 2011 Pregnancy Risk Assessment and Monitoring System (PRAMS) provided data from

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24 states in regard to various demographics and the percent of births to smoking mothers. This data can be found in Table 1.12 Quitting smoking within the first three to four months of pregnancy can yield many benefits including a reduction in risk of low birth weight, premature birth and stillbirth. 13 Considering the extensive need for smoking cessation interventions in pregnant patients among a variety of demographics, there exists considerable opportunity for pharmacists to initiate smoking cessation with patients particularly in the community setting. Behavioral and psychological therapy should be offered to smoking patients who are pregnant before a pharmacotherapy option is considered. Nonpharmacologic behavioral strategies are used to help the patient identify the triggers that cause patients to smoke and

how to control impulses.14 Pharmacists should offer coping strategies to help patients overcome barriers to smoking cessation. The American College of Obstetricians and Gynecologists (ACOG) guidelines suggest strategies to overcoming common barriers in smoking cessation which pharmacists can use to initiate smoking cessation interventions (Table 2).15 Approaches to Smoking Cessation: Pharmacologic and Nonpharmacologic Among the available interventions pharmacists can recommend in initiating smoking cessation, the 5 A’s approach (Table 3) is a preferred nonpharmacologic intervention.3,15 Given the lack of evidence regarding safety and efficacy of pharmacologic options for smoking cessation during pregnancy, use of the 5 A’s as a first-line measure to assess the pregnant patient’s willingness to quit is recommended. This

Table 1. The 2011 Pregnancy Risk Assessment and Monitoring System (PRAMS) Data for Pregnant Smokers’ Demographics.12 Demographic

Percent of births to smoking mothers

Race American Indian or Alaska Native mothers

18.0%

Non-Hispanic white mothers

12.4%

African American mothers

7.0%

Asian or Pacific Islander mothers

1.2%

Hispanic mothers

2.0%

Age (years) <15

2.5%

15-19

10.6%

20-24

13.3%

25+

<10.0%

Mother’s Education Bachelor’s degree or more

1.0%

Some college or associate’s degree

9.0%

High school diploma

13.8%

9-12 grade education

16.7%

8th grade or less

4.4%

Adapted from: Child Trends Data Bank. Bethesda (MD): Child Trends. Mothers who smoke while pregnant.

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Table 2. Barriers and Coping Strategies for Smoking Cessation.15 Barrier

Coping Strategy

Negative mood

Participate in physical activity, talking to a friend, journaling, taking 10 deep breaths.

Being around other smokers

Spend more time with nonsmokers, walk away from smokers when you feel like smoking, ask others around you not to smoke, create a smoke free area in your house.

Triggers

Identify situations that trigger a craving, change your routine after meals such as brushing your teeth instead of smoking.

Time pressures

Change lifestyle to reduce stress, participate in physical activity.

Adapted from: Phelan S, Albrecht S, Melvin C, Rohweder C, Laping J, Chapin J, Mahoney J. The American College of Obstetricians and Gynecologists. Smoking cessation during pregnancy: a clinician’s guide to helping pregnant women quit smoking.

Table 3. The 5 A’s Approach to Smoking Cessation: Applied to Pregnant Patients.3,15

Ask

Ask patient at every health care visit about her tobacco use.

Document answer as a vital sign.

Avoid asking in the form of a yes or no question.  For example, include a multiple-choice question about tobacco use in the personal patient information that the patient files upon the first visit, and updates at every subsequent visit.

Advise

Strongly advise every patient to quit using tobacco in a way that is personalized to the patient’s situation.  Focus on the benefits of quitting for her and the fetus, instead of focusing on negative outcomes for greatest efficacy. Some patients may know other women who have smoked during pregnancy and delivered healthy babies.  Provide educational materials about benefits and risks of tobacco use, Advise any patients that have quit smoking in the past of the importance to remain abstinent.

Assess

Assess willingness to quit within the next 30 days.  If the patient is willing, move on to the Assist phase.  If not, discuss the 5 R’s (Table 4) with the patient to motivate them.15 The 5 R’s discussion is directed by the patient and is meant to have the patient generate their own ideas. This discussion can be spread out over multiple visits if necessary.

Assist

Arrange

Assist in quitting by offering counseling and treatment options.  Form a “quit contract” that states “I agree to stop smoking on (date). I understand that quitting smoking is the best thing I can do to protect my health and the health of my baby.”

Include signatures of the patient and the physician.15  Utilize the STAR approach (Table 5) to plan ahead for challenges in the quitting process.  Provide self-help materials and ways to get help:  1-800-QUIT NOW  www.smokefree.gov  Identify people close to the patient that can help in the quitting process.

Arrange a follow-up date, either to follow up on the phone or in person.  Provide encouragement and positive reinforcement.  Encourage the patient to talk about successes and challenges.  Express empathy and acknowledge that quitting is difficult and setbacks may occur.

Adapted from: Fiore MC, Jaen CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Rockville (MD): U.S. Department of Health and Human Services; 2008 May. Phelan S, Albrecht S, Melvin C, Rohweder C, Laping J, Chapin J, Mahoney J. The American College of Obstetricians and Gynecologists. Smoking cessation during pregnancy: a clinician’s guide to helping pregnant women quit smoking.

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approach has had the most success in helping pregnant patients to quit and is considered noninferior to pharmacologic therapy.15 According to ACOG, if a pregnant patient is unwilling to quit after evaluation using the 5 A’s strategy, the patient should be asked to think about quitting between doctor/pharmacy visits. The 5 R’s (Table 4) is a motivational strategy that may help encourage patients who do not want to quit. The 5 R’s can easily be implemented at the close of conversation. For patients who have decided to quit, the STAR approach (Table 5) is useful in planning an official quit date and accounting for challenges the patient may encounter throughout the process.3 Pharmacists should be mindful of utilizing these approaches in patient encounters.

Nonpharmacologic therapy is the preferred method for smoking cessation in pregnancy. However, it can be difficult to implement, and many patients are unsuccessful. Pharmacologic options are available but, generally, pregnant women are excluded from randomized controlled trials and thus little information exists on the safety and efficacy of the available pharmacologic interventions.3 Evidence is also lacking that pharmacologic treatment is superior in efficacy to nonpharmacologic treatment.15 In pregnant patients that have been unable to quit using counseling techniques, pharmacists should counsel on the risks and benefits of drug treatment for the patient and the fetus. The maternal benefit of quitting smoking using drug treatment is likely greater than the risk Table 4. The 5 R’s: A Motivational Intervention for Patients That Do Not Want to Quit.15

Relevance

Discuss why quitting might be relevant to the patient personally and to her unborn child. The goal is to encourage the patient to quit for personal reasons.

Risk

Ensure the patient understands the negative health risks of smoking for her and her baby.

Reward

Ensure the patient understands the benefits to herself and her family if she quits smoking. Setting a good example is an important part of parenting and prevention of smoking habits in the patient’s children.

Roadblocks

Reassure the patient that there are strategies for overcoming roadblocks and help is available any time she decides she is ready to make the steps to quit smoking.

Repetition

Follow up at every visit and reassess the patient’s willingness to quit. Continue to repeat the 5 A’s and the 5 R’s until the patient is ready to quit.

Adapted from: Phelan S, Albrecht S, Melvin C, Rohweder C, Laping J, Chapin J, Mahoney J. The American College of Obstetricians and Gynecologists [Internet]. Smoking cessation during pregnancy: a clinician’s guide to helping pregnant women quit smoking.

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Table 5. STAR Approach to Planning for Quit Date.3 Set

Set a definite quit date.

Tell

Tell family and friends about quitting so they may facilitate the process.

Anticipate

Anticipate challenges and identify barriers that will or have in the past inhibited the patient from successfully quitting.

Remove

Remove tobacco products and related items from the patient’s immediate environment, and have the patient try to avoid items and places that will trigger thoughts of tobacco usage.

Adapted from: Fiore MC, Jaen CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Rockville (MD): U.S. Department of Health and Human Services; 2008 May.

to the fetus and, if the mother and physician ultimately decide that pharmacologic treatment is the next best option to try, close monitoring is required to maximize the safety of the patient and fetus.13 There are seven FDA-approved pharmacologic treatment options that are first-line in nonpregnant patients. The options include varenicline (Chantix®), bupropion SR Zyban®), and a variety of nicotine replacement therapies (NRT).16 Table 6 outlines the FDA-approved dosing and pregnancy risk levels for each drug.17 Even though the dosages are FDA -pproved, the data assessing safety and efficacy in pregnancy is limited with risk categories of C and D for the options available.18 Pregnancy risk category C implies inadequate studies completed to assess safety, or adverse effects occurred in animal populations, but human data is unavailable. Category D medications have evidence of fetal risk in humans and appropriateness of use depends upon the risks and benefits for the patient.

Conclusion Women who smoke and are pregnant or planning to become pregnant may be unaware of the dangers smoking poses to the fetus and the developing child. Pharmacists, as health care professionals who are widely available and accessible, are in an ideal position to positively influence patients, and particularly pregnant women, to quit smoking. By assessing willingness to quit smoking and offering extensive counseling, pharmacists can help decrease the number of patients who smoke and encourage them with successfully achieving smoking cessation.

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Table 6. Pharmacologic Treatment Options for Smoking Cessation. 17 Drug Name

Varenicline (Chantix®)

Pregnancy Risk Category

Dose

C

 Day 1-3: take 0.5 mg by mouth in the morning.  Day 4-7: take 0.5 mg by mouth twice daily.  Weeks 2 - 12: take 1 mg by mouth twice daily.

 Begin treatment 1 week before quit date.  Take dose after eating with a large glass of water.  Typical duration: 12 weeks, but may be continued another 12 weeks in select patients.

 Day 1-3: take 150 mg tablet by mouth in the morning.  Day 4 and beyond: take 150 mg by mouth twice daily.  Do not exceed 300 mg per day.

 Begin treatment 1- 2 weeks before quit date.  Separate doses by at least 8 hours.  Do not take before bed in order to minimize insomnia.  Typical duration: 7 to 12 weeks, but may be continued for up to 6 months in select patients.

Bupropion SR (Zyban®)

C

Nicotine Replacement Therapy:

D

Other Notes

 Ensure the patient is aware that if they continue to smoke while using NRT, the risk to the fetus is greater than either alone.13

Gum

If first cigarette is used within 30 minutes of waking, use 4 mg gum.

If first cigarette is used after 30 minutes of waking, use 2 mg.  Week 1-6: chew one piece every 1-2 hours.  Week 7-9: chew one piece every 2-4 hours.  Week 10-12: chew one piece every 4-8 hours.

 Maximum: 24 pieces per day.  Chew gum slowly and “park” on inside of cheek when the tingling sensation appears.  When the sensation disappears, chew again.  Park in different areas of the mouth each time.  Continue chewing and parking; cycle for about 30 minutes until effect stops.  Do not eat or drink 15 minutes before or while using gum.  Treatment duration: up to 12 weeks.

Lozenge

See gum dosing.

    

Patch

If more than 10 cigarettes are used in one day:  Week 1-6: apply 21 mg patch once daily  Week 7-8: apply 14 mg patch once daily  Week 9-10: apply 7 mg patch once daily.

If less than 10 cigarettes are used in one day:  Week 1-6: apply 14 mg patch once daily  Week 7-8: apply 7 mg patch once daily.

 Apply the patch to dry, hairless, clean skin.  Rotate the patch site with each application.  Patch may be worn up to 16 hours, and it may be removed at bedtime if the patient has trouble sleeping or has bothersome vivid dreams.  Treatment duration: 8-10 weeks.

Nasal Spray (prescription only)

Spray once in each nostril once or twice per hour (0.5 mg per spray).

   

Oral Inhaler (prescription only)

Initially use one cartridge every 1-2 hours, or 6 cartridges per day.

 Maximum:16 cartridges per day.  Continuously puff for 20 minutes for greatest efficacy.  Inhale in short breaths toward the back of the throat, and not the lungs.  Do not eat or drink 15 minutes prior to or during inhalation treatment.  Treatment duration: 3-6 months.

Maximum: 20 lozenges per day.

Do not chew, bite or swallow the lozenge.

Let lozenge dissolve slowly.

Rotate the lozenge around the mouth.

Do not eat or drink 15 minutes before or while using lozenges.  Treatment duration: up to 12 weeks.

Maximum: 5 doses per hour or 40 doses per day.

Initial use of 8 doses per day is recommended.

Do not sniff, inhale or swallow when spraying.

Treatment duration: 3-6 months.

Adapted from: Pharmacologic product guide: FDA-approved medications for smoking cessation. Regents of the University of California; 1999.

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References 1. Ekblad M, Korkeila J, Lehtonen L. Smoking during pregnancy affects foetal brain development. Acta Paediatrica. 2014;104:12-18.

2. Anblagan D, Jones N, Costigan C, Parker A, Allcock K, Aleong R, et al.

Maternal smoking during pregnancy and fetal organ growth: a magnetic resonance imaging study. PLOS One. 2013 Jun;8(6)1-7.

3. Fiore MC, Jaen CR, Baker TB, Bailey WC, Benowitz NL, Curry S et al.

Treating tobacco use and dependence: 2008 update. Rockville (MD): U.S. Department of Health and Human Services; 2008 May. Available from: www.ncbi.nlm.nih.gov/books/NBK63952/.

4. Massachusetts General Hospital Center for Women’s Mental Health [Internet]. Boston (MA). You asked: is smoking while breastfeeding safe?; [updated 11 Feb 2015; cited 29 Jan 2016]; [about 2 screens].

Available from: womensmentalhealth.org/posts/asked-smoking-breast feeding-safe/.

5. Primo C, Ruela P, Brotto L, Garcia T, Lima E. Effects of maternal nicotine on breastfeeding infants. Rev Paul Pediatr. 2013;31(3)392-397.

6. Merriam Webster Online [Internet]. Springfield (MA): Merriam Webster, Inc; c2010. Secondhand smoke; [cited 24 April 2016]; Available from: www.merriam-webster.com/dictionary/secondhand%20smoke.

7. HealthyChildren.org [Internet]. Elk Grove Village (IL): American Academy of Pediatrics. Dangers of secondhand smoke; [updated 20 Oct 2015; cited 29 Jan 2016]; [about 5 screens]. Available from: www.healthy children.org/English/health-issues/conditions/tobacco/Pages/Danger s-of-Secondhand-Smoke.aspx.

8. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): U.S. Department of Health and Human Services. Health effects of secondhand smoke; [updated 5 Mar 14; cited 29 Jan 2016]; [about 5 screens]. Available from: www.cdc.gov/tobacco/data_statistics/fact_ sheets/secondhand_smoke/health_effects/index.htm#children.

9. Smoke Free Women [Internet]. Nine myths about smoking and pregnancy; [cited 2016 March 31]; Available from: women.smokefree.gov/9 -myths-about-smoking-pregnancy.aspx.

10. American College of Nurse-Midwives [Internet]. October 2014. Myths vs facts about smoking during pregnancy; [cited 2016 March 31]; Available from: midwife.org/acnm/files/ccLibraryFiles/Filename/0000000 04522/CDC-SC-For-Clinicians-10-Myth-Vs-Facts-101314.pdf.

11. Center for Disease Control and Prevention [Internet]. Atlanta (GA): Center for Disease Control and Prevention. Tobacco use and pregnancy; [updated 2015 Sept. 9; cited 2016 March 31]; Available from: www.cdc.gov/reproductivehealth/maternalinfanthealth/tobaccouse pregnancy/index.htm.

12. Child Trends Data Bank [Internet]. Bethesda (MD): Child Trends. Mothers who smoke while pregnant; [updated 2015 March; cited 2016 March 31]; Available from: www.childtrends.org/?indicators=motherswho-smoke-while-pregnant.

13. Briggs G, Freeman R, Yaffe S. Drugs in pregnancy and lactation. 9th ed.

Philadelphia (PA): Lippincott Williams and Wilkins; 2011.

14. U.S. Preventative Services [Internet]. Final recommendation statement: tobacco smoking cessation in adults, including pregnant women: behavioral and pharmacotherapy interventions; [updated 2016 Jan; cited 2016 March 31]; Available from: www.uspreventiveservicestask force.org/Page/Document/RecommendationStatementFinal/tobaccouse-in-adults-and-pregnant-women-counseling-and-interventions1.

15. Phelan S, Albrecht S, Melvin C, Rohweder C, Laping J, Chapin J, Mahoney J. The American College of Obstetricians and Gynecologists [Internet].

Smoking cessation during pregnancy: a clinician’s guide to helping pregnant women quit smoking; [released 2010 Aug 31; cited 2016 March 31]; Available from: www.acog.org/-/media/Departments/ Tobacco-Alcohol-and-Substance-Abuse/SCDP.pdf?dmc=1&ts=20160 221T0955445345.

16. Agency for Healthcare Research and Quality [Internet]. U.S. Department of Health & Human Services; Clinical guidelines for prescribing pharmacotherapy for smoking cessation; 2012 Dec [cited 2015 Feb 10]; [2 screens]. Available from: www.ahrq.gov/professionals/ clinicians-providers/guidelines-recommendations/tobacco/prescrib. html.

17. Pharmacologic product guide: FDA-approved medications for smoking cessation [Internet]. Regents of the University of California; 1999 [updated 2015 Mar 6; cited 2016 Apr 22]; [2 screens]. Available from: smokingcessationleadership.ucsf.edu/sites/smokingcessationleader ship.ucsf.edu/files/Pharmacologic-Product-Guide.pdf.

18. Merck Manual Professional Version [Internet]. Kenilworth (NJ): Merck Sharp and Dohme Corporation. Drugs in pregnancy; [updated 2016;

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cited 2016 Apr 22]; [about 4 screens]. Available from: www.merck manuals.com/professional/gynecology-and-obstetrics/drugs-in-preg nancy/drugs-in-pregnancy.

The authors have no conflict of interest or funding support to disclose.

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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.

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