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Benzodiazepines: A Major Component in Unintentional Prescription Drug Overdoses With Opioid Analgesics Michael Jann, William Klugh Kennedy and Gaylord Lopez Journal of Pharmacy Practice 2014 27: 5 DOI: 10.1177/0897190013515001 The online version of this article can be found at: http://jpp.sagepub.com/content/27/1/5

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Continuing Education Article

Benzodiazepines: A Major Component in Unintentional Prescription Drug Overdoses With Opioid Analgesics

Journal of Pharmacy Practice 2014, Vol. 27(1) 5-16 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190013515001 jpp.sagepub.com

Michael Jann1, William Klugh Kennedy1, and Gaylord Lopez2

Abstract The misuse and abuse of prescription medications in the United States continues to increase despite interventions by health care professionals, regulatory, and law enforcement agencies. Opioid analgesics are the leading class of prescription drugs that have caused unintentional overdose deaths. Benzodiazepines when taken alone are relatively safe agents in overdose. However, a 5fold increase in deaths attributed to benzodiazepines occurred from 1999 to 2009. Emergency department visits related to opioid analgesics increased by 111% followed by benzodiazepines 89%. During 2003 to 2009, the 2 prescriptions drugs with the highest increase in death rates were oxycodone 264.6% and alprazolam 233.8%. Therefore, benzodiazepines have a significant impact on prescription drug unintentional overdoses second only to the opioid analgesics. The combination prescribing of benzodiazepines and opioid analgesics commonly takes place. The pharmacokinetic drug interactions between benzodiazepines and opioid analgesics are complex. The pharmacodynamic actions of these agents differ as their combined effects produce significant respiratory depression. Physician and pharmacy shopping by patients occurs, and prescription drug-monitoring programs can provide important information on benzodiazepine and opioid analgesic prescribing patterns and patient usage. Health care professionals need to inform patients and work closely with regulatory agencies and legislatures to stem the increasing fatalities from prescription drug unintentional overdoses. Keywords benzodiazepines, opioid analgesics, unintentional, overdose, prescription drugs Continuing Education Learning Objectives By the end of the article, the reader should be able to: 1. 2. 3. 4. 5. 6. 7.

Discuss the findings regarding benzodiazepines use among persons using opioid analgesics. Describe the impact of benzodiazepines alone and in combination with opioid analgesics in unintentional drug overdoses in emergency department usage, hospitalizations, and fatalities. Identify the results from poison control centers regarding benzodiazepines exposures. Integrate the pharmacokinetic and pharmacodynamic profiles of the different benzodiazepines with the various opioid analgesics. Link the appropriate use of benzodiazepines and opioid analgesics with various chronic disease states. Discuss the role of prescribers, pharmacists, and prescription monitoring programs. Describe the pharmacoeconimic impact of benzodiazepine usage.

Introduction Prescription drug abuse and its associated consequences such as overdose are an epidemic problem in the United States. The Centers for Disease Control and Prevention (CDC) reported that 20 848 overdose deaths involving prescription medications occurred in the United States in 2009.1 The most common prescription medication class involved in overdoses was reported the opioid analgesics or narcotics.1,2 Although opioid analgesics are commonly recognized as the main source of prescription drug abuse, other prescription medications are often overlooked.

1 2

Mercer University, Atlanta, GA, USA Georgia Poison Control Center, Atlanta, GA, USA

Corresponding Author: Michael Jann, Mercer University, 3001 Mercer University Dr, Atlanta, GA 30341, USA. Email: [email protected]

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Table 1. Benzodiazepine (BZ) deaths, indirect (Ind.) deaths, and major effects as reported from the American Association of Poison Control Centers (AAPCC) from 2006 to 2011.a,8,13-17 Item Deaths Ind. deaths Major effect Total Total BZ calls Total calls

2006

2007

2008

2009

2010

2011

249 (8%) 10 (0%) 2962 (92%) 3221 66 177 2 403 539

228 (6%) 7 (0%) 3330 (93%) 3565 73 199 2 484 041

272 (7%) 58 (1%) 3713 (92%) 4043 78 658 2 491 049

253 (6%) 14 (0%) 3758 (93%) 4025 80 548 2 479 355

286 (7%) 76 (2%) 3900 (92%) 4262 81 641 2 384 825

253 (6%) 287 (6%) 3934 (88%) 4474 82 156 2 416 352

a

Percentages are rounded to the nearest whole number.

A common group of medications typically found with overdose deaths involving opioid analgesics are the benzodiazepines and sedative–hypnotic agents. In fact, benzodiazepines were involved in more than 5500 deaths in 2009—nearly a 5-fold increase since 1999.1 However, the combined use of benzodiazepines with opiate analgesics has been recognized to be dramatically increased.3 Patients with chronic pain who used opiate analgesics and benzodiazepines together reported either an increased euphoric effect from the opioids or an insufficient pain management along with possible comorbid anxiety or mood disorders.4 Various studies have reported that benzodiazepines are the most common additional agents found among opioid analgesic overdose fatalities.5-8 Benzodiazepines listed as psychotherapeutic agents were involved in 48.8% of the fatalities occurring with opioid analgesics in West Virginia.5 Diazepam (22.4%) and alprazolam (18.3%) accounted for the majority of the benzodiazepines used in combination with opioids. This problem is not restricted to the United States. In a Canadian study, benzodiazepines were prevalent in 84.5% of the cases in patients with nonmalignant pain who died from opioid-related causes.6 Benzodiazepines were the most frequent (72%) additional agents reported during a 1-year observational study of fatalities due to acute poisonings with opioid analgesics in Norway.7 The prevalence of ethanol with opioid use was substantially lower (18%). A study of accidental deaths from opioid misusers in the United Kingdom from 1997 to 2007 reported that benzodiazepines were prescribed in 69.8% of patients, again with a lower incidence of dihydrocodeine and ethanol 30.3%.8 This article will examine the role of benzodiazepines in prescription drug abuse patterns either in combination with the opioid analgesics or alone regarding drug overdoses. Benzodiazepines are widely prescribed agents for a variety of medical conditions. However, benzodiazepines are often prescribed in patients with opioid analgesics, and the rise of nonmedical benzodiazepine use among drug abusers has become highly prevalent. In 2011, the American Association of Poison Control Centers (AAPCC) reported 82 156 benzodiazepine exposures. Of these, 61 298 (74.6%) were coded as intentional abuse, misuse, or suspected suicide.9 These circumstances present tremendous challenges to the health care system and law enforcement in providing appropriate patient care outcomes, minimizing misuse, and illegal nonmedical exploitation of these medications.

Statement of the Problem Using PubMed and PsycINFO, a search was conducted that identified English language articles on the topic of benzodiazepines and opiate analgesic abuse from 1960 to 2012. Publications selected focused on the clinical studies between these 2 categories of agents. Due to the enormous number of publications, a Boolean operator was conducted and articles selected with the key words benzodiazepines, opiate analgesics, prescription drugs, overdose, pharmacokinetics (PKs), and pharmacodynamics (PDs). Over 200 articles were generated using these 6 parameters. Case reports that did not contain PK information were excluded. Retrospective studies that included only opioid analgesics without benzodiazepines were also excluded and the following references used for this article. Benzodiazepines were first introduced in the 1960s. Because of their large therapeutic index, fatalities from drug overdoses when taken as a single agent are relatively few.10,11 Even recently, when compared to opioid analgesics overdoses, it was reported that among 61 single-drug deaths that only 1 fatality was due to a benzodiazepine. This finding suggests that a fatal single-drug overdose is more likely to take place with an opioid analgesic and much less likely with a benzodiazepine.5,12 Furthermore, death as a direct effect of benzodiazepine exposure was recorded in only 253 (0.3%) of the 82 156 patients reported to the AAPCC in 2011 (shown in Table 1).9 Therefore, the perception by health care professionals of benzodiazepine safety in single-drug overdose situations is well recognized. Despite their relatively good safety profile when used alone, disturbing trends with benzodiazepines have emerged. Emergency department (ED) visits for the nonmedical uses of benzodiazepines in the United States from 2004 to 2010 increased by 139% from 174 471 in 2004 to 408 021 in 2010.13 Reports of benzodiazepine exposures to the AAPCC have been increasing annually from 61 659 in 2006 to 82 156 in 2011. These exposures also represent a growing percentage of total poison center calls (see Figures 1 and 2).9,14-18 While the Drug Abuse Warning Network (DAWN) Report stated that ED visits from opioid analgesics were higher from 2004 to 2010 than the benzodiazepines (156% increased from 166 338 to 425 427 visits), abuse of benzodiazepines still contributes a significant impact on the health care system.13 For individual benzodiazepines, the CDC in 2004 to 2008 reported an increased ED visits were the highest for alprazolam 168.8% with lower incidences for clonazepam

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Figure 1. Plot of benzodiazepine exposures/calls reported to the American Association of Poison Control Centers (AAPCC) from 2006 to 2011.8,13-17

Figure 2. Plot of benzodiazepine exposures/calls as a percentage of total calls reported to the poison centrol centers from 2006 to 2011.8,13-17

126.6%, lorazepam 113%, and diazepam 67.4%. The estimated number of ED visits for alprazolam in 2010 was 152 168 and was more than twice the number of visits for the next most common benzodiazepine clonazepam at 73 452.19 Approximately 30% of these patients were admitted to the hospital. Together, opioid analgesics and benzodiazepines represent the largest contributors to the increase in ED visits involving the nonmedical use of prescription or over-the-counter drugs. Based on the AAPCC data from 2006 to 2011, adults comprise the majority of cases from 20 to 51 years contributing 72% of benzodiazepines reports. Adults >60 years and younger ages 6 to 19 years had incidents of 8% and 10%, respectively. Children from 0 to 5 years had a reported incidence of 10% most likely representing accidental ingestions. Toxic exposures tend to be more prevalent in females than in males (49 489 females vs 32 268 males).9,14-18 Based upon 2010 data, persons aged >20 years or older had significantly higher ED visits for benzodiazepines (168.8 visits/100 000 persons vs 38.6 visits/100 000 persons) compared to persons 20 years had 177.4 visits/100 000 persons and persons 8000 ng/mL on admission and required ventilation. The patients recovered within 24 hours and were discharged without sequelae. In all, 9 patients had benzodiazepines with other CNS depressants and 4 patients had a coma grade of 3 or greater (Matthew and Lawson scale)29 that required intubation. Plasma diazepam concentrations were moderately elevated and ranged from 993 to 1727 ng/mL in 4 patients. One patient had ingested oxazepam with a plasma drug concentration of 9540 ng/mL (usual normal range 200-500 ng/mL)37 with only drowsiness and was discharged within 24 hours. These results indicate that benzodiazepine plasma concentrations are not predictive of clinical outcome, and that the overdose severity is dependent on whether other CNS depressants are taken. Other important factors must be taken into consideration regarding benzodiazepine disposition in overdose situations. Volume of distribution, impaired hepatic function, and drug–drug interactions (via CYP inhibition) can contribute to prolong or enhance benzodiazepine adverse events.

Opiate Analgesic Pharmacology and PKs The pharmacology of opiate analgesics has been extensively studied, and their mechanism of action occurs via the m, d, and k opiate receptors.37 Analgesic effects occur via their agonistic actions upon these 3 opiate receptors. Sedation and gastrointestinal effects are mediated via the m and k receptors. The CNS respiratory depression occurs with only the m receptor. Opiate analgesics, especially among opioid naive individuals, have a narrow therapeutic index with respiratory depression as the most serious toxic effect that can lead to fatality. Prescribers are faced with providing patients with optimal pain relief while minimizing respiratory depression. Like benzodiazepines, opioids undergo phase I oxidative metabolism and phase II glucuronidation.38,39 Oxycodone is primarily metabolized (about 80%) by N-demethylation via CYP3A4 to an inactive metabolite noroxycodone and to a minor extent by CYP2D6 (less than 10%) to a much more active metabolite oxymorphone.40-42 Hydrocodone is a prodrug and converted to its active compound hydromorphone that is much more potent than hydrocodone via CYP2D6 and to norhydrocodone by CYP3A4.43 Metabolites that are more potent than the parent drug possess difficult challenges for clinicians in unintentional overdoses due to complex PK and PD interactions. Methadone has a complex metabolic profile that includes metabolism by CYP3A4, CYP2B6, CYP2D6, and to a lesser extent CYP2C9 and CYP2C19.38,39 Fentanyl is metabolized

by CYP3A4, codeine is converted to morphine via CYP2D6, and dihydrocodeine and tramadol are metabolized by both CYP3A4 and CYP2D6.38,39 Morphine, hydromorphone, oxymorphone, and dihydrocodeine are metabolized by phase II glucuronidation.38,39,44 Morphine is converted to an active glucoronide metabolite, and it is primarily renally excreted leading to many of morphine’s adverse effects during overdoes situations. The potency effects of oxymorpohone and hydromorphone contribute to the complex PK and PD interactions and play a major role in unintentional overdoses, where prescriber errors can cause additional problems leading to the need for immediate treatment. The CYP2D6 polymorphisms impacting certain opioid analgesics were recognized in the 1990s with an estimated 5% to 10% caucasians being PMs, 1% to 7% ultrarapid metabolizers (UMs), and the remaining population extensive metabolizers (EMs).12 The prevalence of PMs in the Asian population is quite low (60 years had an extraordinarily high fatality with an odds ratio (OR) of 7.1 (95% confidence interval [CI] 3.2-15.5) due to benzodiazepine poisoning compared to persons 72%) of benzodiazepines were dispensed. Pierce and colleagues defined pharmacy shopping as patients who filled prescriptions from 4 or more pharmacies during a 6-month time period using a case controlled study design that compared fatalities with physician and pharmacy shopping.67 A significantly greater number of patients who died were physician shoppers (25.2% vs 3.6% living subjects) and pharmacy shoppers (17.5% vs 1.3% living subjects). About 20.2% of the physician shoppers were also pharmacy shoppers, and 55.6% of the pharmacy shoppers were physician shoppers. A logistic regression model (OR, 95% CI) for drug-related mortality reported a significant increase (P < .05) in predicting fatality with physician shoppers (2.028, 1.598-2.573) and pharmacy shoppers (3.176, 2.253-4.732). Persons who also had prescriptions filled for an opioid analgesic (3.398, 1.601-7.211) or benzodiazepines (7.213, 3.334-15.605) had significantly greater odds of a drug-related fatality. The opiate and benzodiazepine combination had the highest predicted model for a drugrelated fatality (14.917, 7.004-31.767).

The PMPs were designed to reduce drug diversion and minimize detrimental effects on legitimate prescriptions.68 Various states, but not all states, have implemented these programs for opioid analgesics and other controlled substances. The CDC reported that utilization of these PMPs with insurance restrictions can prevent physician shopping and reduce inappropriate opioid use.3 The other strategies recommended were improving and enforcing existing laws and improving medical practice in prescribing opioids. Yet, despite the PMPs implementation, the sales of controlled substances including opioid analgesics have soared.69 The PMPs studies have identified variables that defined physician shopping, but it was not as clear for pharmacy shopping. The PMPs have identified that the combination of opioid analgesics and benzodiazepines are commonly prescribed by multiple providers.55,58 The Georgia Legislature recently approved a PMP for 2013, and the state was among the last to institute this type of program.70 The only state PMP program specific for benzodiazepines is in New York. Its implementation occurred in 1989 that included the use of a triplicate prescription program (TPP).71 The NY program has been tracking scheduled II opioids for many years and expanded to schedule III opioids in the last 5 years. Numerous studies have been conducted with the NY database and have reported that the benzodiazepine use decreased but had unintended consequences for some populations. After implementation in 1989, benzodiazepine usage dramatically decreased while meprobamate, hydroxyzine, and nonbenzodiazepine hypnotics substantially increased in New York, while the rest of the nation had anxiolytic and hypnotic usage decreased except with the benzodiazepine anticonvulsants.72 Many prescribers did not have a favorable view of the program upon implementation. Patients with chronic mental illness, seizure disorders, cancer, and cardiac conditions had benzodiazepine usage decline disproportionately higher than other populations. Poor, urban, and noncaucasian groups also had a high disproportionate decline in benzodiazepine utilization compared to the caucasian population.71 No evidence was found that the TPP reduced inappropriate benzodiazepine use. Among the elderly patient, the incidence of hip fractures and falls from benzodiazepine use did not significantly change prior to and post-TPP implementation. The NY program does offer insights into the applications of PMPs.71 Restrictions (eg, limiting refills) to benzodiazepine access for appropriately prescribed patients may be another avenue of controlling amounts to prevent unintentional overdoses. The PMPs were compared between New York and Pennsylvania, where the NY program was better funded by the state legislature and made use of serialized tamperproof prescription forms for opioid analgesics.72 Data analyzed from 2006 indicated that the opiate analgesic per capita use in New York was two-thirds of Pennsylvania. The overdose death rate in Pennsylvania was 1.6 times higher than New York. The DAWN 2007 data reported that the death rates involving opioid analgesics in Philadelphia (10.2/100 000 persons) occurred at a higher rate than New York City (3.5/100 000 persons).73 These differences could be due to the regulatory environment in New York.

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Pharmacoeconomic Impact Prescription drug misuse and unintentional overdose with opioid analgesics and particularly in combination with benzodiazepines has reached an epidemic level in the United States, which can impact prescribing agreements with health care entities, treatment plans, and patient risk assessments.74 Besides, the morbidity and mortality associated the misuse and unintentional overdose of these agents, their pharmacoeconomic impact on the health care system is enormous. The mean annual direct costs in 2003 US dollars were estimated to be US$15 884 per opiate abuser compared to only US$1830 per nonabuser.75,76 Hospital inpatient expenses and physician outpatient visits comprised 82% of the direct costs, while medications expenditures were only 13% in opiate abusers. Medicaid is the primary public payer for the benzodiazepines.77 Prescriptions for benzodiazepines more than doubled from 8.0 million in 1991 to 17.1 million in 2009 and the US Medicaid enrollment increased from 22.9 million to 53.6 million during the time period. The annual Medicaid expenditures for benzodiazepines rose 30% from US$131 million to US$171 million dollars. When generic formulations were introduced, it lowered the overall direct costs for the benzodiazepines. Trends for generic alprazolam and lorazepam have shown a constant prescription volume increase over the past 2 decades. Pergolizzi quantified the influence of opioid drug–drug interactions from a pharmacoeconomic perspective from a retrospective analysis of paid claims in a commercially insured population.78 Patients who received opioids that were metabolized by the CYP system had a greater overall total costs compared to matched patients who did not have a suspected PK opioid drug–drug interaction (mean US$8165 vs US$7498, P < .01). A casual relationship between the drug–drug interactions, and increased costs were not established and were severely limited by the retrospective nature of utilizing claims data. The PD interactions were not assessed and cannot be neglected, especially when benzodiazepines are present.79 The CDC reported that the total cost to insurance companies from just the nonmedical use of opioid analgesics was estimated to be US$72.5 billion dollars from 1999 to 2008.80 When unintentional overdoses with opioid analgesics and combined benzodiazepine usage occurs, the cost to the health care system becomes gargantuan.

Addressing the Need Responding to the crisis and epidemic of prescription drugs, the National Drug Control Strategy (NDCS) recommended these action steps to reduce abuse: education, drug monitoring, proper disposal, and enforcement.81 Similar to the NDCS, the CDC recommended prescription drug-monitoring programs, patient review and restriction programs, health care provider accountability, laws to prevent prescription drug abuse and prevention, and better access to substance abuse treatment.82 Prevention strategies for the use of prescription databases along with evidence-based guidelines to reduce or minimize physician shopping and reduce inappropriate use of opioid

analgesics.2 Most states have implemented PMPs for the opioids and scheduled II to IV medications. Combined opioid analgesics and benzodiazepine use have led to increased overdose fatalities. In addition to reducing and preventing physician shopping, reducing pharmacy shopping must also be included in the PMPs. This can be especially important for Medicaid recipients and low-income groups as these populations are at a higher risk of prescription drug overdose.2 Unfortunately, PMPs cannot absolutely guarantee reduction in inappropriate use of medications. The TPP for benzodiazepines become unnecessary when included in the PMPs. However, when PMPs can alert prescribers and pharmacists regarding patient shopping patterns, this can initiate appropriate steps for health care professionals to carefully examine patient treatment and screen patients for substance abuse and help them access treatment. The characteristics of an ‘‘ideal’’ PMP was suggested to include a variety of items including monitoring of all controlled substances class II to V and ‘‘best’’ practice models.83 Improving and enforcing legislation of existing laws are needed to keep abreast of the dynamic circumstances with substance abuse problems.81,82 Although the rates of drug overdose fatalities differ among the states,73 state legislatures must provide adequate funding resources for regulatory agencies to implement and continue PMPs. State and federal agencies working together can enforce the existing laws to reduce prescriptions generated from illegal pain clinics (eg, ‘‘pill mills’’) and other types of nonmedical establishments. Education and improved medical practice in prescribing opioid analgesics and benzodiazepines is necessary for all health care professionals and patients using evidence-based guidelines.81,82 Prescribers, pharmacists, and other health care professionals must be aware of the complex PK and PD drug– drug interactions between these 2 agents. Benzodiazepines alone are relatively safe agents, but when combined with opioid analgesics, can be a danger to patients that is often overlooked by health care professionals. Accredited continuing education programs can be integrated into the health care systems for prescribers and health care professionals regarding opioid analgesics and benzodiazepine usage in an effort to minimize unintentional overdoses. Pharmacists can carefully examine benzodiazepine and opiate prescriptions and verify suspected prescriptions utilizing the PMPs to reduce illegal prescriptions. Pharmacists can also refuse to fill suspected illegal prescriptions and alert law enforcement and regulatory agencies. Patients should be counseled for opioid analgesics, benzodiazepines, and their combined use. Patients should be cautioned about obtaining these medications from friends and family members and their proper disposal. Balancing prescription misuse and abuse and safeguarding legitimate access to treatment can be difficult challenges for the health care system. Establishment of specific patient treatment goals and outcomes with continuous communication with health professionals can maximize therapeutic benefits and minimize adverse consequences. Careful patient monitoring is needed by all health care professionals. When a suspected PK or PD drug–drug interaction occurs with a change in patient symptomatology, a thorough

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patient assessment must occur. Patient assessment should include urine drug screens or other methods of drug detection may be considered as benzodiazepines, opioid analgesics, or other medications may have been obtained by illicit means or from friends and family members.

Conclusions Fatalities from prescription drug overdose are a national problem and have become an epidemic issue facing our health care system. The opioid analgesics are well recognized as the main class of prescription medications involved in prescription drug overdose. Benzodiazepines when taken as a single agent have a wide margin of safety. However, when benzodiazepines are taken with opioid analgesics or other CNS depressants including alcohol, this combination can be hazardous. In the past several years, the incidence of ED visits and fatalities from overdoses involving from 2 medication categories have dramatically risen. The PK and PD interactions between benzodiazepines and opioid analgesics are complex and needs to be taken into consideration when prescribing for and monitoring patients. Specific therapeutic outcomes should be defined when using these medications. Patients must be educated in therapeutic expectations and drug adverse side effects with caution. Studies and medical examiner’s reports linking benzodiazepines cause to mortality continue to be challenging and can be very difficult to prove as multiple variables and confounding conditions occur. Physician and pharmacy shopping can be minimized by PMPs or other types of systematic monitoring programs by health care organizations. The pharmacoeconomic impact of prescription drug unintentional overdose has a significant impact on the health care system. Health care professionals working closely with regulatory agencies and legislatures can provide overall goals to optimize patient care with appropriate safety measures. Acknowledgment The authors wish to acknowledge comments from Christopher M. Jones, PharmD, Division of Unintentional Injury Prevention, National Center for Injury and Control, Center for Disease Control, Atlanta, GA.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: Dr. Kennedy has received research funding from Janssen Pharmaceuticals.

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Continuing Education Credit The New York State Council of Health-system Pharmacists (NYSCHP) is pleased to provide you with the opportunity to obtain continuing education credit for this article online at HealthSystemCE.org (http://www.healthsystemce.org); login using your email address and HSCE password; then click the ‘‘Journal CE’’ tab. There is no charge to NYSCHP members. If you are not a member of NYSCHP, call 1-518-456-8819 to pay the $15 fee to access the quiz and obtain the password necessary to access the Journal’s CE article. In lieu of this fee, a completed membership application with your dues may be submitted. A grade of 70% or above is required to earn the CE credit. Repeat examinations will be permitted once for a grade below 70%. The NYSCHP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1.4 contact hours (0.14 CEUs) of continuing education. Universal Activity Number is 0134-0000-14-006-H01-P. Submission of exam for CE credit expires February 28, 2017.

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