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Medications for Opioid Use Disorder Save Lives (2019)

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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press. doi: 10.17226/25310.
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1 Introduction Opioid use disorder is a treatable chronic brain disease.

16 MEDICATIONS FOR OPIOID USE DISORDER SAVE LIVES The United States is facing an epidemic of opioid-related mortality and morbidity that is unparalleled in its scope and staggering in its impact. Drug overdoses are the leading cause of accidental deaths in the United States (Volkow et al., 2014). The U.S. Centers for Disease Control and Preven- tion (CDC) reports that more than 70,000 people in the United States died of drug overdoses in 2017 (Hedegaard et al., 2018), and the rise in drug overdoses has been linked to recent declines in American life expectancy (Joszt, 2018). Two-thirds (more than 47,000) of drug overdose deaths were caused by opioids—both legal and illicit (CDC, 2018b). Emergency depart- ments had 358,000 visits from opioid poisoning in 2015 alone (Weiss and Heslin, 2018). This public health crisis has emerged from two intertwined epidemics: ­ the excessive use of opioids for both legal and illicit purposes, and un- precedented levels of consequent opioid use disorder (OUD). According to 2016 data from the National Survey on Drug Use and Health, more than 11.8 million people over age 12 had misused opioids within the prior 12 months, with 11.5 million people having misused prescription opioids (of an estimated 91.8 million adults who used prescription opioids), and 948,000 people had used heroin that year—including 641,000 people who used both types of opioids (Ahrnsbrak et al., 2017; Han et al., 2017). Among these, an estimated 2.1 million people suffered from an OUD, including 1.8 million with prescription OUD and 646,000 people with heroin use disorder, which are not mutually exclusive (Ahrnsbrak et al., 2017). People who misuse prescription opioids are almost 20 times more likely to use heroin for the first time, and, although just 4 to 6 percent of people who misuse prescription opioids transition to heroin within 5 years, 80 percent of people who use heroin have previously misused prescribed opioids (Carlson et al., 2016; Cicero et al., 2014a; Muhuri et al., 2013). The current U.S. opioid epidemic began in the 1990s, when over-­ prescribing of opioids for pain management1 led to their extensive diver- sion and misuse (Axeen, 2018; Bohnert et al., 2011; Kolodny et al., 2015; L ­ yapustina and Alexander, 2015; Yang et al., 2018). Heroin overdoses began ­ to escalate rapidly in 2010, followed by a wave of overdose deaths due to synthetic opioids that began in 2013 and continues to rise each year as the illicitly manufactured, synthetic opioid fentanyl floods street-drug markets ­ (Seth et al., 2018). Together, overdoses of legally prescribed and ­llicit ­ pioids i o killed almost 400,000 people in the United States between 1999 and 2017, 1  Around two-thirds of people who misuse opioids report doing so for pain management; more than one-third of people who misuse opioids report obtaining them by prescription from a health care provider. Between 21 and 29 percent of people who are prescribed opioids for chronic pain will misuse them, and an estimated 8 to 12 percent of people who misuse them will develop an OUD (Vowles et al., 2015).

INTRODUCTION 17 with the annual death toll increasing five-fold between the beginning and end of that period (CDC, 2018a). Synthetic-opioid overdose deaths increased by 45 percent between 2016 and 2017 (Hedegaard et al., 2018). The impact of the opioid epidemic extends far beyond overdose mor- tality or the immediate consequences to individuals who use opioids or their families. There has been a re-emerging public health crisis of infec- tious diseases driven by the opioid epidemic, with the transmission of HIV and hepatitis C virus increasing with the rise in the numbers of young adults injecting drugs, which also increases susceptibility to endocarditis and infections of the skin, bones, and joints (CDC, 2017). Given the com- pounding risk factors of overdose, infectious diseases, trauma, and suicide, people with OUD have a 20-fold greater chance of early death (Schuckit, 2016). Women who use opioids while pregnant can give birth to newborns with neonatal abstinence syndrome; the number of cases of this syndrome i ­ncreased by 500 percent between 2000 and 2012 in the United States (Ko et al., 2016; Patrick et al., 2015). The socioeconomic consequences of the opioid epidemic are also proliferating in the form of health care costs, loss of productivity, and criminal involve­ ent. CDC estimated that the economic burden of prescrip- m tion opioid misuse in the United States is upward of $78 billion per year ­ (­ lorence et al., 2016). The Council of Economic Advisers estimated the F social cost of the opioid epidemic to be $504 billion in 2015 (Council of Economic Advisers, 2017). In addition, the OUD epidemic has been linked to an increase in the number of children in foster care (Radel et al., 2018) and linked to homelessness and housing insecurity (Doran et al., 2018). Consensus is growing that the opioid epidemic needs to be addressed on multiple fronts by implementing evidence-based strategies to prevent OUD, to treat OUD successfully, and to manage pain effectively while miti- gating the risks of addiction, misuse, and diversion (IOM, 2011; NASEM, 2017). The most common approaches for treating OUD in the United States can be divided into medication-based treatment programs (see Box 1-1) and non-medication-based models. This Consensus Study Report focuses on medication-based treatment for OUD; other treatment approaches were not reviewed in detail because that would have been outside the scope of the committee’s task. However, the issue of whether behavioral interventions are required for medication to be effective is considered in other sections of this Consensus Study Report. Three medications are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of OUD: methadone, buprenorphine, and the long-acting form of naltrexone (see Box 1-2 for more information on the medications). Treating OUD with medication is an evidence-based modality, in which medications are part of a comprehensive “whole patient” approach that may also involve behavioral counseling, community-based peer support,

18 MEDICATIONS FOR OPIOID USE DISORDER SAVE LIVES BOX 1-1 Medication-Based Treatment for Opioid Use Disorder Although medication-assisted treatment (MAT) is a term commonly used to describe treatment programs for opioid use disorder (OUD) that include any of the three opioid agonist or antagonist medications, the committee has chosen to use the term “medication-based treatment for OUD” rather than MAT throughout this report. This change in nomenclature aligns with the committee’s conceptual framework of OUD as a chronic disorder for which medications are first-line treat- ments that are often an integral part of a person’s long-term treatment plan, rather than complementary or temporary aids on the path to recovery. primary care, and wrap-around services that support the long-term care of people with OUD. As part of an overall treatment strategy, the use of medi- cations supports long-term remission. Medication is also a core component of medically supervised withdrawal from opioids, as it can alleviate acute withdrawal symptoms and reduce cravings. Each medication has its own treatment characteristics—and can affect individuals in different ways—so the treatment regimen needs to be tailored to patients’ specific conditions and needs. As presented in Chapter 2, the available evidence clearly establishes that a core element of successful treatment of OUD is medication that is administered appropriately—that is, with medical management that con- sists of regular provider meetings with ongoing monitoring of drug use and psychosocial functioning. Large systematic reviews and randomized controlled trials have demonstrated that treatment with either methadone or buprenorphine is asso­ iated with an array of positive outcomes, including c fewer fatal overdose deaths (Schwartz et al., 2013), better treatment reten- tion rates (Bart, 2012; Mattick et al., 2009, 2014; Schuckit, 2016), lower rates of other opioid use (Bart, 2012; Kakko et al., 2003; Mattick et al., 2009, 2014; Thomas et al., 2014), decreased mortality (Schuckit, 2016), less injection drug use (Woody et al., 2014), reduced transmission of HIV infections (Gowing et al., 2011), improved social functioning (Bart, 2012; Schuckit, 2016), decreased engagement in criminal activity (Schuckit, 2016), and lower rates of neonatal abstinence syndrome (Thomas et al., 2014). Expanding access to these medications reduces the number of deaths due to opioid overdose (Cicero et al., 2014b). Extended-release naltrexone is newer and has not been studied as extensively. However, the studies that have been done have consistently found that its administration demonstrates better retention in treatment, lower rates of opioid use, and lower rates of opioid craving than a placebo (Jarvis et al., 2018). Retention rates of individuals in

INTRODUCTION 19 BOX 1-2 U.S. Food and Drug Administration–Approved Medications for the Treatment of Opioid Use Disorder Methadone, buprenorphine, and extended-release naltrexone are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of opioid use disorder (OUD). Methadone and buprenorphine are known to be ­ e ­ ffective in relieving withdrawal symptoms during the acute phase of treatment (medically supervised withdrawal) and in reducing cravings and illicit opioid use when used for the long term (known as the maintenance phase). Naltrexone is only used as maintenance treatment. As an opioid-agonist medication, methadone fully activates the brain’s opioid receptors through the same mechanism as prescription or illicit opioids, but it is safer and less addictive because its uptake is slower and its effects less euphoric. Methadone is typically taken orally once daily and administered in person at opioid treatment programs. Long-term use of methadone is commonly referred to as methadone maintenance. When the term “methadone treatment” is used in this report, it refers to methadone maintenance treatment. Buprenorphine is a partial opioid-agonist medication that activates opioid receptors. It is typically taken under the tongue and prescribed by a certified provider, without requiring the administration of the medication to be observed. It is available by injection, which lasts 28 days, or by implant, which lasts 6 months. The most commonly prescribed formulation contains naloxone as a deterrent to misuse, because it triggers withdrawal if injected. When the term “buprenorphine treatment” is used in this report, it may refer to any of the forms of buprenorphine. Naltrexone is an opioid antagonist, and it works by blocking opioid receptors and eliminating the euphoric and pain-relieving effects of opioids. It can be admin- istered by mouth daily or as depot injection once monthly, but the oral formulation has been shown to be ineffective for OUD. Only an extended-release formula- tion of naltrexone is approved by FDA for treatment of OUD. Unlike the other two medications, naltrexone treatment requires stopping the use of any opioids for a period of 7 to 10 days prior to treatment initiation, which can be extremely chal- lenging for people with OUD. SOURCES: Schuckit, 2016; Volkow et al., 2014, 2018. medication-based treatment for OUD are generally low, but they vary widely across treatment settings (Timko et al., 2016). Despite the preponderance of evidence that medications to treat OUD are safe and effective, they remain highly underused in the United States. In 2017, about 80 percent of people who needed OUD treatment did not receive it, amounting to some 1.7 million people (Park-Lee et al., 2017). Chapter 3 examines the nature and extent of OUD and access to medica- tions across subgroups of the population. The treatment gap widens further for vulnerable populations. For example, only 1 in 20 people with OUD

20 MEDICATIONS FOR OPIOID USE DISORDER SAVE LIVES in prison receives treatment during incarceration, and opioid overdose is a leading cause of death in people who have recently been released (Binswanger et al., 2013; Krawczyk et al., 2017). Medication-based treat- ment is rare and unavailable for most pregnant women with OUD (Terplan et al., 2015). People with OUD in rural communities, which are hard hit by the opioid epidemic, often face administrative, infrastructural, and trans- portation barriers to accessing these medications (NRHA, 2017). Around 2.5 million people received treatment at a specialty facility in 2016 for a substance use disorder (SUD) (Park-Lee et al., 2017).2 The pro- portion of these facilities that offered any of the FDA-approved medications increased from only 20 percent in 2007 to 36 percent in 2016, mainly due to increases in offering buprenorphine and extended-release naltrexone. Only 6 percent of facilities offered all three medications in 2016 (Mojtabai et al., 2019). A 2015 study found that in 48 states and the District of Columbia, the rates of OUD exceeded buprenorphine treatment capacity (Jones et al., 2015). Chapter 4 describes evidence for implementing medication-based treatment for OUD in different care settings, including opioid treatment programs (OTPs), office-based, acute care, and criminal justice and other care settings. The low usage rates of medications to treat OUD are a consequence of multiple barriers, which are discussed in Chapter 5. Medications to treat OUD remain highly stigmatized among the general public as well as among professionals who commonly interact with persons with OUD (Brondani et al., 2017; DeFlavio et al., 2015; Kennedy-Hendricks et al., 2016, 2017; Livingston et al., 2018; van Boekel et al., 2013). Most of these pro­ essionals f receive inadequate education and training about OUD and its treatment (Merrill et al., 2002; Moran et al., 2017). Regulatory and policy barriers around methadone and buprenorphine—such as current buprenorphine waiver policies, patient limits, and restrictions on settings—also impede the expansion of medication for OUD. Finance and payment policies impose further restrictions on medications that can prevent patients from accessing medications (Clark and Baxter, 2013; Huskamp et al., 2018; Peters and Wengle, 2016). CHARGE TO THE COMMITTEE AND STUDY SCOPE In September 2018, the National Institute on Drug Abuse and the Substance Abuse and Mental Health Services Administration charged the 2  These estimates are based on the Substance Abuse and Mental Health Services Administration’s 2016 National Survey on Drug Use and Health (Ahrnsbrak et al., 2017). One limitation of the survey is that it does not currently measure the use of medications to treat OUD.

INTRODUCTION 21 National Academies of Sciences, Engineering, and Medicine (the National Academies) with developing a Consensus Study Report to synthesize the current knowledge on medication-based treatment for OUD and to highlight gaps in the evidence base to guide future research, policy, and service provi- sion; to ensure that evidence-based treatment is delivered effectively; and to help identify impediments to its wider adoption (see Box 1-3 for the full Statement of Task). The National Academies convened a 14-member ad hoc committee of experts in the fields of neurobiology, pharmacology, addiction ­ medicine, psychology, social work, nursing, health policy, and epidemiology to respond to the charge based on their experience and knowledge in the treatment of OUD. The committee also included individuals with lived expe- rience as patients and family members of individuals with OUD. CONCEPTUAL FRAMEWORK AND KEY TERMS Addiction is a chronic disease that involves compulsive or uncontrolled use of one or more substances in the face of negative consequences (HHS, 2016). As with other chronic medical conditions, a confluence of genetic, BOX 1-3 Statement of Task To support the dissemination of accurate patient-focused information about treatments for addiction and to help provide scientific solutions to the current o ­ pioid crisis, an ad hoc committee under the auspices of the National Academies of Sciences, Engineering, and Medicine will conduct a study of the evidence base on medication-assisted treatment (MAT)a for opioid use disorder (OUD). Specifi- cally, the committee will • Review current knowledge and gaps in understanding regarding the effective­ ess of MAT for treating OUD; n • Examine available evidence on the range of parameters and circumstances in which MAT can be effectively delivered (e.g., duration of treatment, popu- lations, settings, and Interventions to address social determinants of health as a component of MAT); • Identify challenges in implementation and uptake; and • Identify additional research needed on MAT for OUD. Based on its review of the literature and input from the public workshop, the com- mittee will develop a report with its findings and conclusions. a See Box 1-1 for an explanation of the committee’s decision to not use the term MAT in this report.

22 MEDICATIONS FOR OPIOID USE DISORDER SAVE LIVES environmental, and social factors shape a person’s vulnerability to addic- tion. These factors determine a person’s propensity to start using drugs and to keep using them, as well as a person’s susceptibility to the particular types of neurobiological changes in the brain that characterize the pro- gression to addiction (Demers et al., 2014; Volkow and Muenke, 2012). Addiction to opioids or OUD results from changes in the brain caused by prolonged opioid use, which should be treated with individualized, multi- disciplinary care similarly to how other chronic diseases, such as diabetes or asthma, are treated. Box 1-4 provides an overview of the diagnostic criteria for OUD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. OUD can be treated successfully, allowing a person to attain BOX 1-4 Diagnostic Criteria for Opioid Use Disorder The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, defines opioid use disorder as the presence of two or more of the criteria shown below within a 12-month period. The severity is defined as mild if two to three criteria are met, moderate if four to five criteria are met, and severe if six or more criteria are met. (The final two criteria are not counted toward a diagnosis of pre- scription opioid use disorder.) • Using larger amounts of opioids or over a longer period than was intended • Persistent desire to cut down or unsuccessful efforts to control use • Great deal of time spent obtaining, using, or recovering from use • Craving, or a strong desire or urge to use opioids • Failure to fulfill major role obligations at work, school, or home due to recurrent opioid use • Continued use despite recurrent or persistent social or interpersonal problems caused or exacerbated by opioid use • Giving up or reducing social, occupational, or recreational activities due to opioid use • Recurrent opioid use in physically hazardous situations • Continued opioid use despite physical or psychological problems caused or exacerbated by its use • Tolerance (marked increase in amount; marked decrease in effect)* • Withdrawal syndrome as manifested by cessation of opioids or use of opioids (or a closely related substance) to relieve or avoid withdrawal symptoms* * These criteria do not apply to people taking opioids as prescribed by their medi- cal provider. SOURCE: Adapted from APA, 2013.

INTRODUCTION 23 full functionality and a high quality of life (Volkow et al., 2014). However, a major gap exists between the scientific evidence around addictions and SUDs and the public perceptions of those issues. There is substantial stigma attached to being a person with OUD that is not generally applied to others with chronic diseases (Barry et al., 2014; Leshner, 1997), due in part to the negative social effects of drug use and addiction on the broader population (Humphreys, 2017). The stigmatization of OUD and medications to treat it is underpinned by the faulty premise that addiction is simply a moral failure, rather than a chronic condition that warrants appropriate evidence- based treatment (Kennedy-Hendricks et al., 2016, 2017). There has been a growing understanding within the scientific research and medical communities that OUD and other SUDs are in fact chronic diseases susceptible to relapse and should be treated as such, rather than treating them only as episodic acute care incidents (Leshner, 1997; White et al., 2002). Tolerance and withdrawal symptoms are the hallmarks of prolonged opioid use. Over time, progressively higher doses of opioids are required to yield the same effect because the functional response of the brain’s opioid receptors becomes impaired (Williams et al., 2013). Escalating tolerance due to chronic opioid use causes acute physical and ­ psychological withdrawal symptoms that can develop within hours of discontinuation (Schuckit, 2016). Reduced tolerance after a period with- out opioids leads to an increased risk of overdose if the person returns to use with an opioid that has a relatively more potent effect (Strang et al., 2003). This explains, for example, the high overdose risk of former inmates after release from prison (Binswanger et al., 2007, 2013). People with OUD need treatment and support to cope with their symptoms dur- ing the acute withdrawal phase and to reduce their cravings and illicit opioid use during the maintenance phase. Research has shown that SUD treatment is more effective when viewed, like other chronic conditions, as requiring continuing care with treatment goals focused on management rather than a cure, defined as the total stopping of drug use for the rest of one’s life (Humphreys and Tucker, 2002; McLellan et al., 2000; O’Brien and McLellan, 1996). Underpinning the understanding of OUD as a chronic disease is the brain disease model of addiction. According to this model, SUDs are dis- eases of the brain because of the effects that those substances have on brain structure and function. Opioids target a naturally occurring opioid system in the brain that has evolved to play an important role in the control of pain, stress, reward, eating, sleep, emotions, and cognition (Brown et al., 2011; Elman and Borsook, 2016). The natural opioids, also known as endorphins ­ or endogenous opioids, activate the brain’s opioid receptors to produce ­ their critical effects on brain function and behavior. Extensive neuro­cience s r ­esearch has defined the key features of this natural system. These fea-

24 MEDICATIONS FOR OPIOID USE DISORDER SAVE LIVES tures include the system’s many component molecules,3 their brain distribu- ­ tion, and the three classes of opioid receptors that mediate the actions of e ­ ndogenous and exogenous opioids (Darcq and Kieffer, 2018; Valentino and Volkow, 2018). Prolonged opioid use may lead to OUD by superseding the actions of the natural endorphins at the opioid receptors, which can overtake the opioid system and prevent its ability to self-­ egulate. In a brain without r OUD, the effects of endorphins are self-limited by numerous checks and balances, but repeated use of opioids can produce powerful and sustained effects that dramatically disrupt this regulation, resulting in tolerance, physi- cal dependence, and addiction. Among their many effects, opioids initially produce positive feelings (or euphoria) not only through the stimulation of the mu-opioid receptor, but also through the subsequent release of the neuro­ transmitter dopamine in the brain’s reward circuits. The dopamine system is ­ one of several brain systems involved in drug reward processes (Koob, 1992). With repeated opioid use, the ­ opamine response becomes more “sensitized” d (i.e., magnified after repeated exposures), which contributes to active craving of the drug (­ obinson and Berridge, 2008). Over time, the use of opioids R also dampens the influence of brain circuits tied to “executive function” and decision making that restrain drug-seeking behavior (Koob, 2006; Volkow et al., 2016). This combination of an increased drive for reward and crav- ing coupled with the loss of inhibitory control can lead an individual to act impulsively and pursue instant gratification by consuming the drug. The altered reward and cognitive processes in combination with the emergence of a chronic stress and negative mood state have been hypoth- esized to be responsible for a “dark side of addiction” (Koob, 2006), in which the attempts to alleviate negative emotions and the inability to feel pleasure that arise during non-intoxication periods contribute to compul- sive drug-taking behavior. A particular component of the brain opioid system—the dynorphin-kappa system—has been strongly implicated in a persistent negative effect that is thought to drive continued drug use, crav- ing, and relapse (Chavkin and Koob, 2016). Moreover, these changes to the brain continue even after an individual discontinues opioid use and no longer has symptoms of acute withdrawal, making long-term recovery more difficult (Leshner, 1997; Volkow et al., 2016). Ultimately, the committee contends, framing OUD as a chronic disease that is responsive to treatment broadly available through the health care delivery system through a chronic disease management approach will help to decrease the stigma around OUD and allow more individuals to receive high-quality, long-term care. This conceptual framework requires precision and sensitivity to the terminology used to describe OUD; Box 1-5 presents a list of terms and definitions. 3  Such as the endogenous opioid neuropeptides beta-endorphin, the enkephalins, and dynorphin.

INTRODUCTION 25 BOX 1-5 Key Terms Abstinence—This term typically is used to refer to not using alcohol or illicit drugs. This term is complex and often misused. This committee will not use this term, opting instead to using the term remission (see below). Addiction—Another term for a substance use disorder, which is associated with compulsive or uncontrolled use of one or more substances in the face of negative consequences. Addiction is a chronic brain disease that has the potential for both recurrence and remission. Agonist—A chemical substance that binds to and activates certain receptors on cells, causing a biological response. Methadone is an example of an opioid-­ eceptor r full agonist. Buprenorphine is an example of an opioid-receptor partial agonist. Antagonist—A chemical substance that binds to and blocks the activation of cer- tain receptors on cells, preventing a biological response. Naltrexone and naloxone are examples of opioid-receptor antagonists. Behavioral interventions—Interventions (e.g., cognitive behavioral therapy, con- tingency management, structured family therapy) designed to engage people in opioid use disorder treatment, provide incentives to not use illicit opioids, modify attitudes and behaviors related to the use of opioids, and increase life skills to handle stressful circumstances and environmental cues that may trigger intense craving for opioids. Dependence—A physical state in which an organism only functions normally in the presence of a substance and experiences physical disturbance when the substance is removed. A person can be dependent on a substance without being addicted, but dependence sometimes leads to addiction. Diversion—A legal concept involving the transfer of any legally prescribed con- trolled substance from the person for whom it was prescribed to another person for illicit use. Misuse—Use of any substance in a manner, situation, amount, or frequency that can cause harm to users. Medication misuse is the use of a medication in any way a doctor did not direct an individual to use it. Opioid treatment program (OTP)—The Substance Abuse and Mental Health Services Administration–certified program, usually comprising a facility, staff, admin­stration, patients, and services, that engages in the supervised assessment i and treatment using methadone, buprenorphine, or naltrexone of individuals who have opioid use disorder. OTPs can exist in a number of settings, including but not limited to outpatient, residential, and hospital settings. Services may include continued

26 MEDICATIONS FOR OPIOID USE DISORDER SAVE LIVES BOX 1-5 Continued medically supervised withdrawal or maintenance treatment as well as various levels of medical, psychiatric, psychosocial, and other types of supportive care. Opioid use disorder (OUD)—The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, defines OUD as a problematic pattern of opioid use lead- ing to clinically significant impairment or distress, as manifested by at least 2 out of 11 criteria within a 12-month period. See Box 1-4 for the full list of diagnostic criteria for OUD. Recovery—A process of change through which individuals improve their health and wellness, live self-directed lives, and strive to reach their full potential. Recovery is built on access to evidence-based clinical treatment and recovery support services. Remission—A medical term meaning that major disease symptoms are elimi- nated or diminished below a pre-determined, harmful level. Return to use—The return to drug use after a significant period without opioids, often referred to as relapse. Tolerance—Alteration of the body’s responsiveness to alcohol or a drug such that higher doses are required to produce the same effect achieved during initial use. Treatment for opioid use disorder—A service or set of services that may include medication, behavioral interventions, and other supportive services designed to enable an individual to reduce or eliminate drug use, address associated physical or mental health problems, and restore one’s maximum functional ability. Withdrawal—A set of extreme physical symptoms that are experienced when discontinuing the use of a substance to which a person has become dependent or addicted, which can include nausea, vomiting, muscle aches, and cramping, among others, and stress, anxiety, and depression. Withdrawal symptoms often lead a person to use the substance again. SOURCES: Adapted from HHS, 2016; NIDA, 2018; SAMSHA, 2012. STUDY METHODOLOGY The consensus study was carried out by the committee between October 2018 and March 2019. Study activities included a comprehensive literature review of the landscape of treatment for OUD; one 1.5-day public work- shop held in Washington, DC, which was summarized in a Proceedings of a W ­ orkshop—in Brief; and two 2-day closed committee meetings. See Appen- dix A for a more detailed description of the study methodology.

INTRODUCTION 27 ORGANIZATION OF THE CONSENSUS STUDY REPORT The Consensus Study Report is structured into five chapters, including the introductory Chapter 1. Chapter 2, The Effectiveness of Medication- Based Treatment for Opioid Use Disorder, examines the evidence base, knowledge gaps, and future research needs for medications to treat OUD as well as for behavioral interventions in conjunction with medication for OUD. Chapter 3, Treatment with Medications for Opioid Use Disorder in Different Populations, surveys existing evidence and knowledge gaps re- lated to the treatment of OUD across different subpopulations in the United States, including adolescents, older adults, pregnant women, persons with co-occurring conditions, racial and ethnic minorities, and people with low socioeconomic status. Chapter 4, Medications for Opioid Use Disorder in Various Treatment Settings, reviews the evidence concerning differences in medication access and use in different treatment settings including OTPs, office-based care, acute care settings, criminal justice, and other care set- tings. Finally, in Chapter 5, Barriers to Broader Use of Medications to Treat Opioid Use Disorder, the major barriers to full access and use are explored, including issues related to stigma, workforce education and training, law and regulation, and health care delivery and payment. Conclusion 1: Opioid use disorder is a treatable chronic brain disease. OUD is a treatable chronic brain disease resulting from the changes in neural structure and function that are caused over time by repeated opioid use. The behavioral and social contexts are critically important to both its development and treatment. Stopping opioid misuse is extremely difficult. Medications are intended to normalize brain structure and function.

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The opioid crisis in the United States has come about because of excessive use of these drugs for both legal and illicit purposes and unprecedented levels of consequent opioid use disorder (OUD). More than 2 million people in the United States are estimated to have OUD, which is caused by prolonged use of prescription opioids, heroin, or other illicit opioids. OUD is a life-threatening condition associated with a 20-fold greater risk of early death due to overdose, infectious diseases, trauma, and suicide. Mortality related to OUD continues to escalate as this public health crisis gathers momentum across the country, with opioid overdoses killing more than 47,000 people in 2017 in the United States. Efforts to date have made no real headway in stemming this crisis, in large part because tools that already exist—like evidence-based medications—are not being deployed to maximum impact.

To support the dissemination of accurate patient-focused information about treatments for addiction, and to help provide scientific solutions to the current opioid crisis, this report studies the evidence base on medication assisted treatment (MAT) for OUD. It examines available evidence on the range of parameters and circumstances in which MAT can be effectively delivered and identifies additional research needed.

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