Opioid use disorder is a treatable chronic brain disease.
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 Prevention (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 departments 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 unprecedented 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 diversion and misuse (Axeen, 2018; Bohnert et al., 2011; Kolodny et al., 2015; Lyapustina 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 illicit opioids 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).
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 mortality or the immediate consequences to individuals who use opioids or their families. There has been a re-emerging public health crisis of infectious 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 compounding 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 increased 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 involvement. CDC estimated that the economic burden of prescription opioid misuse in the United States is upward of $78 billion per year (Florence et al., 2016). The Council of Economic Advisers estimated the 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 mitigating 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,
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 medications 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 consists 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 associated with an array of positive outcomes, including fewer fatal overdose deaths (Schwartz et al., 2013), better treatment retention 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
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 medications across subgroups of the population. The treatment gap widens further for vulnerable populations. For example, only 1 in 20 people with OUD
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 treatment 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 transportation 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 proportion 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 professionals 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).
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.
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 provision; 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 experience as patients and family members of individuals with OUD.
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,
environmental, and social factors shape a person’s vulnerability to addiction. 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 progression 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, multidisciplinary 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
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 without 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 during 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 diseases 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 neuroscience research has defined the key features of this natural system. These fea-
tures include the system’s many component molecules,3 their brain distribution, and the three classes of opioid receptors that mediate the actions of endogenous 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-regulate. In a brain without 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, physical 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 neurotransmitter 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 dopamine response becomes more “sensitized” (i.e., magnified after repeated exposures), which contributes to active craving of the drug (Robinson and Berridge, 2008). Over time, the use of opioids 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 craving 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 hypothesized 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 compulsive 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, craving, 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.
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 workshop held in Washington, DC, which was summarized in a Proceedings of a Workshop—in Brief; and two 2-day closed committee meetings. See Appendix A for a more detailed description of the study methodology.
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 related 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 settings. 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.
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