3

Treatment with Medications for Opioid Use Disorder in Different Populations

Medications are effective treatments for opioid use disorder (OUD) across a broad range of populations that have been studied, but access to these medications varies widely and is inequitable both across patient groups and across treatment settings. This chapter examines the evidence about the provision of OUD medications within the United States to different populations, including children and adolescents; older persons; different sexes and genders; pregnant women; sexual minorities; individuals with comorbidities; racial and ethnic minorities; people of low socioeconomic status; and rural and urban populations. However, more and better data are needed to track the rates of people with OUD receiving medication nationally and within subsets of the population (see Box 3-1).

MEDICATION-BASED TREATMENT FOR OUD ACROSS THE LIFE COURSE

Adolescents and Young Adults

Opioid use has escalated among the U.S. population under 25 years old, with rates of OUD increasing six-fold between 2001 and 2014 among this age group (Hadland et al., 2017). This population can be segmented into adolescents between 12 and 17 years old and young adults between 18 and 25 years old. The 2017 National Survey on Drug Use and Health

(NSDUH) indicates that 3.1 percent of adolescents had misused opioids in the previous year, with 0.1 percent having used heroin and 3.1 percent having misused prescription opioids. Among persons between 18 and 25 years of age, around 7.3 percent had misused opioids in the previous year, with 0.7 percent using heroin and 7.1 percent misusing prescription opioids (SAMHSA, 2018). A study of administrative databases in Massachusetts found that the prevalence of OUD was significantly higher than the national prevalence estimated by NSDUH; it was increasing most rapidly in that state among people aged between 11 and 25 years (Barocas et al., 2018). According to the American Academy of Pediatrics (AAP), OUD is the leading cause of morbidity and mortality among adolescents and young adults in the United States (Committee on Substance Use and Prevention, 2016). However, national prevalence data suggest that opioid use among adolescents is decreasing, with the annual prevalence of past-year, non-heroin, narcotic use among 12th grade students decreasing from 9.5 percent in 2003 to 3.4 percent in 2018 and past-year use of heroin decreasing from 1.5 percent in 2000 to 0.4 percent in 2018 among the same age group. This suggests that prevention strategies may be having a positive effect, but it may also suggest that adolescents who use opioids may not be frequent presenters to the health care system.

Adolescents with OUD have unique treatment needs and may have complex pre-morbid issues. Given the developmental changes that people undergo during adolescence, treatment strategies designed for adults may not be appropriate for those who are not yet 18 (Center for Substance Abuse Treatment, 2006). Risk factors for substance use and disorders among adolescents include genetic predisposition, peer influence, a family history of substance use, emotional or affective disorders, troubled family relations, school problems, and a history of victimization (Weinberg et al., 1998; Whitesell et al., 2013). Brain development is also a factor in both vulnerability and susceptibility within this age group. The maturing adolescent brain has been shown to be vulnerable to the acute effects of drugs and substance use during adolescence, which increase a person’s risk of developing a chronic substance use disorder (SUD) later in life (Casey et al., 2008). Moreover, substance use can delay normal development during adolescence (Center for Substance Abuse Treatment, 2006). People with OUD in this age group likely need a comprehensive assessment to determine whether adolescent or adult treatment strategies would be most appropriate.

Methadone and naltrexone have not been well studied in adolescents with OUD due to federal restrictions, but the limited data available do support the use of medication-based treatment in this population. Buprenorphine treatment in adolescents with OUD has an existing evidence base. In a clinical trial, adolescent patients who received buprenorphine maintenance treatment plus counseling after medically supervised with-

drawal were more likely to remain in treatment after 3 months than patients who only received counseling after withdrawal (Woody et al., 2008). A retrospective review of long-term treatment outcomes for buprenorphine–naloxone treatment among adolescents with OUD found that treatment retention helps to promote long-term remission (Matson et al., 2014). A multistate retrospective cohort study found that adolescents and young adults who received medication for OUD (buprenorphine, naltrexone, or methadone) within 3 months of diagnosis were more likely to stay in treatment than those who received behavioral therapy alone (Hadland et al., 2018a). Compared to adults, however, adolescents tend to have lower rates of treatment retention (Dreifuss et al., 2013; Marsch et al., 2005; Schuman-Olivier et al., 2014). Creating innovative, developmentally appropriate treatment strategies tailored to this age group could help to improve treatment outcomes (Committee on Substance Use and Prevention, 2016). A key knowledge gap in this area is the dearth of randomized controlled trials specifically focused on adolescents’ use of and retention in medication-based treatment.

Access to medication-based treatment for adolescents and young adults remains vastly inadequate in the United States (Committee on Substance Use and Prevention, 2016; Knudsen et al., 2011). In 2016 the AAP officially recommended that pediatricians consider offering medication-based treatment to adolescents and young adults with OUD, but it remains highly restricted and widely underused (Committee on Substance Use and Prevention, 2016). The exact number of adolescents with OUD who receive medications is unknown. However, a study using the 2013 Treatment Episode Data Set found that among adolescents being treated for OUD in publicly funded programs, only 2.4 percent of those being treated for heroin use and just 0.4 percent of those being treated for prescription opioid misuse had received medication (Feder et al., 2017). A 2018 study reported that among youths (between 13 and 22 years of age) with OUD in the United States, just one-quarter of those who were commercially insured and less than 5 percent of those on Medicaid received medication (Hadland et al., 2018a).

Multiple factors may contribute to adolescents’ lack of access to medication-based treatment; these factors may not necessarily apply to young adults. For example, adolescents who are living at home or covered under a parent’s insurance plan may not wish to disclose their drug use. Parents may be unwilling to provide consent for their minor children to receive medication-based treatment for OUD due to the stigma surrounding the medications. If adolescents and their parents do seek medication-based treatment for OUD, their options are very limited. Naltrexone is only approved for individuals 18 years and older, and federal regulations prohibit most opioid treatment programs (OTPs) from providing methadone to patients younger than 18 years. Buprenorphine is approved by the U.S.

Food and Drug Administration (FDA) for treating patients 16 years and older, but restrictive policies and resource constraints have severely limited its availability (Chang et al., 2018; Feder et al., 2017; Hadland et al., 2018b). As a result of these regulatory restrictions, many adolescents with OUD undergo medically supervised withdrawal with behavioral therapy alone, without the benefit of evidence-based medications.

Older Persons

OUD is on the rise among older populations (SAMHSA, 2017). According to the 2017 NSDUH, 4.6 million adults 50 years or older had had an SUD in the past year (SAMHSA, 2018). Little is known about the mortality and morbidity of OUD in this group or about models of care that can comprehensively address their complex health issues. Due to their age, the use of multiple medications, including sedatives, and a higher likelihood of concurrent chronic illness, older adults are particularly vulnerable to certain consequences of OUD such as delirium, memory loss, suicide, falls and fractures, drug–drug interactions, and drug–disease interactions. One study found that adults over 50 years of age with OUD were more likely to die from any cause and from HIV- or liver-related deaths than their peers without OUD (Larney et al., 2015). Furthermore, OUD can present differently in older populations and requires different types of treatment to restore functional status. However, treatment outcomes for older adults are often equivalent to or better than treatment outcomes among younger people (Clay, 2010).

SEX-RELATED DIFFERENCES IN MEDICATION-BASED TREATMENT FOR OUD

According to data from the NSDUH, 5.15 million females (3.7 percent) had past-year opioid misuse, compared to 6.25 million males (4.7 percent). Almost 60 million females aged 12 and older (35.7 percent) had used pain relievers in the past year, compared to 40.8 million males (30.9 percent). Little is known about sex-related differences in the risk, chronicity, and treatment of OUD (Mazure and Fiellin, 2018). For example, in a recent Cochrane review of the use of buprenorphine for OUD, the majority of the combined sample reviewed was male, and none of the 26 randomized, controlled trials reported results by sex, so the effects of sex/gender could not be assessed (Gowing et al., 2017). According to the NSDUH (2005–2013), OUD in the United States is more common in males (57 percent) than females (42 percent) (Wu et al., 2016), although recent trends over time suggest that drug use among women is increasing at a faster rate than among males (Cicero et al., 2014). Further studies are needed to better

understand the treatment of postpartum women, the treatment of women who are not pregnant, and sex-specific differences in treatment outcomes (Gowing et al., 2017).

Several lines of evidence underscore the need to consider sex and gender in OUD. Women report lower rates of OUD and are more likely to report both widespread and localized pain conditions, including fibromyalgia, migraine, and chronic headache (Bartley and Fillingim, 2013; Serdarevic et al., 2017). Women are more likely than men to have first used prescribed opioids, which they obtain at a higher rate than men (Cicero et al., 2009; Fillingim et al., 2009; Manubay et al., 2015; McHugh et al., 2013). Following an initial opioid exposure, women may transition from initial use to problematic opioid use faster than men (Back et al., 2011; Hernandez-Avila et al., 2004). Among treatment-seeking individuals with OUD, women have more comorbid psychiatric disorders than men, including major depressive and anxiety disorders as well as posttraumatic stress disorder (Grella et al., 2009; McHugh et al., 2013) and psychological distress (Back et al., 2010; Bawor et al., 2015; Manubay et al., 2015; McHugh et al., 2013); men have more comorbid alcohol and other SUDs and legal problems. The analgesic and withdrawal-suppressing effects of opioids are sex sensitive and likely influenced by fluctuations in the female sex hormones estradiol and progesterone (Doyle and Murphy, 2018; Elliott et al., 2006; Loyd and Murphy, 2009; Peckham and Traynor, 2006; Santoro et al., 2017a,b). Finally, some evidence suggests that women may feel more comfortable receiving treatment for OUD in certain settings, such as primary care (Jones and Fiellin, 2007).

Sex-related differences in the treatment of OUD remain largely under-explored, but existing evidence suggests that there are distinct sex-based predictors of methadone treatment response, retention, and outcomes (Levine et al., 2015). Little is known about sex-related differences with respect to dose patterns and length of treatment (Frimpong et al., 2017). An analysis of a nationally representative survey of drug treatment programs found that in methadone treatment programs, an increasing proportion of female patients was associated with a lower proportion of patients in treatment for longer than 1 year (Frimpong et al., 2017), suggesting that some female patients may receive less effective treatment for OUD. A study of all OUD patients enrolled in publicly funded OTPs licensed to dispense methadone in California (2006–2010) found sex differences in mortality risk. Concurrent opioid and methamphetamine/cocaine use increased the mortality risk among women, but it decreased the risk among men; men were more likely than women to benefit from reduced mortality risk through interventions to reduce overdose risk after a period of time without opioid use (Evans et al., 2015).

Clinical and social characteristics also differ between women and men with OUD. A study of methadone treatment programs found that, com-

pared to men, women tended to be admitted at a younger age and after a shorter duration of opioid use (Adelson et al., 2018). Compared with men, women who have SUDs are more likely to have been victims of violent childhood and domestic abuse (Ouimette et al., 2000) and to have co-occurring psychiatric disorders (Zilberman et al., 2003). Although parents who receive medication for OUD are more likely to retain custody of their children (Hall et al., 2016), the fear of losing custody can discourage women from seeking treatment, as can the fear of retribution from a violent domestic partner (Center for Substance Abuse Treatment, 2006). Because women tend to be the primary caregivers, childcare issues can also pose barriers to entering and remaining in treatment for OUD. Women with OUD who have children may benefit from enhanced services in addition to medication-based treatment to address their social service needs (Marsh et al., 2000). Because histories of emotional, physical, and sexual trauma are prominent in the narratives of women who use drugs (Torchalla et al., 2015), many SUD treatment providers have adopted trauma-informed care and integrated treatment, with important subsequent improvements in mental health and service use (Messina et al., 2014). Women-centered treatment for SUDs may also include the provision of family counseling, child care, residential care for clients’ children, transportation assistance, domestic violence services, care options for pregnant women, and comprehensive mental health care; however, such treatment services are declining in availability (Terplan et al., 2015).

PREGNANT WOMEN

Pregnant women with OUD are another population with unique treatment needs that are largely unmet. Among pregnant women in the United States, the prevalence of OUD quadrupled from 0.15 to 0.65 percent between 1999 and 2014, with large variability across states (Haight et al., 2018). Overdose is one of the leading causes of maternal deaths in the United States, with the risk of overdose increasing as the postpartum period progresses (Schiff et al., 2018). A retrospective cohort study looking at women with OUD in Massachusetts found that the rate of overdose was lowest in the third trimester (at 3.3/100,000 person-days) and increased after delivery, with the highest rates 7 to 12 months postdelivery (12.3/100,000 person-days) (Schiff et al., 2018). Pregnant women with untreated OUD are up to six times more likely than other women to have maternal complications, including low birthweight and fetal distress, while neonatal complications among babies born to mothers with OUD range from neonatal abstinence syndrome and neurobehavioral problems to a 74-fold increase in sudden infant death syndrome (Minozzi et al., 2013).

Treatment Outcomes for Pregnant Women and Their Infants

Both methadone and buprenorphine are recommended for treating OUD in pregnancy to improve outcomes for the woman and the newborn (Kotelchuck et al., 2017). The efficacy and safety of methadone treatment for OUD in pregnant women is long established. In women who receive methadone treatment during pregnancy, the outcomes for their infants (e.g., likelihood of the pregnancy going to term and healthy birth weight) are similar or within normal ranges compared with infants who were not exposed to methadone (Kaltenbach and Finnegan, 1984; Stimmel and Adamsons, 1976). Methadone has traditionally been the primary treatment for pregnant women with OUD, but more recent research indicates that buprenorphine treatment has potential benefits compared with methadone in this population. A randomized controlled trial of methadone versus buprenorphine in pregnant women with OUD found that neonates exposed to buprenorphine required 89 percent less morphine, had shorter hospital stays, and received a shorter duration of treatment for neonatal abstinence syndrome relative to pregnant women treated with methadone (Jones et al., 2010). Other outcomes and adverse events were similar between the two groups (Jones et al., 2010).

A comparison of OUD treatments for pregnant women across seven studies found no significant differences in maternal outcomes, neonatal outcomes, or serious adverse outcomes for buprenorphine–naloxone compared with buprenorphine alone, methadone maintenance, or methadone-assisted withdrawal (Lund et al., 2013). The safety of extended-release naltrexone has not yet been established for pregnant women (Connery, 2015) and currently naltrexone is not recommended for the treatment of OUD in women who are pregnant.

Despite the sound evidence base, most pregnant women with OUD do not receive any treatment with medications (Metz et al., 2018; Terplan et al., 2015). Among women who do receive treatment during pregnancy, many fall out of treatment during the postpartum period (sometimes called the “fourth trimester”) due to gaps in insurance coverage and other systemic barriers. The proportion of pregnant women with OUD admitted to publicly funded treatment programs has increased from about 17 to 41 percent since the mid-1990s, but the proportion of those women in treatment who receive medication to treat their OUD has remained static—at roughly 50 percent—with significant regional, demographic, and treatment facility variability (Short et al., 2018). Although the rates of OUD among pregnant women have sharply increased, many women cannot access appropriate services (Terplan et al., 2015). One study that looked at the National Survey of Substance Abuse Treatment Services of 13,000 SUD facilities found that the proportion offering services for pregnant and postpartum

women declined from 19 percent in 2002 to 15 percent in 2009 (Terplan et al., 2015). An integrated approach with close collaboration between OUD treatment providers and prenatal providers has been described as the “gold standard” for care (Klaman et al., 2017). Further research is needed to better understand the effects of medication-based treatment in pregnant women and postpartum women as well as to investigate interventions that could help to increase treatment retention.

SEXUAL MINORITIES

Little is known about opioid use and medication-based treatment for OUD among sexual minority groups, including lesbian, gay, and bisexual adolescents and adults. Sexual minorities accounted for just 2 percent of the sample of approximately 35,000 adults in the 2004–2005 U.S. National Epidemiologic Survey on Alcohol and Related Conditions. Respondents with SUDs who were sexual minorities were less likely to receive OUD treatment than the sexual majority population; sexual minority respondents—particularly women—were more likely to have lifetime SUDs. Sexual minorities also tended to have more extensive family histories of substance misuse (Duncan et al., 2019). According to the 2015 NSDUH, respondents identifying as bisexual were more than 1.5 times more likely to report past-month and past-year opioid misuse than those identifying as heterosexual. A nationally representative sample of U.S. adults revealed disparities in opioid misuse and OUD across different sexual orientations (Duncan et al., 2019). No data exist on the proportion of sexual minorities with OUD who receive medication-based treatment, which is an important area for further research. For sexual minority populations with OUD, for example, treatment programs could be delivered through a trauma-informed approach to care that integrates primary care with behavioral health and specifically addresses the stressors experienced by sexual minorities (Girouard et al., 2019).

INDIVIDUALS WITH OUD AND OTHER MORBIDITIES

Comorbidities are common among people with OUD, particularly co-occurring mental health disorders, other SUDs, and long-term chronic pain. Infectious diseases have also reached epidemic proportions among people with OUD in some communities, driven by the increase in injection drug use. Complex interactions among comorbid conditions can affect treatment strategies and outcomes, and people with OUD and comorbidities would likely benefit from much more integrated care strategies than those that now prevail.

Populations with Co-occurring Mental Health Disorders

Up to 40 percent of people receiving treatment for SUDs may have co-occurring mental health disorders, such as antisocial personality disorder, major depression, or general anxiety (Flynn et al., 1996). According to the NSDUH (2005–2013), 29 percent of people with OUD have had a major depressive episode (Wu et al., 2016). A study of the impact of mental health comorbidities on buprenorphine treatment adherence in patients with an OUD found that 22 percent of patients had comorbid anxiety disorder and about 16 percent had comorbid bipolar disorder (Litz and Leslie, 2017). High rates of attention deficit hyperactivity disorder symptoms have been found among heroin-dependent patients—especially those with severe OUD—who also have higher rates of other comorbid mental health conditions (Lugoboni et al., 2017). Co-occurring mental health disorders appear to be more commonly diagnosed among women than men; they are also more commonly diagnosed among people engaged in the criminal justice system than the general population (Center for Substance Abuse Treatment, 2006; Mbaba et al., 2018).

Comorbid mental health disorders can affect OUD treatment outcomes. Members of this population face unique challenges, making them more likely to drop out of medication-based treatment (Krawczyk et al., 2017b). One study found that patients with bipolar disorder being treated with buprenorphine for comorbid OUD were significantly less likely to adhere to buprenorphine treatment (Litz and Leslie, 2017). Most people with OUD and co-occurring psychiatric disorders do not receive treatment for either problem. Less than half of people with severe mental health and SUDs receive any treatment, and only about 7 percent receive treatment for both disorders (Priester et al., 2016). This may be due in part to their complex treatment needs; for example, they may have interacting symptoms of multiple disorders and compounding social factors such as victimization, poverty, or homelessness. This population tends to have very limited access to evidence-based treatment and poorly coordinated treatment for their co-occurring disorders (Center for Substance Abuse Treatment, 2006; Watkins et al., 2001).

Among people with comorbid mental health disorders, medications to treat OUD have the potential to improve outcomes and reduce the risk of overdose, hospitalization, and emergency department visits (Robertson et al., 2018). A recent study looked at medication-based treatment for adults with schizophrenia, autism spectrum disorder, bipolar disorder, or major depression as well as comorbid moderate to severe OUD. Methadone, buprenorphine, and oral naltrexone were all associated with reductions in the need for inpatient OUD treatment and with improved adherence to medications for the comorbid mental health disorders (Robertson et al.,

2018). A study of methadone treatment among people who use heroin found that depression improves quickly during the first 3 months of treatment, after which it plateaus; depression decreased more rapidly among women and among younger people (Wang et al., 2017).

People with OUD and co-occurring mental health disorders may benefit from integrated, concomitant treatment for their co-occurring disorders, augmented by continuous outreach and support for medication adherence, treatment retention, coordination of care, and accessing social services (Charney et al., 2001; Drake and Mueser, 2000). Ideally, care for the psychiatric comorbidities would be integrated into OUD treatment settings, and the reverse (Krawczyk et al., 2017b).

Populations with Other Substance Use Disorders

According to the NSDUH (2005–2013), 80 percent of individuals with OUD had a co-occurring SUD (Wu et al., 2016). In clinical samples of individuals with OUD, rates of current comorbid SUD range from 13 to 49 percent for alcohol, 20 to 40 percent for stimulant, 28 to 41 percent for cannabis, and 80 to 95 percent for tobacco (Rosic et al., 2017; Strain, 2002). Patients with other SUDs may require special dosing and tolerance considerations when being treated with medication for OUD.

Unhealthy alcohol use can interfere with the treatment for OUD, with heavy drinking often cited by clinicians as a contraindication to medication-based treatment for OUD because both substances may depress respiratory function. However, even heavy alcohol use does not appear to increase the risk of overdose death (Klimas et al., 2018), and FDA released a statement explicitly noting that the use of alcohol or other drugs that depress the central nervous system should not be considered a contraindication to treatment with buprenorphine or methadone (FDA, 2017).

Cocaine and other stimulant use is frequent among individuals in methadone and buprenorphine treatment and has been associated with lower retention and poorer outcomes, although the data are mixed (Kosten et al., 1992; Sullivan et al., 2010). As noted in Chapter 2, contingency management is a behavioral treatment that demonstrated effectiveness in treating stimulant use disorder in patients in methadone treatment (Cunningham et al., 2013; Griffith et al., 2000).

Patients who are receiving medication to treat OUD have disproportionately high rates of tobacco use disorder (Yee et al., 2018). Failing to address tobacco use can negatively affect OUD treatment, and the OUD treatment process provides an opportunity to provide smoking cessation treatment (Mannelli et al., 2013). For example, one study found that patients with OUD retained in office-based buprenorphine treatment were more likely to receive smoking cessation medications than people not

retained in treatment (Nahvi et al., 2014a). A meta-analysis of smoking cessation interventions among patients receiving methadone treatment found that nicotine replacement therapy led to significant reductions in smoking (Yee et al., 2018). Evidence suggests that varenicline can support short-term abstinence from smoking among people with OUD receiving methadone maintenance treatment (Nahvi et al., 2014b). Naltrexone has been studied as a potential treatment to aid in smoking cessation in individuals with OUD, though evidence does not seem to suggest that it has a clinical benefit (David et al., 2006).

Populations with Chronic Pain

Both chronic pain and addiction are conditions driven by neurophysiological processes and shaped by a confluence of genetic and environmental factors (Center for Substance Abuse Treatment, 2012). Studies of people receiving methadone treatment for OUD have found that 37 to 65 percent of patients reported moderate to severe chronic pain (Dhingra et al., 2012; Rosenblum et al., 2003).

Chronic pain might negatively affect drug-use outcomes in people with OUD, although the data are mixed. In one study, people with chronic pain receiving buprenorphine treatment for OUD had similar outcomes to those without chronic pain (Fox et al., 2012). Across several studies of patients on methadone, chronic pain is associated with poor psychosocial and physical function—as it is in the general population—but it is not necessarily associated with a return to use of opioids or other substances (Dennis et al., 2015). The same meta-analysis found no effect of chronic pain on any OUD treatment outcomes for patients maintained on buprenorphine (Dennis et al., 2015). A subsequent trial demonstrated that patients with chronic pain who discontinue buprenorphine are more likely to return to use than patients without chronic pain who discontinue buprenorphine (Worley et al., 2017). Emerging evidence demonstrates improved pain outcomes for patients with chronic pain converted from full agonist opioids to buprenorphine (Daitch et al., 2014; Pade et al., 2012), and future research should compare outcomes across the different OUD medications. Meanwhile, treating OUD in people who have chronic pain remains a clinical challenge, highlighting a critical gap in strategies to manage chronic pain among this population (Delorme et al., 2018).

Populations with Comorbid Infectious Diseases

It is increasingly evident that the ongoing epidemics of OUD, opioid overdose, hepatitis C virus (HCV), and HIV in the United States are linked and warrant combined evidence-based interventions for prevention and

treatment. These would include broad HCV and HIV testing and substance use screening, the provision of medications to treat OUD, and increased population-level HCV treatment (Perlman and Jordan, 2018). A variety of successful models have been described for co-locating the treatment of all three conditions (Rich et al., 2018).

Epidemiological studies reveal that among people who inject drugs in the United States, HIV rates are decreasing and HCV rates are increasing (Schranz et al., 2018). However, rural counties hard hit by the opioid epidemic are experiencing catastrophic increases in HIV transmission as well as HCV (NASEM, 2018). These increases in infectious disease transmission rates are being driven in large part by increases in injection drug use in communities across the country.

Interactions between methadone and older medications for HIV, such as efavirenz, and interactions between buprenorphine and ritonavir-boosted atazanavir may have historically impacted OUD treatment in people living with HIV. However, such interactions are less of a concern with the current first-list antiretroviral therapies, which are regimens containing integrase inhibitors (Gourevitch and Friedland, 2000; McCance-Katz et al., 2007). Methadone and buprenorphine treatment significantly reduce the use of illicit opioids and HIV transmission risk behaviors, such as injection drug use and the sharing of injection equipment (Gowing et al., 2011; Woody et al., 2014). Methadone and buprenorphine also improve HIV viral suppression and adherence to antiretroviral therapy. Extended-release naltrexone has been shown to improve HIV viral suppression in persons with HIV leaving prison (Fanucchi et al., 2019). Co-location of HIV and OUD treatment in primary care or OTPs has been demonstrated to improve treatment outcomes for both conditions (Berg et al., 2011; Low et al., 2016; Lucas et al., 2010). Office-based buprenorphine treatment for OUD provided in HIV treatment settings has also been associated with decreased opioid use (Fiellin et al., 2011).

In the United States today, the majority of people with HCV have a history of injecting drugs (Norton et al., 2017). A retrospective study of clinical data reported that almost half of people receiving office-based buprenorphine had positive screening tests for HCV antibodies, but only 2 percent had initiated HCV treatment (Carey et al., 2016). Methadone and buprenorphine treatment reduce the risk of HCV infection among injection drug users (Tsui et al., 2014), and people retained in OUD treatment are significantly more likely to initiate HCV treatment (Norton et al., 2017). High rates of successful HCV treatment have been achieved among patients receiving their HCV treatment onsite at OTPs (Butner et al., 2017; Litwin et al., 2009).

RACIAL AND ETHNIC MINORITY POPULATIONS

The demographics of the opioid epidemic in the United States have shifted over the past several years, but according to NSDUH data the prevalence of prescription or illicit opioid misuse has remained lower in racial and ethnic minority groups than among whites (CDC, 2018). Data from the NSDUH suggest that racial minorities are treated less often for their OUD compared with whites (Wu et al., 2016), but existing data regarding how minority populations access medication-based treatment compared with whites are mixed. One study of racial and ethnic differences in the receipt of medication for OUD found that while less than 30 percent of all patients received medication, the odds of receiving it were significantly higher among African American and Hispanic patients who used heroin than among white people who used heroin, which could not be explained by differences in clinical need (Krawczyk et al., 2017a). In contrast, a retrospective cohort study of adolescents and young adults with OUD found that African American and Hispanic patients were significantly less likely than white patients to receive treatment with either buprenorphine or naltrexone within 6 months of diagnosis (Hadland et al., 2017). A retrospective cohort study of urban adults receiving office-based buprenorphine for OUD (2002–2014) found that more than half of all patients were no longer in treatment after 1 year, with significantly worse 1-year treatment retention among people who were African American or Hispanic than among white patients (Weinstein et al., 2017).

African Americans with OUD in the United States have a long history of discrimination, social stigma, and criminalization, as well as limited access to some types of medication-based treatment (Hansen, 2017). For example, in a study of treatment providers in New York City, higher rates of buprenorphine prescription were found in areas with lower concentrations of African American and Latino residents, whereas areas with greater concentrations had higher methadone treatment rates (Hansen et al., 2013). A study of veterans with OUD using Veterans Health Administration treatment services in 2012 confirmed that treatment choices about methadone versus buprenorphine appear to be a function of demographic characteristics rather than of a person’s medical, psychiatric, or service-use characteristics—patients who were African American, older, and urban residents were much more likely to receive methadone rather than buprenorphine (Manhapra et al., 2016).

Evidence about OUD among Latino populations in the United States is very limited, and the evidence that is available is mixed. A study of patients receiving methadone maintenance treatment found that Latino patients were significantly more likely to have dropped out of treatment at 6 months (Proctor et al., 2015).

Little is known about the prevalence of OUD treatment among Asian Americans in the United States. However, some research has been carried out among the Hmong population—an ethnic group from Laos—living in Minnesota. Methadone treatment retention after 1 year of treatment was at almost 80 percent among Hmong patients, versus 64 percent among non-Hmong patients; on average, the Hmong patients also required a relatively lower dose of methadone to be stabilized (Bart et al., 2012). Another study of the same population found that Hmong individuals required lower doses of methadone and had significantly lower scores on the psychosocial measures than the non-Hmong participants (Bart, 2018). Native Hawaiians and Pacific Islanders are pooled with Asian Americans in some major data sets—despite being very distinct ethnic groups—so estimates about opioid use and OUD among those populations are particularly limited (Wu et al., 2013).

American Indian and Alaska Native populations are being severely affected by the opioid epidemic, but little evidence is available to understand trends in OUD and medication-based treatment in this group. Limited data indicate that this group has high overdose mortality rates, only slightly lower than whites (Venner et al., 2018). The estimated lifetime prevalence of OUD among Native Americans is very high (Saha et al., 2016). Research and guidance on how to adapt evidence-based programs to be culturally appropriate for these populations is needed (Novins et al., 2011; Venner et al., 2018).

Efforts to expand access to medication-based treatment would benefit greatly from having additional data on treatment for OUD across a diverse range of racial and ethnic groups (Wu et al., 2016). Geographic and demographic variations in medication-based treatment are unknown. The provision of services that are tailored to the unique needs of different ethnic groups is a key factor in effectively treating SUDs among minority populations (Center for Substance Abuse Treatment, 2006). It is important for treatment providers to appreciate how their patients’ cultures may inform their particular needs and response to treatment, but it is also important to avoid stereotyping or presuming that all members of a racial or ethnic group are the same (Center for Substance Abuse Treatment, 2006).

LOW SOCIOECONOMIC STATUS AND HOMELESS POPULATIONS

Low socioeconomic status has been associated with greater 12-month and lifetime prevalence rates of prescription OUD (Saha et al., 2016). People of low socioeconomic status with OUD are at a greater risk of becoming homeless (Chatterjee et al., 2018). Whether an individual with OUD is transient, recently displaced, or chronically homeless, it can negatively affect treatment outcomes (Center for Substance Abuse Treatment, 2006).

As many as three-quarters of individuals with SUD who are homeless do not receive any treatment (Magura et al., 2000). Understandably, people who are homeless often struggle to adhere to treatment and tend to drop out early (Lo et al., 2018). However, evidence suggests that office-based buprenorphine treatment can be effectively delivered to people who are homeless, with outcomes comparable to office-based buprenorphine treatment among people who are not homeless (Alford et al., 2007). Proactive case management may help to coordinate social services to provide homeless patients with food, shelter, and transportation to treatment (Center for Substance Abuse Treatment, 2006), as well as providing people who are homeless with overdose education and naloxone prescriptions (Pietrusza et al., 2018).

RURAL AND URBAN POPULATIONS

Research on OUD focused primarily on urban areas during the 1980s and 1990s. However, in the context of the growing opioid crisis, OUD is also epidemic in rural areas, where access to treatment medications is severely limited (Schranz et al., 2018). In fact, the misuse of prescription opioids is now more prevalent in rural than in urban areas (Keyes et al., 2014). More recently, rural communities have seen heroin and fentanyl become even more widely available than prescription opioids on the illicit market (Havens et al., 2018). Heavily rural states have also seen greater increases in opioid-related mortality and injury than non-rural areas (NRHA, 2017).

Factors driving the rural opioid crisis also differ from those driving opioid use in urban areas. Strong social and kinship network connections may facilitate diversion and distribution, while economic stressors may make people more vulnerable to drug use (Keyes et al., 2014). Moreover, compared with urban residents, people living in rural areas face a host of barriers to accessing treatment for OUD. These include provider and community stigma around OUD medications, a lack of public transportation and the need to travel long distances to access care, and severe shortages in the mental and behavioral health workforce (NRHA, 2017). Health care workforce shortages have left between 60 and 80 percent of rural counties without a single psychiatrist and around 40 percent of rural counties without any buprenorphine-waivered physicians (Corso and Townley, 2016; Larson et al., 2016; Leonardson and Gale, 2016; NRHA, 2017; Young et al., 2010). OTPs providing methadone are generally absent from rural areas, and only around 3 percent of primary care providers living in rural areas are waivered to prescribe buprenorphine (Havens et al., 2018). This shortage contributes to the lack of treatment capacity in rural areas (Zur et al., 2018). As a consequence of these bar-

riers, many of the available OUD services are of low quality and do not provide evidence-based treatment for OUD (Havens et al., 2018). Care for the infectious disease sequelae of opioid injection—HIV and HCV—is dependent on a specialized infrastructure that is typically not available in rural areas. These and other barriers to HIV and HCV treatment urgently warrant research (Schranz et al., 2018). One way to address the workforce shortage is to incentivize health care providers to provide OUD treatment in underserved areas (e.g., via loan repayment programs, such as the Health Resources and Services Administration’s National Health Service Corps). Another strategy might be to incorporate non-physician providers into rural care settings (NRHA, 2017).

REFERENCES

Chang, D. C., J. Klimas, E. Wood, and N. Fairbairn. 2018. Medication-assisted treatment for youth with opioid use disorder: Current dilemmas and remaining questions. American Journal of Drug and Alcohol Abuse 44(2):143–146.

Charney, D. A., A. M. Paraherakis, and K. J. Gill. 2001. Integrated treatment of comorbid depression and substance use disorders. Journal of Clinical Psychiatry 62(9):672–677.

Chatterjee, A., E. J. Yu, and L. Tishberg. 2018. Exploring opioid use disorder, its impact, and treatment among individuals experiencing homelessness as part of a family. Drug and Alcohol Dependence 188:161–168.

Cicero, T. J., G. Wong, Y. Tian, M. Lynskey, A. Todorov, and K. Isenberg. 2009. Co-morbidity and utilization of medical services by pain patients receiving opioid medications: Data from an insurance claims database. Pain 144(1–2):20–27.

Cicero, T. J., M. S. Ellis, H. L. Surratt, and S. P. Kurtz. 2014. The changing face of heroin use in the United States: A retrospective analysis of the past 50 years. JAMA Psychiatry 71(7):821–826.

Clay, S. W. 2010. Treatment of addiction in the elderly. Aging Health 6(2):177–189.

Committee on Substance Use and Prevention. 2016. Medication-assisted treatment of adolescents with opioid use disorders. Pediatrics 138(3):e20161893.

Connery, H. S. 2015. Medication-assisted treatment of opioid use disorder: Review of the evidence and future directions. Harvard Review of Psychiatry 23(2):63–75.

Corso, C., and C. Townley. 2016. Intervention, treatment, and prevention strategies to address opioid use disorders in rural areas. National Academy for State Health Policy. https://nashp.org/wp-content/uploads/2016/09/Rural-Opioid-Primer.pdf (accessed February 11, 2019).

Cunningham, C. O., A. Giovanniello, H. V. Kunins, R. J. Roose, A. D. Fox, and N. L. Sohler. 2013. Buprenorphine treatment outcomes among opioid-dependent cocaine users and non-users. American Journal on Addiction 22(4):352–357.

Daitch, D., J. Daitch, D. Novinson, M. Frey, C. Mitnick, and J. Pergolizzi. 2014. Conversion from high-dose full-opioid agonists to sublingual buprenorphine reduces pain scores and improves quality of life for chronic pain patients. Pain Medicine 15(12):2087–2094.

David, S., T. Lancaster, L. F. Stead, and A. E. Evins. 2006. Opioid antagonists for smoking cessation. Cochrane Database of Systematic Reviews 2006(4):CD003086.

Delorme, J., C. Chenaf, C. Bertin, M. Riquelme, A. Eschalier, D. Ardid, and N. Authier. 2018. Chronic pain opioid-maintained patients receive less analgesic opioid prescriptions. Frontiers in Psychiatry 9:335.

Dennis, B. B., M. Bawor, L. Naji, C. K. Chan, J. Varenbut, J. Paul, M. Varenbut, J. Daiter, C. Plater, G. Pare, D. C. Marsh, A. Worster, D. Desai, L. Thabane, and Z. Samaan. 2015. Impact of chronic pain on treatment prognosis for patients with opioid use disorder: A systematic review and meta-analysis. Substance Abuse: Research and Treatment 9:59–80.

Dhingra, L., C. Masson, D. C. Perlman, R. M. Seewald, J. Katz, C. McKnight, P. Homel, E. Wald, A. E. Jordan, C. Young, and R. K. Portenoy. 2012. Epidemiology of pain among outpatients in methadone maintenance treatment programs. Drug and Alcohol Dependence 128(1–2):161–165.

Doyle, H. H., and A. Z. Murphy. 2018. Sex-dependent influences of morphine and its metabolites on pain sensitivity in the rat. Physiology & Behavior 187:32–41.

Drake, R. E., and K. T. Mueser. 2000. Psychosocial approaches to dual diagnosis. Schizophrenia Bulletin 26(1):105–118.

Dreifuss, J. A., M. L. Griffin, K. Frost, G. M. Fitzmaurice, J. S. Potter, D. A. Fiellin, J. Selzer, M. Hatch-Maillette, S. C. Sonne, and R. D. Weiss. 2013. Patient characteristics associated with buprenorphine/naloxone treatment outcome for prescription opioid dependence: Results from a multisite study. Drug and Alcohol Dependence 131(1–2):112–118.

Duncan, D. T., S. Zweig, H. R. Hambrick, and J. J. Palamar. 2019. Sexual orientation disparities in prescription opioid misuse among U.S. adults. American Journal of Preventive Medicine 56(1):17–26.

Elliott, J. C., M. J. Picker, A. J. Sparrow, and D. T. Lysle. 2006. Dissociation between sex differences in the immunological, behavioral, and physiological effects of kappa- and delta-opioids in Fischer rats. Psychopharmacology (Berl) 185(1):66–75.

Evans, E., A. Kelleghan, L. Li, J. Min, D. Huang, D. Urada, Y. I. Hser, and B. Nosyk. 2015. Gender differences in mortality among treated opioid dependent patients. Drug and Alcohol Dependence 155:228–235.

Fanucchi, L., S. A. Springer, and P. T. Korthuis. 2019. Medications for treatment of opioid use disorder among persons living with HIV. Current HIV/AIDS Reports 2019:1–6.

FDA (U.S. Food and Drug Administration). 2017. Statement from FDA commissioner Scott Gottlieb, M.D., on the agency’s continued efforts to promote the sage adoption of medication-assisted treatment for opioid addiction. FDA News and Events, September 20. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm576752.htm (accessed February 11, 2019).

Feder, K. A., N. Krawczyk, and B. Saloner. 2017. Medication-assisted treatment for adolescents in specialty treatment for opioid use disorder. Journal of Adolescent Health 60(6):747–750.

Fiellin, D. A., L. Weiss, M. Botsko, J. E. Egan, F. L. Altice, L. B. Bazerman, A. Chaudhry, C. O. Cunningham, M. N. Gourevitch, P. J. Lum, L. E. Sullivan, R. S. Schottenfeld, P. G. O’Connor, and B. Collaborative. 2011. Drug treatment outcomes among HIV-infected opioid-dependent patients receiving buprenorphine/naloxone. Journal of Acquired Immune Deficiency Syndromes (1999) 56(Suppl 1):S33–S38.

Fillingim, R. B., C. D. King, M. C. Ribeiro-Dasilva, B. Rahim-Williams, and J. L. Riley. 2009. Sex, gender, and pain: A review of recent clinical and experimental findings. The Journal of Pain 10(5):447–485.

Flynn, P. M., S. G. Craddock, J. W. Luckey, R. L. Hubbard, and G. H. Dunteman. 1996. Co-morbidity of antisocial personality and mood disorders among psychoactive substance-dependent treatment clients. Journal of Personality Disorders 10(1):56–67.

Fox, A. D., N. L. Sohler, J. L. Starrels, Y. Ning, A. Giovanniello, and C. O. Cunningham. 2012. Pain is not associated with worse office-based buprenorphine treatment outcomes. Substance Abuse 33(4):361–365.

Frimpong, J. A., K. Shiu, T. D’Aunno, H. Pollack, and P. Friedmann. 2017. Gender differences in methadone dose patterns and length of treatment in outpatient methadone maintenance treatment programs. Drug and Alcohol Dependence 171:e66.

Gardner, E. M., M. P. McLees, J. F. Steiner, C. del Rio, and W. J. Burman. 2011. The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clinical Infectious Diseases 52(6):793–800.

Girouard, M. P., H. Goldhammer, and A. S. Keuroghlian. 2019. Understanding and treating opioid use disorders in lesbian, gay, bisexual, transgender, and queer populations. Substance Abuse 2019:1–5.

Gourevitch, M. N., and G. H. Friedland. 2000. Interactions between methadone and medications used to treat HIV infection: A review. Mount Sinai Journal of Medicine 67(5–6):429–436.

Gowing, L., M. F. Farrell, R. Bornemann, L. E. Sullivan, and R. Ali. 2011. Oral substitution treatment of injecting opioid users for prevention of HIV infection. Cochrane Database of Systematic Reviews 2011(8):CD004145.

Gowing, L., R. Ali, J. M. White, and D. Mbewe. 2017. Buprenorphine for managing opioid withdrawal. Cochrane Database of Systematic Reviews 2017(2):CD002025.

Grella, C. E., M. P. Karno, U. S. Warda, N. Niv, and A. A. Moore. 2009. Gender and comorbidity among individuals with opioid use disorders in the NESARC study. Addictive Behaviors 34(6–7):498–504.

Griffith, J. D., G. A. Rowan-Szal, R. R. Roark, and D. D. Simpson. 2000. Contingency management in outpatient methadone treatment: A meta-analysis. Drug and Alcohol Dependence 58(1–2):55–66.

Hadland, S. E., J. W. Frank Wharam, M. A. Schuster, F. Zhang, J. H. Samet, and M. R. Larochelle. 2017. Trends in receipt of buprenorphine and naltrexone for opioid use disorder among adolescents and young adults, 2001–2014. JAMA Pediatrics 171(8):747–755.

Hadland, S. E., S. M. Bagley, J. Rodean, M. Silverstein, S. Levy, M. R. Larochelle, J. H. Samet, and B. T. Zima. 2018a. Receipt of timely addiction treatment and association of early medication treatment with retention in care among youths with opioid use disorder. JAMA Pediatrics 172(11):1029–1037.

Hadland, S. E., T. W. Park, and S. M. Bagley. 2018b. Stigma associated with medication treatment for young adults with opioid use disorder: A case series. Addiction Science & Clinical Practice 13(1):15.

Haight, S. C., J. Y. Ko, V. T. Tong, M. K. Bohm, and W. M. Callaghan. 2018. Opioid use disorder documented at delivery hospitalization—United States, 1999–2014. Morbidity and Mortality Weekly Report 67(31):845–849.

Hall, M. T., J. Wilfong, R. A. Huebner, L. Posze, and T. Willauer. 2016. Medication-assisted treatment improves child permanency outcomes for opioid-using families in the child welfare system. Journal of Substance Abuse Treatment 71:63–67.

Hansen, H. 2017. Sociocultural factors impacting access to MAT and care delivery: New qualitative data from buprenorphine prescribers in OTPS. American Journal on Addictions 26(3):236.

Hansen, H. B., C. E. Siegel, B. G. Case, D. N. Bertollo, D. DiRocco, and M. Galanter. 2013. Variation in use of buprenorphine and methadone treatment by racial, ethnic, and income characteristics of residential social areas in New York City. Journal of Behavioral Health Services & Research 40(3):367–377.

Havens, J. R., S. L. Walsh, P. T. Korthuis, and D. A. Fiellin. 2018. Implementing treatment of opioid-use disorder in rural settings: A focus on HIV and hepatitis C prevention and treatment. Current HIV/AIDS Reports 15(4):315–323.

Hernandez-Avila, C. A., B. J. Rounsaville, and H. R. Kranzler. 2004. Opioid-, cannabis- and alcohol-dependent women show more rapid progression to substance abuse treatment. Drug and Alcohol Dependence 74(3):265–272.

Jones, E. S., and D. A. Fiellin. 2007. Women and opioid dependence treatment: Office-based versus opioid treatment program-based care? Substance Abuse 28(2):3–8.

Jones, H. E., K. Kaltenbach, S. H. Heil, S. M. Stine, M. G. Coyle, A. M. Arria, K. E. O’Grady, P. Selby, P. R. Martin, and G. Fischer. 2010. Neonatal abstinence syndrome after methadone or buprenorphine exposure. New England Journal of Medicine 363(24):2320–2331.

Kaltenbach, K., and L. P. Finnegan. 1984. Developmental outcome of children born to methadone maintained women: A review of longitudinal studies. Neurobehavioral Toxicology and Teratology 6(4):271–275.

Keyes, K. M., M. Cerda, J. E. Brady, J. R. Havens, and S. Galea. 2014. Understanding the rural-urban differences in nonmedical prescription opioid use and abuse in the United States. American Journal of Public Health 104(2):e52–e59.

Klaman, S. L., K. Isaacs, A. Leopold, J. Perpich, S. Hayashi, J. Vender, M. Campopiano, and H. E. Jones. 2017. Treating women who are pregnant and parenting for opioid use disorder and the concurrent care of their infants and children: Literature review to support national guidance. Journal of Addiction Medicine 11(3):178–190.

Klimas, J., E. Wood, E. Nosova, M. J. Milloy, T. Kerr, and K. Hayashi. 2018. Prevalence of heavy alcohol use among people receiving methadone following change to methadose. Substance Use and Misuse 53(2):270–275.

Knudsen, H. K., A. J. Abraham, and P. M. Roman. 2011. Adoption and implementation of medications in addiction treatment programs. Journal of Addiction Medicine 5(1):21–27.

Kosten, T. R., C. M. Morgan, J. Falcione, and R. S. Schottenfeld. 1992. Pharmacotherapy for cocaine-abusing methadone-maintained patients using amantadine or desipramine. Archives of General Psychiatry 49(11):894–898.

Kotelchuck, M., E. R. Cheng, C. Belanoff, H. J. Cabral, H. Babakhanlou-Chase, T. M. Derrington, H. Diop, S. R. Evans, and J. Bernstein. 2017. The prevalence and impact of substance use disorder and treatment on maternal obstetric experiences and birth outcomes among singleton deliveries in Massachusetts. Maternal and Child Health Journal 21(4):893–902.

Krawczyk, N., K. A. Feder, M. I. Fingerhood, and B. Saloner. 2017a. Racial and ethnic differences in opioid agonist treatment for opioid use disorder in a U.S. national sample. Drug and Alcohol Dependence 178:512–518.

Krawczyk, N., K. A. Feder, B. Saloner, R. M. Crum, M. Kealhofer, and R. Mojtabai. 2017b. The association of psychiatric comorbidity with treatment completion among clients admitted to substance use treatment programs in a U.S. national sample. Drug and Alcohol Dependence 175:157–163.

Larney, S., A. S. B. Bohnert, D. Ganoczy, M. A. Ilgen, M. Hickman, F. C. Blow, and L. Degenhardt. 2015. Mortality among older adults with opioid use disorders in the Veterans Health Administration, 2000–2011. Drug and Alcohol Dependence 147:32–37.

Larson, E., D. Patterson, L. Garberson, and C. Andrilla. 2016. Supply and distribution of the behavioral health workforce in rural America. Seattle, WA: Washington, Wyoming, Alaska, Montana, Idaho Rural Health Center, University of Washington.

Leonardson, J., and J. Gale. 2016. Distribution of substance abuse treatment facilities across the rural–urban continuum. Maine Rural Health Research Center working paper no. 35. https://muskie.usm.maine.edu/Publications/rural/wp35b.pdf (accessed February 11, 2019).

Levine, A. R., L. H. Lundahl, D. M. Ledgerwood, M. Lisieski, G. L. Rhodes, and M. K. Greenwald. 2015. Gender-specific predictors of retention and opioid abstinence during methadone maintenance treatment. Journal of Substance Abuse Treatment 54:37–43.

Litwin, A. H., K. A. Harris, S. Nahvi, P. J. Zamor, I. J. Soloway, P. L. Tenore, D. Kaswan, M. N. Gourevitch, and J. H. Arnsten. 2009. Successful treatment of chronic hepatitis C with peglyated interferon in combination with ribavirin in a methadone maintenance treatment program. Journal of Substance Abuse Treatment 37(1):32–40.

Litz, M., and D. Leslie. 2017. The impact of mental health comorbidities on adherence to buprenorphine: A claims based analysis. American Journal on Addictions 26(8):859–863.

Lo, A., T. Kerr, K. Hayashi, M. J. Milloy, E. Nosova, Y. Liu, and N. Fairbairn. 2018. Factors associated with methadone maintenance therapy discontinuation among people who inject drugs. Journal of Substance Abuse Treatment 94:41–46.

Low, A. J., G. Mburu, N. J. Welton, M. T. May, C. F. Davies, C. French, K. M. Turner, K. J. Looker, H. Christensen, S. McLean, T. Rhodes, L. Platt, M. Hickman, A. Guise, and P. Vickerman. 2016. Impact of opioid substitution therapy on antiretroviral therapy outcomes: A systematic review and meta-analysis. Clinical Infectious Diseases 63(8):1094–1104.

Loyd, D. R., and A. Z. Murphy. 2009. The role of the periaqueductal gray in the modulation of pain in males and females: Are the anatomy and physiology really that different? Neural Plasticity 2009:462879.

Lucas, G. M., A. Chaudry, J. Hsu, T. Woodson, B. Lau, Y. Olsen, J. C. Keruly, D. A. Fiellin, R. Finkelstein, P. Barditch-Crovo, K. Cook, and R. D. Moore. 2010. Clinic-based treatment of opioid-dependent HIV infected patients versus referral to an opioid treatment program: A randomized trial. Annals of Medicine 152(11):704–711.

Lugoboni, F., F. R. Levin, M. C. Pieri, M. Manfredini, L. Zamboni, L. Somaini, G. Gerra, and GICS. 2017. Co-occurring attention deficit hyperactivity disorder symptoms in adults affected by heroin dependence: Patients characteristics and treatment needs. Psychiatry Research 250:210–216.

Lund, I. O., G. Fischer, G. K. Welle-Strand, K. E. O’Grady, K. Debelak, W. R. Morrone, and H. E. Jones. 2013. A comparison of buprenorphine + naloxone to buprenorphine and methadone in the treatment of opioid dependence during pregnancy: Maternal and neonatal outcomes. Substance Abuse: Research and Treatment 7:61–74.

Magura, S., P. C. Nwakeze, A. Rosenblum, and H. Joseph. 2000. Substance misuse and related infectious diseases in a soup kitchen population. Substance Use and Misuse 35(4):551–583.

Manhapra, A., L. Quinones, and R. Rosenheck. 2016. Characteristics of veterans receiving buprenorphine vs. methadone for opioid use disorder nationally in the Veterans Health Administration. Drug and Alcohol Dependence 160:82–89.

Mannelli, P., L. T. Wu, K. S. Peindl, and D. A. Gorelick. 2013. Smoking and opioid detoxification: Behavioral changes and response to treatment. Nicotine and Tobacco Research 15(10):1705–1713.

Manubay, J., J. Davidson, S. Vosburg, J. Jones, S. Comer, and M. Sullivan. 2015. Sex differences among opioid-abusing chronic pain patients in a clinical trial. Journal of Addiction Medicine 9(1):46–52.

Marsch, L. A., M. A. C. Stephens, T. Mudric, E. C. Strain, G. E. Bigelow, and R. E. Johnson. 2005. Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence. Experimental and Clinical Psychopharmacology 13(4):293–302.

Marsh, J. C., T. A. D’Aunno, and B. D. Smith. 2000. Increasing access and providing social services to improve drug abuse treatment for women with children. Addiction 95(8):1237–1247.

Matson, S. C., G. Hobson, M. Abdel-Rasoul, and A. E. Bonny. 2014. A retrospective study of retention of opioid-dependent adolescents and young adults in an outpatient buprenorphine/naloxone clinic. Journal of Addiction Medicine 8(3):176–182.

Mazure, C. M., and D. A. Fiellin. 2018. Women and opioids: Something different is happening here. Lancet 392(10141):9–11.

Mbaba, M., S. E. Brown, A. Wooditch, M. Kiss, A. Murphy, S. Kumari, F. Taxman, F. Altice, W. B. Lawson, and S. A. Springer. 2018. Prevalence, diagnosis, and treatment rates of mood disorders among opioid users under criminal justice supervision. Substance Use & Misuse 53(9):1519–1528.

McCance-Katz, E. F., D. E. Moody, G. D. Morse, Q. Ma, R. DiFrancesco, G. Friedland, P. Pade, and P. M. Rainey. 2007. Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. Drug & Alcohol Dependence 91(2–3):269–278.

McHugh, R. K., E. E. DeVito, D. Dodd, K. M. Carroll, J. S. Potter, S. F. Greenfield, H. S. Connery, and R. D. Weiss. 2013. Gender differences in a clinical trial for prescription opioid dependence. Journal of Substance Abuse Treatment 45(1):38–43.

Messina, N., S. Calhoun, and J. Braithwaite. 2014. Trauma-informed treatment decreases posttraumatic stress disorder among women offenders. Journal of Trauma & Dissociation 15(1):6–23.

Metz, V. E., Q. L. Brown, S. S. Martins, and J. J. Palamar. 2018. Characteristics of drug use among pregnant women in the United States: Opioid and non-opioid illegal drug use. Drug and Alcohol Dependence 183:261–266.

Minozzi, S., L. Amato, C. Bellisario, M. Ferri, and M. Davoli. 2013. Maintenance agonist treatments for opiate-dependent pregnant women. Cochrane Database of Systematic Reviews 2013(12):CD006318.

Nahvi, S., O. Blackstock, N. L. Sohler, D. Thompson, and C. O. Cunningham. 2014a. Smoking cessation treatment among office-based buprenorphine treatment patients. Journal of Substance Abuse Treatment 47(2):175–179.

Nahvi, S. Y. Ning, K. S. Segal, K. P. Richter, and J. H. Arnsten. 2014b. Varenicline efficacy and safety among methadone maintained smokers: A randomized placebo-controlled trial. Addiction 109(9):1554–1563.

NASEM (National Academies of Sciences, Engineering, and Medicine). 2018. Integrating responses at the intersection of opioid use disorder and infectious disease epidemics: Proceedings of a workshop. Washington, DC: The National Academies Press.

Norton, B. L., A. Beitin, M. Glenn, J. DeLuca, A. H. Litwin, and C. O. Cunningham. 2017. Retention in buprenorphine treatment is associated with improved HCV care outcomes. Journal of Substance Abuse Treatment 75:38–42.

Novins, D. K., G. A. Aarons, S. G. Conti, D. Dahlke, R. Daw, A. Fickenscher, C. Fleming, C. Love, K. Masis, P. Spicer, and the Centers for American Indian and Alaska Native Health’s Substance Abuse Treatment Advisory Board. 2011. Use of the evidence base in substance abuse treatment programs for American Indians and Alaska Natives: Pursuing quality in the crucible of practice and policy. Implementation Science 6(1):63.

NRHA (National Rural Health Association). 2017. Policy brief: Treating the rural opioid epidemic. https://www.ruralhealthweb.org/NRHA/media/Emerge_NRHA/Advocacy/Policy%20documents/Treating-the-Rural-Opioid-Epidemic_Feb-2017_NRHA-Policy-Paper.pdf (accessed February 11, 2019).

Ouimette, P. C., R. Kimerling, J. Shaw, and R. H. Moos. 2000. Physical and sexual abuse among women and men with substance use disorders. Alcoholism Treatment Quarterly 18(3):7–17.

Pade, P. A., K. E. Cardon, R. M. Hoffman, and C. M. Geppert. 2012. Prescription opioid abuse, chronic pain, and primary care: A co-occurring disorders clinic in the chronic disease model. Journal of Substance Abuse Treatment 43(4):446–450.

Peckham, E. M., and J. R. Traynor. 2006. Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague–Dawley rats. Journal of Pharmacology and Experimental Therapeutics 316(3):1195–1201.

Perlman, D. C., and A. E. Jordan. 2018. The syndemic of opioid misuse, overdose, HCV, and HIV: Structural-level causes and interventions. Current HIV/AIDS Reports 15(2):96–112.

Pietrusza, L. M., K. R. Puskar, D. Ren, and A. M. Mitchell. 2018. Evaluation of an opiate overdose educational intervention and naloxone prescribing program in homeless adults who use opiates. Journal of Addictions Nursing 29(3):188–195.

Priester, M. A., T. Browne, A. Iachini, S. Clone, D. DeHart, and K. D. Seay. 2016. Treatment access barriers and disparities among individuals with co-occurring mental health and substance use disorders: An integrative literature review. Journal of Substance Abuse Treatment 61:47–59.

Proctor, S. L., A. L. Copeland, A. M. Kopak, N. G. Hoffmann, P. L. Herschman, and N. Polukhina. 2015. Predictors of patient retention in methadone maintenance treatment. Psychology of Addictive Behaviors 29(4):906–917.

Rich, K. M., J. Bia, F. L. Altice, and J. Feinberg. 2018. Integrated models of care for individuals with opioid use disorder: How do we prevent HIV and HCV? Current HIV/AIDS Reports 15(3):266–275.

Robertson, A. G., M. M. Easter, H. J. Lin, L. K. Frisman, J. W. Swanson, and M. S. Swartz. 2018. Associations between pharmacotherapy for opioid dependence and clinical and criminal justice outcomes among adults with co-occurring serious mental illness. Journal of Substance Abuse Treatment 86:17–25.

Rosenblum, A., H. Joseph, C. Fong, S. Kipnis, C. Cleland, and R. K. Portenoy. 2003. Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA 289(18):2370–2378.

Rosic, T., L. Naji, M. Bawor, B. B. Dennis, C. Plater, D. C. Marsh, L. Thabane, and Z. Samaan. 2017. The impact of comorbid psychiatric disorders on methadone maintenance treatment in opioid use disorder: A prospective cohort study. Neuropsychiatric Disease and Treatment 13:1399–1408.

Saha, T. D., B. T. Kerridge, R. B. Goldstein, S. P. Chou, H. Zhang, J. Jung, R. P. Pickering, W. J. Ruan, S. M. Smith, B. Huang, D. S. Hasin, and B. F. Grant. 2016. Nonmedical prescription opioid use and DSM-5 nonmedical prescription opioid use disorder in the United States. Journal of Clinical Psychiatry 77(6):772–780.

SAMHSA (Substance Abuse and Mental Health Services Administration). 2017. Opioid use in the older adult population. https://www.samhsa.gov/capt/sites/default/files/resources/resources-opiod-use-older-adult-pop.pdf (accessed February 9, 2019).

SAMHSA. 2018. Key substance use and mental health indicators in the United States: Results from the 2017 National Survey on Drug Use and Health. https://www.samhsa.gov/data/sites/default/files/cbhsq-reports/NSDUHFFR2017/NSDUHFFR2017.pdf (accessed December 12, 2018).

Santoro, G. C., J. Carrion, and S. L. Dewey. 2017a. Imaging sex differences in regional brain metabolism during acute opioid withdrawal. Journal of Alcoholism and Drug Dependence 5(2):pii:262.

Santoro, G. C., J. Carrion, K. Patel, C. Vilchez, J. Veith, J. D. Brodie, and S. L. Dewey. 2017b. Sex differences in regional brain glucose metabolism following opioid withdrawal and replacement. Neuropsychopharmacology 42(9):1841–1849.

Schiff, D. M., T. Nielsen, M. Terplan, M. Hood, D. Bernson, H. Diop, M. Bharel, T. E. Wilens, M. LaRochelle, A. Y. Walley, and T. Land. 2018. Fatal and nonfatal overdose among pregnant and postpartum women in Massachusetts. Obstetrics and Gynecology 132(2):466–474.

Schranz, A. J., J. Barrett, C. B. Hurt, C. Malvestutto, and W. C. Miller. 2018. Challenges facing a rural opioid epidemic: Treatment and prevention of HIV and hepatitis C. Current HIV/AIDS Reports 15(3):245–254.

Schuman-Olivier, Z., R. D. Weiss, B. B. Hoeppner, J. Borodovsky, and M. J. Albanese. 2014. Emerging adult age status predicts poor buprenorphine treatment retention. Journal of Substance Abuse Treatment 47(3):202–212.

Serdarevic, M., C. W. Striley, and L. B. Cottler. 2017. Sex differences in prescription opioid use. Current Opinion in Psychiatry 30(4):238–246.

Short, V. L., D. J. Hand, L. MacAfee, D. J. Abatemarco, and M. Terplan. 2018. Trends and disparities in receipt of pharmacotherapy among pregnant women in publically funded treatment programs for opioid use disorder in the United States. Journal of Substance Abuse Treatment 89:67–74.

Socias, M. E., N. Volkow, and E. Wood. 2016. Adopting the “Cascade of Care” framework: An opportunity to close the implementation gap in addiction care? Addiction 111(12):2079–2081.

Stimmel, B., and K. Adamsons. 1976. Narcotic dependency in pregnancy. Methadone maintenance compared to use of street drugs. JAMA 235(11):1121–1124.

Strain, E. C. 2002. Assessment and treatment of comorbid psychiatric disorders in opioid-dependent patients. Clinical Journal of Pain 18(4):S14–S27.

Sullivan, L. E., B. A. Moore, P. G. O’Connor, D. T. Barry, M. C. Chawarski, R. S. Schottenfeld, and D. A. Fiellin. 2010. The association between cocaine use and treatment outcomes in patients receiving office-based buprenorphine/naloxone for the treatment of opioid dependence. American Journal of Addiction 19(1):53–58.

Terplan, M., N. Longinaker, and L. Appel. 2015. Women-centered drug treatment services and need in the United States, 2002–2009. American Journal of Public Health 105(11):e50–e54.

Torchalla, I., I. A. Linden, V. Strehlau, E. K. Neilson, and M. Krausz. 2015. “Like a lots happened with my whole childhood”: Violence, trauma, and addiction in pregnant and postpartum women from Vancouver’s Downtown Eastside. Harm Reduction Journal 11:34.

Tsui, J. I., J. L. Evans, P. J. Lum, J. A. Hahn, and K. Page. 2014. Association of opioid agonist therapy with lower incidence of hepatitis C virus infection in young adult injection drug users. JAMA Internal Medicine 174(12):1974–1981.

Venner, K. L., D. M. Donovan, A. N. C. Campbell, D. C. Wendt, T. Rieckmann, S. M. Radin, S. L. Momper, and C. L. Rosa. 2018. Future directions for medication assisted treatment for opioid use disorder with American Indian/Alaska Natives. Addictive Behaviors 86:111–117.

Wang, P. W., H. C. Lin, Y. C. Yang, C. Y. Hsu, K. S. Chung, H. C. Wu, and C. F. Yen. 2017. Gender and age effects on the trajectory of depression in opioid users during methadone maintenance treatment. Frontiers in Psychiatry 8:288.

Watkins, K. E., A. Burnam, F. Y. Kung, and S. Paddock. 2001. A national survey of care for persons with co-occurring mental and substance use disorders. Psychiatric Services 52(8):1062–1068.

Weinberg, N. Z., E. Rahdert, J. D. Colliver, and M. D. Glantz. 1998. Adolescent substance abuse: A review of the past 10 years. Journal of the American Academy of Child and Adolescent Psychiatry 37(3):252–261.

Weinstein, Z. M., H. W. Kim, D. M. Cheng, E. Quinn, D. Hui, C. T. Labelle, M. L. Drainoni, S. S. Bachman, and J. H. Samet. 2017. Long-term retention in office-based opioid treatment with buprenorphine. Journal of Substance Abuse Treatment 74:65–70.

Whitesell, M., A. Bachand, J. Peel, and M. Brown. 2013. Familial, social, and individual factors contributing to risk for adolescent substance use. Journal of Addiction 2013:579310.

Williams, A. R., E. V. Nunes, and M. Olfson. 2017. To battle the opioid overdose epidemic, deploy the “Cascade of Care” model. Health Affairs blog. https://www.healthaffairs.org/do/10.1377/hblog20170313.059163/full (accessed February 11, 2019).

Williams, A. R., E. V. Nunes, A. Bisaga, H. A. Pincus, K. A. Johnson, A. N. Campbell, R. H. Remien, S. Crystal, P. D. Friedmann, F. R. Levin, and M. Olfson. 2018. Developing an opioid use disorder treatment cascade: A review of quality measures. Journal of Substance Abuse Treatment 91:57–68.

Woody, G. E., S. A. Poole, G. Subramaniam, K. Dugosh, M. Bogenschutz, P. Abbott, A. Patkar, M. Publicker, K. McCain, J. S. Potter, R. Forman, V. Vetter, L. McNicholas, J. Blaine, K. G. Lynch, and P. Fudala. 2008. Extended vs. short-term buprenorphine–naloxone for treatment of opioid-addicted youth: A randomized trial. JAMA 300(17):2003–2011. [Erratum appears in JAMA, February 25, 2009; 301(8):830.] [Erratum appears in JAMA, April 10, 2013; 309(14):1461.]

Woody, G. E., D. Bruce, P. T. Korthuis, S. Chhatre, S. Poole, M. Hillhouse, P. Jacobs, J. Sorensen, A. J. Saxon, D. Metzger, and W. Ling. 2014. HIV risk reduction with buprenorphine-naloxone or methadone: Findings from a randomized trial. Journal of Acquired Immune Deficiency Syndromes 66(3):288–293.

Worley, M. J., K. G. Heinzerling, S. Shoptaw, and W. Ling. 2017. Volatility and change in chronic pain severity predict outcomes of treatment for prescription opioid addiction. Addiction 112(7):1202–1209.

Wu, L.-T., D. G. Blazer, M. S. Swartz, B. Burchett, K. T. Brady, and N. A. Workgroup. 2013. Illicit and nonmedical drug use among Asian Americans, native Hawaiians/Pacific Islanders, and mixed-race individuals. Drug and Alcohol Dependence 133(2):360–367.

Wu, L.-T., H. Zhu, and M. S. Swartz. 2016. Treatment utilization among persons with opioid use disorder in the United States. Drug and Alcohol Dependence 169:117–127.

Yee, A., M. C. Hoong, Y. C. Joyce, and H. S. Loh. 2018. Smoking cessation among methadone-maintained patients: A meta-analysis. Substance Use & Misuse 53(2):276–285.

Young, A. M., J. R. Havens, and C. G. Leukefeld. 2010. Route of administration for illicit prescription opioids: A comparison of rural and urban drug users. Harm Reduction Journal 7:24.

Zilberman, M. L., H. Tavares, S. B. Blume, and N. el-Guebaly. 2003. Substance use disorders: Sex differences and psychiatric comorbidities. Canadian Journal of Psychiatry 48(1):5–13.

Zur, J., J. Tolbert, J. Sharac, and A. Markus. 2018. The role of community health centers in addressing the opioid epidemic. Kaiser Family Foundation. https://www.kff.org/medicaid/issue-brief/the-role-of-community-health-centers-in-addressing-the-opioid-epidemic (accessed February 11, 2019).

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