METHADONE

Methadone is a synthetic, long-lasting opioid agonist (Kreek, 2000). Methadone fully activates the mu-opioid receptors in the brain through the same mechanism of action as prescription or illicit opioids. In persons with OUD, methadone occupies those mu-opioid receptors and has the effect of lessening the painful “lows” of opioid withdrawal, and, at therapeutic doses, it attenuates the euphoric “highs” of shorter-acting opioids such as heroin, codeine, and oxycodone. Because it is an agonist treatment and individuals do not have to go through opioid withdrawal before initiating it, methadone can be started at any time during OUD treatment. However, it does require days to weeks to achieve a therapeutic dose, which needs to be individualized to decrease cravings and prevent return to other opioid use (NIH, 1998).

By law in the United States, outpatient methadone treatment can only be administered to people enrolled in state- and federally certified opioid treatment programs (OTPs), historically called methadone clinics (CRS, 2018). Methadone can also be provided when patients are admitted to a hospital for treatment of other conditions or in emergencies.² Most patients are required to visit an OTP in person every day to receive their daily dose. Eventually, stable patients may receive take-home doses if they meet certain criteria, such as having had a stable period of good functioning without illicit drug use. In addition, patients on methadone are required to attend regular counseling sessions with clinic providers.

As an agonist, methadone sustains the opioid tolerance and physical dependence of the patient, so missing doses can cause opioid withdrawal. The major risk to patients on methadone—opioid overdose death—is elevated within the first 2 weeks of methadone treatment (Degenhardt et al., 2009), after which the risk of overdose death is significantly lower than for people with OUD who are not in treatment (Degenhardt et al., 2011; Sordo et al., 2017). The risk of overdose is higher among patients who are also taking other sedatives, but FDA has advised that “methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system” because overdose risk is even higher for people who are not on medication for OUD (FDA, 2017). This is also true of buprenorphine (see below). The other potential harms of methadone include hypogonadism (low testosterone), which is a common side effect of chronic use of any opioid (Bawor et al., 2015), and an increase in the electrocardiographic corrected QT interval, although the clinical significance of the latter is unclear (Bart et al., 2017). No special training is required for physicians working within an OTP to prescribe methadone.

BUPRENORPHINE

Buprenorphine is a high-affinity partial opioid agonist as well as an antagonist of the kappa-opioid receptor and an agonist of the opioid like-1 receptor (Kleber, 2007). As a partial agonist, buprenorphine does not fully substitute for other opioids on the mu receptor (e.g., heroin, codeine, and oxycodone). Like methadone, buprenorphine can bring relief to a patient in opioid withdrawal. Through its partial agonist effect, it can also reduce the rewarding effect if the patient uses opioids while taking buprenorphine. Because it is a partial agonist, buprenorphine also has less of an effect on respiratory depression, so it has a lower risk of overdose than methadone and other opioids (Dahan et al., 2006), and a therapeutic dose may be achieved within a few days (Connery, 2015).

The most widely available forms of buprenorphine in the United States are tablets or films that are absorbed under the tongue (see Box 2-1). In these formulations, buprenorphine is combined with the opioid antagonist naloxone to discourage injection, because naloxone is not well absorbed sublingually but will rapidly reduce the rewarding effect if the product is injected. Buprenorphine is also available in implantable and extended-release subcutaneous formulations, which are more difficult to divert³ and theoretically increase adherence to treatment.

In the United States, buprenorphine can also be provided at an OTP, but it is most commonly prescribed in an office-based setting (e.g., a primary care clinic) to patients who fill the prescription at regular pharmacies. Patients can then administer buprenorphine sublingually to themselves, as with most other medications for chronic disease. Patients are often seen by providers frequently at first, but as the treatment progresses patients who do not use other opioids are usually able to reduce the frequency of the required office visits (Fiellin et al., 2006). In order to treat OUD with buprenorphine, prescribers in the United States must undergo additional training and obtain a waiver from the Drug Enforcement Administration. Only a limited number of providers pursue these waivers. In fact, until recently only 2 to 3 percent of physicians in the United States were waivered to provide buprenorphine, most of whom are based in urban areas (Rosenblatt et al., 2015). Many physicians who are waivered do not prescribe to their maximum patient limit (Jones et al., 2015). In 2016 nurse practitioners and physician assistants became eligible to apply for training to obtain waivers.⁴ Chapter 5 includes a more detailed discussion on this issue.

As with methadone, buprenorphine sustains opioid tolerance and physical dependence in patients, so discontinuation can lead to withdrawal—although buprenorphine's withdrawal syndrome may be less severe. The most prominent risk of buprenorphine to patients with OUD is precipitation of non-life-threatening opioid withdrawal at first dose. The risk of opioid overdose death declines immediately when patients with OUD initiate buprenorphine treatment (Sordo et al., 2017). Hypogonadotropic effects are less with buprenorphine than with methadone and buprenorphine is not associated with QTc prolongation or cardiac arrhythmias (Fareed et al., 2013).

It is important to note that since methadone and buprenorphine are opioids, they can be misused. As with other opioids, buprenorphine and methadone can result in physical dependence and a diagnosable OUD, which demands that these medications be safely stored and not be taken by anyone other than the individual for whom they are prescribed.

EXTENDED-RELEASE NALTREXONE

Naltrexone is not an opioid but rather is a full antagonist of the mu-opioid receptor and completely blocks the euphoric and analgesic effects of all opioids (Kleber, 2007). Naltrexone does not cause physical dependence, nor does it produce any of the rewarding effects of opioids. It is not uncommon for patients to try to use opioids while on extended-release naltrexone, but it is exceedingly rare that using an opioid can override the effect of naltrexone to the extent that the opioid yields rewarding effects. Ideally, patients on extended-release naltrexone learn quickly not to use the opioids that caused their addictive behaviors, and, after sustained use of the medication, their cravings decline (Krupitsky et al., 2011; Lee et al., 2018; Tanum et al., 2017).

Treatment initiation with extended-release naltrexone is complicated by its mechanism and long duration of action. Because naltrexone can trigger severe withdrawal symptoms, naltrexone treatment initiation typically requires medically supervised withdrawal followed by at least 4 to 7 days without any opioids, including opioids used in medication-based treatment like methadone and buprenorphine (Sullivan et al., 2017). This remains a key barrier to naltrexone use, although shorter outpatient initiation protocols have shown some promise (Sullivan et al., 2017). Risk of overdose for patients being treated with extended-release naltrexone may be reduced compared to treatment with a placebo, non-medication-based treatments, and treatment with oral naltrexone (Kelty and Hulse, 2017; Lee et al., 2016). Emerging evidence suggests that patients can experience an increased risk of overdose when they approach the end of the 28-day period of the extended-release formulation (Binswanger and Glanz, 2018).

Naltrexone is currently available both in a once-daily oral formulation and in a once-monthly, extended-release depot injection. The oral formulation was found to be no better than a placebo in retaining patients in treatment or eliminating their opioid use (Minozzi et al., 2011) and patients treated with oral naltrexone have an increased risk of overdose compared to methadone (Degenhardt et al., 2015). Thus, only the extended-release formulation has been approved for OUD by FDA. No special training is required for medical providers to prescribe naltrexone.

Naltrexone may be most appropriate for patients who need to avoid opioid agonists of any kind (including methadone and buprenorphine); patients who have not returned to use in 2 or more weeks but are at heightened risk of relapse; and patients who use opioids sporadically or at low levels. Naltrexone, unlike other OUD therapies, is not appropriate for the treatment of severe, acute pain—like that caused by a fractured bone or necessary surgery—because the medication completely blocks the effects of opioids. Depression is a relatively rare adverse effect of naltrexone and not a contraindication to its use (Dean et al., 2006).

NALOXONE

The opioid antagonist naloxone is not a medication for OUD per se, but it has been approved by FDA to diagnose or treat the respiratory depressive symptoms of opioid use that can cause fatal opioid overdose. Naloxone is safe and effective, and it is the standard medication administered to reverse opioid overdose. The broader provision of naloxone has been shown to prevent opioid overdose morbidity and mortality (Bird et al., 2016; Coffin et al., 2016). In every state and the District of Columbia, naloxone can be obtained from a pharmacy without having to see a prescriber (Davis and Carr, 2017; Green et al., 2015; NASPA, 2019), and it is available from many community-based organizations and health departments for low or no cost (Wheeler et al., 2015). Notably, guidance from the U.S. Department of Health and Human Services⁵ urges that all patients receiving medications for OUD be co-prescribed naloxone (HHS, 2018).

EVIDENCE ON THE EFFECTIVENESS OF FDA-APPROVED MEDICATIONS IN TREATING OUD

A wealth of evidence about medications to treat OUD has been amassed over the past half century from clinical studies, randomized controlled trials, systematic reviews, and meta-analyses. The verdict is clear: effective agonist medication used for an indefinite period of time is the safest option for treating OUD. According to a recent review of medications to treat OUD, “the evidence for efficacy both in reducing opioid use and retaining patients in care is strongest for agonist treatment” (Connery, 2015, p. 64).

People with OUD are less likely to die when they are in long-term treatment with methadone or buprenorphine than when they are untreated. Treatment using agonist medication is associated with an estimated mortality reduction of approximately 50 percent among people with OUD (Degenhardt et al., 2014; Larochelle et al., 2017; Ma et al., 2018; Pierce et al., 2016; Sordo et al., 2017). Both methadone and buprenorphine treatment retention have been linked to substantially decreased risks of both all-cause and overdose-related mortality among people with OUD (Sordo et al., 2017). Increased access to treatment using agonist medication is associated with reduced opioid overdose deaths (Schwartz et al., 2013). Studies of extended-release naltrexone have not had sufficient power or duration of follow-up to detect a mortality benefit (Jarvis et al., 2018).

Treatment with methadone or buprenorphine is also associated with lower rates of other opioid use (Kakko et al., 2003; Mattick et al., 2009, 2014; Thomas et al., 2014), improved social functioning (Bart, 2012), decreased injection drug use (Woody et al., 2014), reduced HIV transmission risk behaviors (Gowing et al., 2011), reduced risk of HIV diagnosis (MacArthur et al., 2012), reduced risk of hepatitis C virus (HCV) infection (Peles et al., 2011), and better quality of life compared to individuals with OUD not in treatment (Ponizovsky and Grinshpoon, 2007). Methadone is also associated with reduced levels of criminality for individuals with OUD (Bukten et al., 2012; Gearing, 1974; Schwartz et al., 2009, 2011; Sun et al., 2015). Limited evidence suggests that, compared with a placebo, extended-release naltrexone may be associated with reduced opioid use, but more rigorous studies are needed (Jarvis et al., 2018).

Compared with a placebo, both buprenorphine alone and buprenorphine in combination with naloxone administered in office-based treatment settings significantly reduce opioid use and opioid cravings (Fudala et al., 2003). In women who are pregnant, buprenorphine treatment has been linked to improved maternal and fetal outcomes; infants also tend to have less severe symptoms of neonatal abstinence syndrome when their mothers were treated with buprenorphine during pregnancy (Thomas et al., 2014).

KNOWLEDGE GAPS AND FUTURE DIRECTIONS FOR RESEARCH ON MEDICATIONS FOR OUD

In spite of the extensive evidence supporting the use of medications to treat OUD, there remain major gaps in knowledge about which medication works best and for whom as well as how the medications compare over the long term. Additionally, as with all medical disorders, there is a need to expand the OUD treatment toolkit to help individuals who do not respond well to the current options.

BEHAVIORAL THERAPY IN CONJUNCTION WITH MEDICATIONS

Behavioral interventions are often used in conjunction with medications in treating OUD, for two primary reasons. The first is to target a broad range of problems and issues not addressed by the medications themselves (e.g., comorbid psychiatric symptoms, concurrent use of other drugs, the need for social support, HIV risk behaviors, behavioral changes, motivation). The second is to address limitations associated with each form of medication (e.g., high attrition rates). See Box 2-2 for a description of different types of behavioral interventions that have been used with medication-based treatment for OUD. However, the evidence about the efficacy of different behavioral interventions used to complement each of the FDA-approved medications is limited to date, and the evidence that has been reported is mixed. Interpreting the outcomes is complicated by differences in the outcomes targeted in most studies—that is, retention in treatment and reducing opioid use versus addressing comorbid problems such as other drug use, psychosocial functioning, and HIV risk behaviors.

BOX 2-2

Types of Behavioral Interventions.

It is generally accepted that the best outcomes are typically achieved through a combination of pharmacological and behavioral therapies (NIDA, 2018), but there is evidence that some individuals may respond adequately to medications plus medical management alone (e.g., evaluation of medication safety and adherence, monitoring, or advice by the prescribing provider) (Gruber et al., 2008; McLellan et al., 1993; Schwartz et al., 2007, 2012; Weiss et al., 2011; Yancovitz et al., 1991). Given the resource limitations and the lack of empirical evidence about specific behavioral interventions to improve outcomes from medications for OUD, some have argued that clinicians should not be dissuaded from initiating medications for OUD simply because evidence-based behavioral therapies are not available (beyond medical management with monitoring) (Schwartz, 2016). At the same time, while medications to treat OUD prevent death and stabilize patients so that their comorbid psychiatric, medical, and social problems can be identified and addressed, these medications alone do not address the many complex problems that many individuals with OUD may have. Therefore, it is critical to take individual differences into account and select a treatment plan that is best suited to each patient's needs (Carroll and Onken, 2005). Provision of behavioral interventions can and often do occur in the medical management encounter with the prescriber.

KNOWLEDGE GAPS AND ADDITIONAL RESEARCH NEEDED ON THE ROLE OF BEHAVIORAL INTERVENTIONS WITH MEDICATIONS IN TREATMENT FOR OUD

Apart from contingency management, it is difficult to say which behavioral intervention will be most effective with a given medication or a given outcome in a given patient. Relatively few studies have investigated the comparative or differential effectiveness of different types of behavioral interventions in treating OUD at different points in the continuum of care, among different populations, or in different treatment settings (Dugosh et al., 2016). Given the mortality benefit of the medications, more research into behavioral interventions that result in improved treatment adherence is critical; behavioral techniques also have promising potential to assist patients in achieving good long-term functional outcomes. Investigating behavioral techniques to facilitate improvements in psychiatric, legal, interpersonal, and occupational functioning may support sustained remission (Carroll and Weiss, 2017). Other techniques may reduce HIV and HCV risk behaviors, regardless of other treatment outcomes (Edelman et al., 2014; Meade et al., 2010).

Another knowledge gap in OUD behavioral treatment innovations pertains to the provision of peer support to enhance treatment. Peer support is “the process of giving and receiving nonprofessional, nonclinical assistance from individuals with similar conditions or circumstances to achieve long-term recovery from psychiatric, alcohol, and/or other drug-related problems” (Tracy and Wallace, 2016, p. 143). Peer-based recovery support has a long history in addiction treatment and was advocated for by Dole and Nyswander, who developed the methadone maintenance treatment model for OUD (White, 2009). Peer support groups to supplement treatment for addiction have promising potential to increase treatment engagement and to reduce substance use and risk behaviors for infectious disease transmission, but more rigorous studies are needed (Tracy and Wallace, 2016). Peer providers with lived experience related to addiction may be able to contribute positively to other people's OUD treatments and to help address the vast workforce shortages in behavioral health. However, the inclusion of peer providers gives rise to important concerns about their training, certification, methodological consistency across programs, opportunities for career advancement, and fair compensation. Despite the high degree of public investment in these programs nationally, there are no data from well-controlled trials evaluating peer support. More research is needed to explore how peer providers may be able to support OUD treatment and to establish the effect size of such interventions (Chapman et al., 2018; Reif et al., 2014).

Box

Conclusion 2: U.S. Food and Drug Administration–approved medications to treat opioid use disorder are effective and save lives.

Box

Conclusion 3: Long-term retention on medication for opioid use disorder is associated with improved outcomes.

Box

Conclusion 4: Lack of availability or utilization of behavioral interventions is not a sufficient justification to withhold medications to treat opioid use disorder.

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