Opioids are drugs that slow down the actions of the body, such as breathing and heartbeat, by binding with certain receptors in the body. Some patients are prescribed opioids to treat pain. Opioid medications are available as immediate or extended release and in different forms, such as a pill, liquid, or a patch worn on the skin. Over time, the body becomes tolerant to them, which means that larger doses are needed to achieve the same effect. People may use opioids in a manner other than as prescribed—that is, they can be abused or misused. Because opioids are highly addictive substances, they can pose serious risks when they are abused or misused, which can lead to addiction and cause death. Symptoms of opioid addiction include a strong desire for opioids, inability to control or reduce use, and continued use despite interference with major obligations or social functioning, among others. Three medications are currently approved by the FDA for use in MAT for opioid addiction—methadone, buprenorphine, and naltrexone. Methadone: Methadone is a full opioid agonist, meaning it binds to and activates opioid receptors to help prevent withdrawal symptoms and reduce drug craving. It has a long history of use in treatment of opioid dependence in adults. It suppresses withdrawal symptoms in detoxification therapy, which involves stabilizing patients who are addicted by withdrawing them in a controlled manner. Methadone also controls the craving for opioids in maintenance therapy, which is ongoing therapy meant to prevent relapse and increase treatment retention. It can be administered to patients as an oral solution or in tablet form. Methadone also carries risk of abuse. Buprenorphine: Buprenorphine is a partial opioid agonist, meaning it binds to opioid receptors and activates them, but not as much as full opioid agonists. It reduces or eliminates opioid withdrawal symptoms, including drug cravings, and it may do so without producing the euphoria or dangerous side effects of heroin and other opioids. It can be used for detoxification treatment and maintenance therapy. It is available in tablet form or film for sublingual (under the tongue) administration both in a stand-alone formulation and in combination with another agent called naloxone, and as a subdermal (under the skin) implant. Buprenorphine also carries risk of abuse. Naltrexone: Naltrexone is an opioid antagonist, meaning it binds to opioid receptors but does not activate them. It is used for relapse prevention following complete detoxification from opioids. Naltrexone prevents opioid drugs from binding to and activating opioid receptors, thus blocking the euphoria the user would normally feel and causing severe withdrawal symptoms if recent opioid use has occurred. It can be taken orally in tablets or as a once-monthly injection given in a doctor’s office. Naltrexone carries no known risk of abuse. Two of the three medications used to treat opioid addiction—methadone and buprenorphine—are controlled substances and are governed at the federal level by the Controlled Substances Act (CSA). Enacted in 1970, the CSA and its implementing regulations establish a framework through which the federal government regulates the use of these substances for legitimate medical, scientific, research, and industrial purposes, while preventing them from being diverted for illegal purposes. The CSA assigns controlled substances—including narcotics, stimulants, depressants, hallucinogens, and anabolic steroids—to one of five schedules based on the substance’s medical use, potential for abuse, and risk of dependence. Schedule I contains substances that have no currently accepted medical use and may not be manufactured, distributed, or dispensed under federal law. In contrast, Schedules II, III, IV, and V include substances that have recognized medical uses and may be manufactured, distributed, and dispensed in accordance with the CSA. The order of the schedules reflects substances that are progressively less dangerous and addictive, as shown in table 1 below. When used for pain management, methadone and buprenorphine are regulated under federal laws and regulations that apply to controlled substances generally and do not impose requirements unique to methadone or buprenorphine. However, certain requirements—such as restrictions on prescriptions—vary based on the schedule in which a controlled substance is classified. Methadone, like oxycodone (i.e., OxyContin), is a Schedule II controlled substance, which has the highest potential for abuse among scheduled drugs with an accepted medical use. Buprenorphine is a Schedule III controlled substance, which has currently accepted medical uses and a lower potential for abuse. The CSA requires practitioners who dispense, administer, or prescribe methadone or buprenorphine and all other controlled substances in Schedules II-V to register with DEA. In order to be registered, an applicant must meet certain criteria, including being licensed or otherwise authorized to dispense, administer, or prescribe controlled substances under the laws of the state in which they practice. Practitioners must reapply for this registration every three years. The CSA also imposes certain requirements regarding the issuance of prescriptions for methadone and buprenorphine; these requirements vary depending on the controlled substance’s schedule. For example, when used for pain management, methadone and other Schedule II controlled substances may typically only be dispensed by pharmacists based on a written or electronic prescription. In contrast, buprenorphine and other Schedule III controlled substances may be dispensed based on a written, electronic, or oral prescription (i.e., a practitioner calls a pharmacist with the prescription). In addition, when used for pain management, prescriptions for Schedule II controlled substances may not be refilled, whereas prescriptions for Schedule III controlled substances may be refilled up to five times within six months after the date of the original prescription. All prescriptions for controlled substances—regardless of their schedule—must be issued for a legitimate medical purpose by a registered practitioner acting in the usual course of professional practice. However, certain CSA requirements do not apply when Schedule II-IV controlled substances such as methadone and buprenorphine are used for pain management. For example, the CSA’s inventory and recordkeeping requirement—which requires certain practitioners to maintain inventories of controlled substances and to make those inventories available for inspection for at least two years—generally does not apply when a practitioner prescribes or administers Schedule II-V controlled substances in the lawful course of professional practice for pain management purposes. When used for opioid addiction treatment, the CSA and implementing regulations issued by DEA and SAMHSA impose requirements in addition to those that generally apply when methadone and buprenorphine are used to treat pain. See table 2 for a comparison of these requirements. Prescriptions cannot be issued for methadone when used for opioid addiction treatment. Therefore, when used for that purpose, methadone may generally only be administered or dispensed within an OTP. Under the CSA, OTPs must be certified by SAMSHA and registered by DEA. To be eligible for full certification, an OTP must first be accredited by a SAMHSA-approved accrediting organization. Accreditation is a peer- review process in which an accrediting organization evaluates an OTP by making site visits and reviewing policies, procedures, and practices. Once accredited, SAMHSA may certify an OTP if it determines that the OTP conforms with federal regulations governing opioid treatment standards. Among other things, federal opioid treatment standards set forth patient admission criteria, recordkeeping guidelines, and required services, such as counseling. Once certified by SAMHSA, the OTP must apply for a separate registration from DEA—that is, a registration distinct from and in addition to the previously described DEA registration generally required of all practitioners who administer, dispense, or prescribe controlled substances. In order to register an OTP, DEA must determine that the OTP will comply with any applicable DEA requirements regarding the security of the stocks of controlled substances being used for treatment, as well as inventory and recordkeeping requirements. OTP registration from DEA must be renewed annually. With limited exceptions, OTPs must administer methadone while patients are at the OTP facility. Federal opioid treatment standards permit patients to receive a single take-home dose for a day when an OTP is closed, including weekends and federal holidays. The medical director of an OTP may also allow certain patients to take home a specific number of doses based on the duration of the treatment the patient has completed. OTPs are required to maintain current procedures adequate to identify the theft or diversion of take-home medications. Methadone could also be used outside of an OTP, such as in an emergency room, under an exception known as the “3-day rule,” which permits a practitioner who is not separately registered as an OTP to administer—but not prescribe— narcotic drugs to a patient to relieve acute withdrawal symptoms while arranging for the patient’s referral to treatment. Like methadone, buprenorphine can be administered or dispensed in an OTP when used for addiction treatment. In addition, qualifying practitioners who receive a Drug Addiction Treatment Act of 2000 (DATA 2000) waiver may dispense or prescribe buprenorphine for opioid addiction treatment to a limited number of patients in an outpatient setting, such as a doctor’s office. Until recently, only physicians were eligible to receive a DATA 2000 waiver. On July 22, 2016, the Comprehensive Addiction and Recovery Act of 2016 amended the CSA to also permit qualifying nurse practitioners and physicians’ assistants to receive a DATA 2000 waiver from the date of the act’s enactment until October 1, 2021. To qualify for a waiver, practitioners must be appropriately licensed under state law and have expertise as evidenced by certain certification, training, or experience. In addition, practitioners must have the capacity to refer patients for appropriate counseling and other services.