Section Editor Andrew J Saxon, MD

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1 Official reprint from UpToDate UpToDate Pharmacotherapy for opioid use disorder Author Eric Strain, MD Section Editor Andrew J Saxon, MD Deputy Editor Richard Hermann, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jul This topic last updated: May 04, INTRODUCTION Opioids, used medically for pain relief, have analgesic and central nervous system depressant effects, as well as the potential to cause euphoria. Opioid use disorder can involve prescribed or nonprescribed use of pharmaceutical opioids or use of illicitly obtained heroin. Opioid use disorder is typically a chronic, relapsing illness, associated with significantly increased rates of morbidity and mortality. In patients with opioid use disorder who have achieved abstinence through medically supervised withdrawal or other means, there are medication and non medication options for long term maintenance treatment. Medication treatment is often much more effective in opioid use disorder compared with abstinence based therapy, a nonmedication treatment [1,2]. Maintenance treatment for opioid use disorder is reviewed here. The related topics, below, are discussed separately: (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis".) (See "Medically supervised opioid withdrawal during treatment for addiction".) (See "Management of acute pain in the patient chronically using opioids".) (See "Prescription drug misuse: Epidemiology, prevention, identification, and management".) (See "Addiction in the impaired physician: Epidemiology, clinical manifestations, identification, and engagement".) (See "Addiction in the impaired physician: Assessment and treatment".) OVERVIEW Patients with opioid use disorder who achieve abstinence through medically supervised opioid withdrawal or other means often require long term treatment to prevent relapse. Long term treatment can take several forms: Opioid agonist treatment Methadone, buprenorphine (or, in selected countries, heroin administered in a controlled setting). (See 'Opioid agonists' below.) Opioid antagonist treatment Naltrexone. (See 'Opioid antagonists' below.) Psychosocial treatment Psychosocial interventions are often used in conjunction with medication. Abstinence based therapy is a non medication treatment that can consist of a number of different types of psychosocial services. Clinician education and training The SAMHSA funded Providers Clinical Support System for Medication Assisted Treatment (PCSS MAT) in the US provides training and educational materials for physicians prescribing buprenorphine for opioid use disorder. PCSS MAT also advises clinicians on the use of methadone, buprenorphine, and naltrexone. PCSS MAT provides clinicians with access to a nationwide network of mentors for prescribing clinicians who are unfamiliar with the treatment of OUDs. Opioid use disorder in DSM 5 Most clinical trials on the efficacy of treatments for opioid use disorders

2 studied patients with a DSM IV diagnosis of opioid dependence. Applying these findings to patients diagnosed under DSM 5 is imprecise, but the most closely comparable group of patients is those with opioid use disorder, moderate to severe subtype (ie, patients with four or more diagnostic criteria within a 12 month period). DSM 5 criteria for the diagnosis of opioid use disorder are described separately. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis", section on 'Diagnosis'.) OPIOID AGONISTS Opioid agonists suppress craving and withdrawal symptoms, and block the acute effects of other opioids. Treatment with an opioid agonist at an appropriate dose allows patients to return to a productive lifestyle, engage in pro social behaviors, and address the problems (eg, impaired family relationships) that often develop over time as a part of opioid use. Patients stabilized on an appropriate dose can safely operate machinery and drive without significant impairment [3]. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis", section on 'Clinical manifestations'.) Although patients treated with methadone or buprenorphine are physically dependent upon the medications, they do not typically have the pattern and severity of problematic behaviors associated with addiction to heroin or pharmaceutical opioids [4,5]. Methadone Methadone, a long acting opioid agonist, binds to and occupies mu opioid receptors, preventing withdrawal symptoms for 24 hours or longer, reduces craving for opioids, and, by maintaining high levels of opioid tolerance, reduces the euphoric effects of subsequent illicit opioid use. As a controlled substance with potential for abuse, methadone use is regulated in the US and other countries. (See 'Regulation' below.) Efficacy A meta analysis of 1969 participants in 11 randomized trials compared methadone maintenance therapy to placebo or non medication treatment for DSM IV opioid dependence [6]. Patients receiving methadone were more likely to remain in treatment and to reduce opioid use compared to placebo or nonmedication treatment. As an example, a trial conducted more than 20 years ago randomly assigned 247 participants with opioid dependence to 20 weeks of methadone treatment, the latter 15 weeks of which at stable doses of 50 mg or 20 mg/day of methadone, or placebo [7]. All three groups additionally received individual counseling and group therapy. By treatment week 20, retention was 52.4 percent for the 50 mg group, 41.5 percent for the 20 mg group, and 21 percent for the placebo group. The 50 mg treatment group had a reduced rate of opioid positive urine samples compared to the 0 mg group (56.4 versus 73.6 percent), while the 20 mg group showed no difference compared to the placebo group. The 20 mg/day dose used in this study is no longer considered to be adequate for most patients based on current knowledge. One fifth of patients receiving placebo remained in treatment at 20 weeks, illustrating how the non pharmacological aspects of methadone treatment can have compelling value to some patients. (See 'Administration' below.) Methadone maintenance treatment can have beneficial effects beyond the use of opioids; methadone treatment has been associated with reductions in the spread of human immunodeficiency virus [8 10], and in some studies, with reduced criminal behavior [6,11]. Methadone treatment may reduce mortality from opioid use disorder. A 10 year follow up study of 405 patients randomly assigned to receive either methadone or buprenorphine found an association between the duration of treatment with either medication and lower rates of mortality [12]. Adverse effects Side effects of chronic methadone therapy include constipation, mild drowsiness, excess sweating, and peripheral edema [13,14]. Reduced libido and erectile dysfunction are common among heroin users and those in treatment for opioid use disorder. Methadone use is believed to contribute to erectile dysfunction, possibly through reduction in serum testosterone levels; however, psychological and social factors are also associated with erectile dysfunction [15,16]. These other factors should be considered before attributing erectile dysfunction solely to methadone treatment.

3 Cardiac arrhythmias Some [17 19], but not all [20], studies have noted a significant but weak relationship between the methadone dose and the degree of QTc prolongation at doses of up to 300 mg/day. Methadone use, in both therapeutic doses and overdoses, has been associated with QTc interval prolongation and torsades de pointes, which in some cases has been fatal [21]. Many patients who develop torsades de pointes while taking methadone have other risk factors for this arrhythmia. Drug induced QTc prolongation is discussed in detail separately. (See "Acquired long QT syndrome".) Concern regarding the proarrhythmic potential of methadone prompted a physician safety alert from the US Food and Drug Administration (FDA). While the risk of QTc prolongation in methadone treated patients is controversial, we favor the following steps: Inform patients of the potential risk of arrhythmia when they are prescribed methadone Ask patients about a history of structural heart disease, arrhythmia, or syncope Assess the patient for other risk factors for QTc prolongation There is no compelling research evidence to base a decision on whether to obtain an ECG prior to the start of methadone treatment [22,23]. On the basis of our clinical experience, an ECG is suggested in patients with cardiac risk factors, including a history of structural heart disease, arrhythmia, a family history of prolonged QTc, the patient having a history of a prolonged QTc, the patient being treated with other medications that can prolong the QTc, or syncope. Follow up ECGs in such cases should be obtained within 30 days of starting methadone and annually. Some patients have a sufficiently high risk of mortality or serious morbidity due to the opioid use disorder that the benefits of methadone outweigh the risks indicated by a prolonged QTC interval [22 25]. Potential risks and benefits of methadone therapy should be discussed with the patient for QTc interval >450 msec but <500 msec, and the ECG should monitored. For QTc interval >500 msec, consideration should be made for discontinuing or reducing the methadone dose; contributing factors (eg hypokalemia, other drugs) also should be eliminated and alternative therapy considered. Clinicians should be aware of interactions between methadone and other drugs that prolong the QTc interval, or that can slow methadone elimination (table 1 and table 2). (See "Acquired long QT syndrome".) Some research suggests that substitution of (R,S) methadone with (R) methadone reduces the methadoneinduced prolonged QTc interval among opioid dependent patients [26]. Further work is needed to confirm this finding. Hyperalgesia Chronic use of methadone and other opioid agonists may result in an increased sensitivity to pain, which may develop within a month of initiating chronic opioid therapy [27 29]. A study of patients in methadone treatment programs found chronic severe pain was reported by 37 percent of the patients, and 65 percent of those with pain experienced a significant impact on physical and psychosocial functioning [29]. Patients in methadone treatment may have a history of physical trauma resulting in chronic pain, but may also have increased sensitivity to pain related to chronic opioid use [30]. (See "Management of acute pain in the patient chronically using opioids", section on 'Patients receiving opioid maintenance therapy for addiction'.) Overdose Methadone has a greater potential for lethal overdose compared to buprenorphine. (See 'Buprenorphine versus methadone' below.) Patients are at increased risk of overdose at specific stages of treatment for opioid dependence: Death during induction into methadone maintenance treatment has been reported in a series of cases from New South Wales Australia in 1994 and 1996 [31,32]. The overall mortality rate during methadone maintenance induction was 7.1 deaths per 10,000 inductions [32]. Benzodiazepines were significantly more likely to contribute to death both in methadone maintenance patients and in patients taking methadone for chronic pain [33].

4 Patients who complete medically supervised withdrawal from opioids are at risk of serious overdose consequences should they resume their former drug use. One small study found that individuals who had completely withdrawn from opioids were at increased risk of death from a drug overdose over the next year compared to those who did not complete withdrawal [34]. Data from the US and other countries have shown a rising rate of methadone related deaths over the past two decades [35,36]. The increase in methadone related deaths has been related to increased availability of methadone tablets used for treatment of pain [37]. Methadone maintenance treatment of opioid use disorder is associated with reduced overall mortality rates [38], with a 70 percent reduction in the risk of mortality (especially due to heroin overdose) comparing patients on methadone maintenance to untreated heroin abusers [39]. A longitudinal, observational study found a reduction in mortality of 40 percent in patients on methadone maintenance compared to predicted mortality risk prior to methadone maintenance [40]. The reduced mortality was due to reductions in both all cause mortality and overdose death; most overdoses were due to polysubstance intoxication in which illicit opioid use may or may not have been involved. Drug interactions Methadone has a number of drug interactions based on metabolism by the Cytochrome P450 isoenzyme system, specifically 3A4 (table 1). This can affect the daily methadone maintenance dose when the patient starts or stops medications that induce or inhibit this isoenzyme and affect serum methadone levels. This may result in opioid withdrawal or intoxication. Clinicians should be aware that drug drug interactions may occur with several common mediations (antibiotics, antidepressants, antiretrovirals). This may require the client s daily methadone dose to be adjusted to prevent complications from such drug drug interactions. Regulation Methadone is regulated in many countries including the US, where it is classified as a Schedule II drug. Many of the regulations on methadone s use are aimed at preventing diversion of medication and reducing the risk of overdose. Only licensed opioid treatment programs or licensed inpatient hospital units in the US are permitted to order and dispense methadone for withdrawal or long term treatment of an opioid use disorder [41]. Exceptions to this restriction include: Patients already receiving methadone from a licensed program may continue to receive the medication during inpatient hospitalization, to treat opioid use disorder or other conditions, such as pain. Any physician or other licensed prescriber may use methadone to treat a patient with acute opioid withdrawal for up to three days, provided they follow federal regulations (21 CRF (b)). The intent is to relieve suffering and prevent withdrawal that would complicate the primary medical or surgical condition. While methadone may be administered to a patient during the 72 hour period, it may not be dispensed or prescribed for unsupervised use. Licensed US outpatient treatment programs are required to provide counseling and social services in addition to methadone. Patients are required to attend individual counseling as clinically indicated. To be eligible for methadone maintenance in the US, a prospective patient must have: Documentation of the presence of an opioid use disorder for at least one year of continuous use. Exceptions to this criterion include: Patients who have been on methadone maintenance within the past two years do not need to demonstrate current physical dependence or a current opioid use disorder if the program clinician documents a likelihood of an imminent relapse to opioid use. Patients recently released from incarceration or hospitalization do not need to show current physiologic dependence or opioid use disorder but are required to have a history of an opioid use disorder and have a clinician document a likelihood of relapse to opioid use and physiologic dependence.

5 Pregnant women are eligible for methadone maintenance even if an opioid use disorder has been present for less than one year. An age of 18 years or older. Younger individuals are eligible for treatment with the consent of a parent, guardian, or designated responsible adult if they have current opioid physical dependence and have at least two previous attempts at detoxification or psychosocial substance abuse treatment. In addition to federal regulations, many US states have imposed additional restrictions on methadone for use in the treatment of an opioid use disorder. Administration Methadone dosing can vary widely among patients, and doses do not correlate well with blood levels. A relatively low dose of methadone (eg, 20 to 30 mg per day) can attenuate acute opioid withdrawal, but is usually not as effective at suppressing craving and blocking the effects of other opioids. Most patients do best on methadone doses between 80 to 120 mg/day, which typically create sufficient tolerance to blunt a euphoric response if patients self administer additional opioids. Some patients may not need doses as high as 80 mg/day, and some patients may need doses greater than 120 mg per day. The dose of methadone used should be based upon clinical response and considered in the context of non pharmacological treatment provided to the patient. Methadone dosing for opioid addiction differs significantly from doses used in the treatment of pain. Methadone is usually administered in a single daily dose. Some clinics may offer split dosing, provided twice daily (eg, in cases of pregnancy or rapid methadone metabolism). The initial dose of methadone maintenance treatment may vary based on the time of the last opioid use, the amount used, and whether the patient has developed a reduction in tolerance to opioids (eg, patients who were recently released from incarceration or hospitalization may have significantly reduced tolerance). A typical initial dose for opioid use disorder is 20 to 30 mg on the first day; most opioid treatment programs provide a first day dose of 30 mg. An additional 10 mg may be administered if the patient has significant withdrawal symptoms a few hours after the 30 mg dose. It is recommended that the first day dose not exceed 40 mg total. Methadone is typically given as a liquid, often diluted with juice or water or artificially colored water. (Each patient receives a full cup of uniformly colored liquid regardless of the dose of methadone in order to reduce anxiety among patients about differences in dose. The dilution and coloring is also intended to reduce the likelihood of a patient injecting take home methadone.) Methadone is available in a tablet form, as well as a dissolvable diskette, but these forms are less commonly used in opioid treatment programs in the US. The dose is titrated up in 5 to 10 mg increments no more frequently than every three to five days over the next several weeks until a dose in the range of 60 to 80 mg daily is attained. If excessive opioid agonist effects (eg, sedation) from the methadone occur, then further dose increases would be halted. Titration beyond 60 to 80 mg per day in patients without side effects proceeds more slowly over the next several weeks (frequently 10 mg a week), and is based upon alleviating cravings and opioid withdrawal symptoms (which are assessed daily), and the cessation of illicit opioid use (as determined by patient reports and urine testing). This gradual adjustment allows methadone to reach a pharmacologic steady state to match the patient s level of opioid tolerance and avoid intoxication or oversedation. The dose may be adjusted every one to two weeks by 5 to 10 mg each time based on patient assessment and feedback. A variety of methadone doses have been used for maintenance treatment [42]. Methadone is given in doses sufficiently high that additional doses of opioid do not cause euphoria. Several randomized trials found that patients do better on higher (80 to 100 mg/day) rather than lower methadone doses [43 45]; doses at these levels are not overly sedating following the development of tolerance. Patients who concurrently take benzodiazepines or use alcohol may be more likely to become sedated from methadone. Initiation of methadone should be accompanied by ongoing monitoring. Administration in the US mostly takes place in a controlled setting (eg, a licensed opioid treatment program) with direct observation of ingestion. There

6 should be limited use of take home doses (individual bottled doses of methadone to be taken outside the treatment setting, used with patients who are at low risk for diversion) early in treatment [31,33,46]. Eligibility for take home doses is usually based on adherence to program requirements for counseling and abstinence from illicit drugs (based on urine toxicology testing) as well as absence of recent criminal activity and capacity to store the take home doses safely in the home environment. Patients generally should have 30 to 90 days of continuous abstinence from illicit drugs to be eligible for take home doses, although by federal regulations any patient can be given a single take home dose on days the clinic is closed such as Sundays or holidays. Illustrating the variability of dosing, a study of 222 heroin addicted patients treated in a VA setting and followed for one year found a wide range in methadone doses (1.5 to mg per day [47]. Higher methadone doses were necessary in patients with: Depression or other psychiatric comorbidities A greater number of previous heroin detoxifications Residence in areas where heroin was likely to be less pure Special populations Pregnancy Methadone maintenance is first line treatment for pregnant women with an opioid use disorder [48]. A stable methadone dose reduces the fluctuations in maternal opioid levels that can occur with illicit opioid use, and this stabilization reduces stress on the fetus. Illicitly purchased heroin is adulterated with other compounds that may be harmful to the fetus; methadone use in pregnancy reduces the risk of fetal harm from exposure to such adulterants. (See "Overview of substance misuse in pregnant women".) Methadone maintenance also enhances the ability of the woman to participate in prenatal care and addiction treatment [49]. Methadone dose requirements may increase during the third trimester due to larger plasma volume, reduced protein binding, increased tissue binding, and increased metabolism. Splitting the total daily methadone dose into a morning and evening dose is preferred [50,51]. Small amounts of methadone are secreted in breast milk; however, the benefits of breast feeding for the infant far outweigh risks from the small amounts ingestion. Breastfeeding is recommended as long as the mother is not using other drugs and is not HIV infected [52,53]. Hospitalization If a patient receiving maintenance treatment with methadone is hospitalized, such as for a traumatic injury or medical illness, the maintenance dose should be continued throughout the hospitalization. The hospital clinician should contact the methadone maintenance program to verify the patient's current dose and to arrange for resumption of the medication after discharge. Buprenorphine Buprenorphine, a partial mu opioid agonist, reduces illicit opioid use when used in the longterm treatment of patients with DSM IV opioid dependence (or a moderate to severe opioid use disorder) [2,44,54]. In contrast to methadone, buprenorphine can be prescribed in a clinician's office in the US for medically supervised opioid withdrawal and maintenance treatment. Efficacy A meta analysis of five clinical trials found that sublingual buprenorphine improved treatment retention and reduced opioid use in patients with DSM IV opioid dependence compared to placebo treatment [54]. As an example, in a four week randomized trial of office based treatment of 326 patients with DSM IV opioid dependence, subjects who received buprenorphine (16 mg), buprenorphine naloxone (16 mg/4 mg), or placebo had rates of urine screens negative for opiates of 20.8, 17.8, and 5.8 percent, respectively [55]. Initiating buprenorphine during a medical hospitalization and linkage to outpatient buprenorphine treatment in patients with untreated opioid use disorder has shown promise in reducing illicit opioid use. A clinical trial randomly assigned 139 patients to buprenorphine detoxification or buprenorphine induction, intrahospital dose stabilization, and postdischarge transition to outpatient treatment [56]. At six months follow up, patients assigned to in hospital buprenorphine initiation and outpatient linkage were more likely to be engaged in buprenorphine treatment and reported less illicit opioid use (incidence rate ratio=0.60; 95% CI, ) compared to patients

7 assigned to detoxification. Adverse effects Common side effects of buprenorphine include sedation, headache, nausea, constipation, and insomnia. Adverse effects include respiratory depression, but its clinical impact is typically negligible due to the partial agonist properties of buprenorphine that prevent complete activation of the mu opioid receptors. Buprenorphine related deaths in patients on maintenance therapy have occurred primarily when buprenorphine is taken in combination with other substances, especially benzodiazepines and alcohol [57] and with intravenous abuse of high doses of the buprenorphine [58]. Death is caused by oversedation leading to respiratory depression and hypoxia. Buprenorphine appears to have a lower potential for lethal overdose compared to methadone. (See 'Buprenorphine versus methadone' below.) US regulation Buprenorphine is classified as a Schedule III controlled substance in the US; its use is limited to certified and specially trained physicians who have registered with the US Center for Substance Abuse Treatment (CSAT) of the Substance Abuse and Mental Health Services Administration (SAMHSA) and with the Drug Enforcement Administration (DEA). Information on the training and registration process is available at buprenorphine.samhsa.gov. Other information about US buprenorphine regulations includes: Clinicians providing office based buprenorphine must indicate that they have the capacity to provide or to refer patients for counseling. Induction may be accomplished in the clinician s office under observation or at the patient s home [59]. When on a stable dose, patients may receive a prescription for up to a one month supply of medication with refills for up to six months, similar to other Schedule III controlled substances. A hospitalized medical patient may be treated with buprenorphine by a physician without a DEA waiver. Administration Buprenorphine is marketed as a sublingual tablet, and as a sublingual or buccal soluble film strip, with or without naloxone. Buprenorphine is taken sublingually when used for the treatment of an OUD. It is typically administered in a combination preparation with naloxone, an opioid antagonist that has poor sublingual bioavailability. The combination is used to prevent people from abusing the drug by crushing the tablets and dissolving them for intravenous injection, or dissolving the soluble film for injection [60]. Naloxone has little to no activity when administered sublingually but would discourage intravenous buprenorphine abuse since the naloxone can precipitate withdrawal when given parenterally to individuals with physiologic dependence on opioids. The ratio of buprenorphine to naloxone is 4 to 1, and a variety of dose sizes are available (eg, 2/0.5, 4/1, 8/2, 12/3). Because buprenorphine is a partial mu opioid agonist with high affinity for the mu opioid receptor, it can displace full agonist opioids from the receptor and precipitate opioid withdrawal. When initiating buprenorphine or buprenorphine naloxone, it is recommended that the patient be abstinent from other opioids for a sufficient period, to enter a state of moderate opioid withdrawal. This period of abstinence will vary as a function of the half life of the opioid being used by the patient (eg, withdrawal from heroin can appear 6 to 12 hours after the last dose, while withdrawal from methadone will be much longer). At the point at which early evidence of withdrawal appears, buprenorphine will then ameliorate the withdrawal by binding to and activating the muopioid receptors [60]. To determine that the patient has entered a state of moderate opioid withdrawal, the physician should observe that the patient displays some early signs of opioid withdrawal at the time of induction. (See "Medically supervised opioid withdrawal during treatment for addiction", section on 'Symptoms of opiate withdrawal'.) A typical starting dose is buprenorphine naloxone 4 mg/1 mg given sublingually. After two hours observation, if withdrawal symptoms remain, an additional 2 to 4 mg of buprenorphine naloxone can be administered. On the following day, the patient is given a single dose consisting of the total of the doses received the first day.

8 Following observation for residual withdrawal symptoms, the dose may be increased in 4 mg increments, up to a maximum of 16 mg total (ie, 16/4 mg of buprenorphine naloxone). Most patients will stabilize on 8 to 16 mg/day of buprenorphine [61], so the dose should not be increased above 16 mg for several days to allow time to reach pharmacologic steady state. Some patients may need doses up to 32 mg/day, but this is rare [62,63]. As is true for methadone, there can be considerable variability between patients in the dose of buprenorphine and the blood levels produced, and dosing should be based upon clinical response and in the context of the provision of non pharmacological treatments. Buprenorphine naloxone may be ineffective in patients with severe liver impairment due to increased bioavailability of naloxone. For this reason use of buprenorphine naloxone is not recommended in patients with severe liver impairment [64]. When discontinued, buprenorphine should be tapered gradually. We typically reduce the dose by 2 mg every one to two weeks. If a more rapid taper is necessary (eg, prior to elective surgery or incarceration), the dose can be reduced by 2 mg every one to three days. The relative efficacy of different buprenorphine tapering schedules has not been well studied, but available data suggest that slow, gradual tapers (eg, over months) are more effective and better tolerated than rapid tapers (eg, over days) [65]. (See "Medically supervised opioid withdrawal during treatment for addiction", section on 'Buprenorphine'.) Patients with physiologic opioid dependence who are transitioned directly from methadone maintenance to buprenorphine may experience acute opioid withdrawal syndrome [66,67]. To avoid this reaction, patients on methadone maintenance are generally tapered down to 30 mg or less of methadone daily before being given buprenorphine [68]. In one study, however, patients who were maintained on methadone 100 mg daily and received repeated small doses of buprenorphine naloxone did not experience significant precipitated withdrawal symptoms [69]. Buprenorphine is not detected by standard urine drug screens, which identify the presence of naturally occurring opiates and their metabolites. A specialized assay can be ordered to detect buprenorphine. Long acting buprenorphine Limitations related to adherence, diversion, and misuse of sublingual buprenorphine have prompted interest in an implantable long acting formulation. Data from a randomized trial found that patients who received buprenorphine implants for DSM IV opioid dependence had better opioid use related outcomes compared to those who received placebo implants. A randomized trial of 163 patients with DSM IV opioid dependence compared treatment with subdermal buprenorphine implants to placebo implants over a six month period [70]. Both groups received manual based drug counseling and limited amounts of supplementary sublingual buprenorphine naloxone. The group that received buprenorphine implants had a higher proportion of observed urine tests that were negative for illicit opioids compared to the placebo group (40.4 versus 28.3 percent after 16 weeks). They were also more likely to complete the study and less likely to report withdrawal symptoms or cravings. Minor implant site reactions were the most common adverse effect. Further study of the implants is needed, particularly in comparison with daily maintenance medications for opioid use disorder. Pregnancy Methadone is the first line treatment in pregnant women with opioid use disorder because of the many years of experience with its use [71,72]. Available evidence suggests that buprenorphine is safe and effective for both the mother and her newborn, with the potential for reduced severity of neonatal abstinence syndrome compared to methadone [73 75]. Regardless of the medication used (methadone or buprenorphine), for pregnant patients treated with medication for opioid use disorder, coordination among the prescribing clinician, physician providing obstetrical care, and neonatologist is optimal. As an example, a randomized trial compared buprenorphine and methadone in the treatment of 175 pregnant women with DSM IV opioid dependence [76]. Sixty seven percent of women receiving buprenorphine and 82 percent of women receiving methadone continued treatment through the end of the pregnancy. The neonates born to women in the buprenorphine treated group required less morphine (mean dose, 1.1 mg versus 10.4 mg),

9 experienced shorter hospital stays (10 versus 17.5 days), and had a shorter duration of treatment for neonatal abstinence syndrome (4.1 versus 9.9 days) compared to neonates born to women in the methadone treated group. There were no differences between groups in adverse events. Levo alpha acetyl methadol Levo alpha acetyl methadol (LAAM), a long acting synthetic opioid, was used for the treatment of DSM IV opioid dependence in the US and other parts of the world. LAAM requires dosing only three days per week (typically Monday/Wednesday/Friday), thus decreasing clinic attendance burden for the patient and staffing needs at the opioid treatment program. It is no longer being manufactured, in part related to concerns noted that LAAM was found to increase the risk of cardiac arrhythmia [77]. If used in the US in the future, as a Schedule II medication, it would only be available through opioid treatment programs. Heroin maintenance programs Several countries, including Switzerland and the Netherlands, have instituted programs that include provision of injectable heroin to addicted individuals who have failed other maintenance therapy [78 80]. An open label, randomized trial conducted in Canada compared injectable diacetylmorphine (another term for heroin) with oral methadone maintenance therapy in 226 patients with treatment refractory DSM IV opioid dependence [81]. Patients treated with diacetylmorphine were more likely to remain in addiction treatment after one year (87.8 versus 54.1 percent) and experienced a greater reduction in illegal activity, including illicit drug use (67.0 versus 47.7 percent). A relatively high incidence of serious adverse events, including ten overdoses and six seizures, occurred among patients receiving diacetylmorphine (versus no serious adverse events related to methadone treatment) suggesting that heroin should be administered with caution in a medically supervised setting. A study of the Swiss heroin treatment program found a reduction in the risk of infection with hepatitis B and C viruses [82], decreased heroin use, and early entry (within two years) of users into methadone substitution programs [79]. It is hypothesized that the "medicalization" of heroin use made it less attractive for young people. A Dutch study suggested a cost utility benefit for heroin co prescription in treatment resistant heroin users, with program costs offset by lower estimated costs for law enforcement and damage to victims of crime [83]. Treatment of opiate use disorder with heroin is controversial. Potential risks of heroin injection programs, including adverse events, drug substitution, drug diversion, and co addiction, need further study and should be weighed against evidence of efficacy, from both a societal and patient perspective. Practices are likely to continue to differ by country, as attitudes toward drug treatment are influenced by culture as well as research evidence [84]. Duration Some patients remain on maintenance treatment with an opioid agonist for many years, while others are tapered off of agonist therapy. Candidates for a taper are patients who have no illicit drug use or problematic alcohol use, and have good psychosocial stability and supports. After discussion with a physician (and typically their program counselor when attending an opioid treatment program), a patient may elect to discontinue agonist medication by very slow tapering of the dose over several months to years. Clinicians without experience tapering a patient off of a maintenance medication would benefit from consultation with a clinician who has such experience. OPIOID ANTAGONISTS Treatment with an opioid antagonist prevents the user from experiencing opioid intoxication or physiologic dependence with subsequent use, and thus reinforces abstinence. Naltrexone The opioid antagonist naltrexone is an option for maintenance treatment to prevent relapse in opioid use disorder. Naltrexone blocks the effects of opioids if they are used. Naltrexone should not be used prior to the completion of a medically supervised withdrawal from opioids, because naltrexone can cause immediate withdrawal symptoms (precipitated withdrawal) in the person with active physical dependence on opioids. Taken daily, naltrexone maintenance is most effective in patients who are highly motivated or legally mandated to receive treatment, and/or when taking the medication is closely supervised. A long acting naltrexone formulation is available for patients with difficulty adhering to daily medication; this extended release

10 form requires a once monthly injection. Naltrexone has few side effects or adverse effects. Occasionally patients will report nausea. More severe adverse effects include liver damage, but this is very rare (seen with supra therapeutic doses), and has always resolved with discontinuation of naltrexone. Patients who discontinue antagonist therapy and resume opioid use should be made aware of the risks associated with an opioid overdose, and especially the increased risk of death. This is due to the loss of tolerance to opioids and a resulting misjudgment of dose at the time of relapse [34]. Oral naltrexone Oral naltrexone has been found to be effective in the treatment of DSM IV opioid dependence when adherence is enforced. A meta analysis of 1158 participants in 13 randomized trials compared oral naltrexone maintenance treatment to either placebo or non medication for DSM IV opioid dependence treatment [85]. No difference was seen between the active and control groups in sustained abstinence or most other primary outcomes. The findings from these trials were limited by poor adherence and high dropout rates. Oral naltrexone was more effective than placebo in sustaining abstinence in three trials where patients were forced to adhere to daily doses of the medication [85]. Oral naltrexone is taken as a single 50 mg tablet once daily. The medication can be started three to six days after last use of short acting opioids and seven to ten days after last use of methadone. To avoid severe, prolonged precipitated withdrawal it can be helpful under some circumstances to perform a naloxone challenge test prior to administration of naltrexone. Naloxone challenge test A naloxone challenge test may be performed before initiating antagonist treatment to ensure that the patient has completed withdrawal from opioids and is no longer physically dependent on this class of drugs. The patient should be totally free of spontaneous opioid withdrawal signs and symptoms at the start of the naloxone challenge session. Baseline vital signs are obtained, and naloxone is then administered parenterally (subcutaneously, intramuscularly, or intravenously), up to a total dose of 0.8 mg. The patient is observed for up to one hour, and a validated measure for assessing opioid withdrawal, such as the Clinical Opioid Withdrawal Scale can be helpful to use. If any symptoms or signs of opioid withdrawal emerge or if pulse rate or blood pressure increase, administration of naltrexone should be postponed for another 24 hours. Since naloxone has a short half life, any withdrawal precipitated by naloxone typically will resolve within one to two hours or less. Long acting naltrexone Long acting naltrexone has been found to be more effective than placebo for DSM IV opioid dependence in randomized trials, although trials were limited by high dropout rates [86,87]. One trial found the drug to be efficacious in patients dependent on more than one drug, a common presentation [88]. As examples: A trial randomly assigned 60 patients with heroin dependence to receive injectable depot naltrexone (at doses of 384 or 192 mg) or placebo [86]. This was not the form of long acting naltrexone approved by the FDA in the US. The medication and placebo were administered at four week intervals. At the end of two months, retention in treatment was greater in both treatment groups (higher and lower dose) than in the placebo group (68 and 60 percent versus 39 percent). Treatment resulted in negative urine drug tests in a greater proportion of patients treated with depot naltrexone compared to 25 percent of the placebo group (62 versus 25 percent). However, when missing urine tests were considered to be positive for opioids, no differences in urine drug test results were seen between groups. Adverse events were minimal and generally mild. A trial compared a once monthly, injectable depot formulation of naltrexone to placebo in 250 patients with a DSM IV diagnosis of opioid dependence over 24 weeks [87], finding that the median proportion of weeks of confirmed abstinence was 90 percent in the actively treated group compared to 35 percent in the placebo group; however, these findings exclude 47 percent of the patients who did not complete the study.

11 A trial in 100 heroin and amphetamine dependent outpatients compared the efficacy of a non approved naltrexone implant to placebo [88]. After ten weeks of treatment, patients in the naltrexone group had higher retention in the study (52 versus 28 percent), a higher proportion of urine samples free of heroin and amphetamines (38 versus 16 percent), and a higher rate of clinically significant improvement on the clinical global impressions scale, compared to the placebo group. The depot formulation of naltrexone can be given every four weeks by deep intramuscular injection in the gluteal muscle at a set dosage of 380 mg per injection. TREATMENT SELECTION Based on the limited data available and our clinical experience, we describe our approach to treatment of opioid use disorder below. Opioid agonist versus antagonist medication We suggest first line treatment of a moderate to severe opioid use disorder with an opioid agonist (methadone or buprenorphine) rather than opioid antagonist medication. There are no trials comparing opioid agonist to opioid antagonist medication. In our clinical experience, treatment with naltrexone is a reasonable first line alternative to methadone or buprenorphine in: Highly motivated patients with a mild opioid use disorder. Situations in which medication use can be supervised. For patients in occupations that do not permit opioid agonist treatment. In areas such as public safety, transport of hazardous materials, licensed drivers, and healthcare, some employees are not allowed to use methadone and, in some cases, buprenorphine. We suggest switching to treatment with naltrexone in patients who continue to use opioids despite treatment with methadone and buprenorphine. (See 'Naltrexone' above and 'Naloxone challenge test' above.) Buprenorphine versus methadone We suggest buprenorphine rather than methadone as first line maintenance treatment in patients with opioid use disorder. Both medications are effective. Although available data suggest that methadone is on average more efficacious than buprenorphine in most clinical circumstance, buprenorphine is safer than methadone, which has a greater potential for lethal overdose. Unlike buprenorphine, methadone requires clinic based treatment (and essentially daily in clinic observed ingestion during the initial treatment period). Methadone is a reasonable choice for patients with continued opioid use despite buprenorphine treatment, a history of a poor response to buprenorphine, or previous misuse or diversion of buprenorphine. Data on the efficacy and safety of the two medications individually are described above; data comparing their efficacy and safety are described immediately below. (See 'Buprenorphine' above and 'Methadone' above.) Comparative efficacy A meta analysis of 11 randomized trials comparing methadone to buprenorphine in maintenance treatment for DSM IV opioid dependence concluded that buprenorphine was effective in opioid use disorder but slightly less effective than methadone in its capacity to retain patients in treatment [54]. As an example, a trial comparing buprenorphine (maximum daily dose 8 mg sublingual) with methadone maintenance (up to 80 mg) found that more patients receiving methadone continued therapy [89]. However, of patients who completed the study, those taking buprenorphine had significantly lower rates of illicit opioid consumption. Similar results have been reported by others, suggesting that maintenance with this agent may be most useful in highly motivated patients [90]. Comparative safety Methadone has significantly higher risks of abuse and lethal overdose compared to buprenorphine [91]. Buprenorphine, as a partial agonist, has a lower potential for causing respiratory depression. Methadone doses used for opioid use disorder exceed the lethal dose (50 mg) for opioid naive adults, while the typical buprenorphine dose is well below this threshold (8 to 16 mg/day). As an example, a study of 16,434 individuals with a DSM IV diagnosis of opioid dependence treated with

12 medication had a fourfold greater rate of mortality from overdose associated with methadone treatment compared with buprenorphine [92]. Stepped care A stepped care approach, beginning treatment with buprenorphine and switching to methadone in patients with an inadequate response, yielded high rates of response in a clinical trial. 96 patients with heroin dependence were randomly assigned to either stepped care or methadone; both groups additionally received behavioral therapy [93]. Buprenorphine was dosed at 16 mg at day 3, and titrated as needed to a maximum of 32 mg daily. Methadone was titrated to 70 mg by day 10, to a maximum of 120 mg/day. A treatment retention rate of 78 percent was achieved in both groups, while the percentage of opiate free urine samples ultimately reached approximately 80 percent. Short acting versus long acting medications In patients who are unable to adhere to daily medication treatment for opioid use disorder, we suggest treatment with long acting naltrexone. A trial compared a single administration of a naltrexone implant (2.3 g; plus pill placebo) to oral naltrexone (50 mg/day) for six months in 70 patients with heroin dependence [94]. Patients receiving naltrexone implants were less likely to have returned to regular heroin use by six months and returned later (158 versus 115 days) compared to patients receiving oral naltrexone. (See 'Long acting naltrexone' above.) Psychosocial augmentation of medication For patients who are treated with medication for opioid use disorder, we suggest adjunctive treatment with individual or group addiction counseling and participation in a peer support program such as Narcotics Anonymous. Augmentation of pharmacotherapy with a program employing contingency management is suggested in patients for whom opioid agonists and antagonists are ineffective. Regulatory requirements in the US and other countries require that patients receiving methadone also receive psychosocial treatment. Physicians providing patients with buprenorphine in office based practice are required to have the capacity to provide or refer patients for psychosocial care, but patients are not required to receive such care. (See 'Regulation' above and 'US regulation' above.) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy to read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Prescription drug abuse (The Basics)" and "Patient information: Opioid use disorder (The Basics)") SUMMARY AND RECOMMENDATIONS Patients with opioid use disorder who achieve abstinence through medically supervised withdrawal or other means often require long term treatment to prevent relapse. Treatment options include long term medication maintenance with either an opioid agonist or an opioid antagonist, or abstinence based therapy, a non medication treatment. (See 'Overview' above.) For patients with a moderate to severe opioid use disorder, we suggest maintenance treatment with medication rather than abstinence based therapy (Grade 1B). (See 'Opioid agonists' above.) For most patients treated with medication for a moderate to severe opioid use disorder, we suggest use of buprenorphine rather than other medications (Grade 2B). While methadone may have slightly better

13 capacity to retain patients in treatment, it has a higher risk of lethal overdose. (See 'Opioid agonist versus antagonist medication' above and 'Buprenorphine versus methadone' above.) Buprenorphine is taken in a combined formulation with naloxone to discourage abuse. Following training and certification, physicians in the US can prescribe buprenorphine in an office based practice setting. Buprenorphine can be started at 4 mg (with 1 mg of naloxone), sublingually. Most patients will stabilize on up to 16 mg/day, although selected patients may need higher doses. (See 'Buprenorphine' above.) For patients who continue to use opioids despite buprenorphine treatment, or have a history of a prior poor response to, misuse or diversion of buprenorphine, we suggest treatment with methadone rather than other medications (Grade 2C). Methadone cannot not be prescribed for self administration in the US; patients receive the medication in treatment at an opioid treatment program (ie, a methadone clinic). Naltrexone is suggested as third line medication treatment for moderate to severe opioid use disorder in patients who have had poor responses to buprenorphine and methadone. (See 'Buprenorphine versus methadone' above and 'Opioid agonist versus antagonist medication' above and 'Naltrexone' above.) Most patients treated with methadone do best on doses between 80 to 120 mg/day, which is typically sufficient to block a euphoric response if the patients self administer additional opioids; however, patients vary in their response to methadone dosing, which should be based upon the patient s clinical response rather than a particular target dose. (See 'Methadone' above.) For most patients with a mild opioid use disorder, we suggest treatment with naltrexone rather than other treatments (Grade 2C). For patients with a mild form of the disorder who are highly motivated to participate in treatment and prefer a non medication approach, abstinence based therapy is a reasonable alternative. (See 'Naltrexone' above.) For patients with opioid use disorder in safety sensitive occupations that prohibit opioid agonist use, we suggest naltrexone as first line medication treatment rather than other medications. (Grade 2C). To ensure adherence, administration of oral naltrexone should be supervised. (See 'Oral naltrexone' above.) Oral naltrexone is taken as a single 50 mg tablet once daily. Long acting naltrexone can be used in patients who have problems with adherence to daily medications. Patients who fail treatment with naltrexone should be treated with an opioid agonist. (See 'Opioid agonist versus antagonist medication' above and 'Oral naltrexone' above and 'Long acting naltrexone' above.) For patients who are treated with medication for opioid use disorder, we suggest adjunctive treatment with addiction counseling and participation in a peer support program such as Narcotics Anonymous (Grade 2B). Methadone programs in the US (opioid treatment programs) are required to provide drug counseling. Physicians who prescribe buprenorphine in an office based practice are required to have the capability to provide or refer patients for drug counseling. ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge Michael Weaver, MD and John Hopper, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Gunne LM, Grönbladh L. The Swedish methadone maintenance program: a controlled study. Drug Alcohol Depend 1981; 7: Kakko J, Svanborg KD, Kreek MJ, Heilig M. 1 year retention and social function after buprenorphineassisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebocontrolled trial. Lancet 2003; 361: Hauri Bionda R, Bär W, Friedrich Koch A. [Driving fitness/driving capacity of patients treated with

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18 GRAPHICS Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers* Strong inhibitors Moderate inhibitors Strong inducers Carbamazepine Moderate inducers Atazanavir Boceprevir Abiraterone Amiodarone Dexamethasone Enzalutamide Bexarotene Bosentan Chloramphenicol Aprepitant Fosphenytoin Dabrafenib Clarithromycin Bicalutamide Mitotane Efavirenz Cobicistat and cobicistat containing coformulations Ceritinib Cimetidine Ciprofloxacin Nevirapine Oxcarbazepine Pentobarbital Eslicarbazepine Etravirine Modafinil Conivaptan Clotrimazole Phenobarbital Nafcillin Darunavir Crizotinib Phenytoin Delavirdine Cyclosporine Primidone Fosamprenavir Desipramine Rifabutin Idelalisib Indinavir Itraconazole Ketoconazole Diltiazem Danazol Dasatinib Dronedarone Rifampin (rifampicin) Rifapentine St. John's wort Lopinavir Erythromycin Nefazodone Fluconazole Nelfinavir Fosaprepitant Nicardipine Grapefruit juice Posaconazole Haloperidol Ritonavir and ritonavir containing coformulations Saquinavir Stiripentol Telaprevir Telithromycin Voriconazole Iloperidone Isavuconazole Imatinib Lomitapide Metronidazole Mifepristone Norfloxacin Quinupristindalfopristin Sitaxsentan Tetracycline Verapamil

19 Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Specific drug interactions and management suggestions may be determined by using Lexi Interact, the drug interactions program included with UpToDate. Refer to UpToDate topics on specific agents and indications for further details. * The CYP3A4 inhibitors and inducers listed in this table are relevant for determining potential interactions of drugs that are CYP3A subfamily substrates. Less potent effect on CYP3A4 reported in some references. Data from: 1. Lexicomp Online. Copyright Lexicomp, Inc. All Rights Reserved. 2. Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2014 ed, H&H Publications, Freeland, WA Inhibitors and inducers of CYP enzymes and P glycoprotein. Med Lett Drugs Ther 2013; 55:e44. Graphic Version 28.0

20 Some reported causes and potentiators of the long QT syndrome* Congenital Jervell and Lange Nielsen syndrome (including "channelopathies") Romano Ward syndrome Idiopathic Acquired Metabolic disorders Hypokalemia Hypomagnesemia Hypocalcemia Starvation Anorexia nervosa Liquid protein diets Hypothyroidism Bradyarrhythmias Sinus node dysfunction Atrioventricular (AV) block second or third degree Antiarrhythmic drugs Quinidine, procainamide, disopyramide Flecainide, propafenone Amiodarone, dronedarone Sotalol Dofetilide, ibutilide Androgen deprivation therapy Gonadotropin releasing hormone agonists and antagonists: buserelin, degarelix, goserelin, histrelin, leuprolide, triptorelin Antianginal drugs Ranolazine, ivabradine Antiinfective drugs Antimalarial Higher risk: artemether lumefantrine, chloroquine, halofantrine, quinidine, quinine Lower/conditional risk: hydroxychloroquine, Acquired (continued) Antihistamines Terfenadine Δ, astemizole Δ, hydroxyzine Antineoplastic drugs Arsenic trioxide, ceritinib, crizotinib, dasatinib, eribulin, nilotinib, lapatinib, panobinostat, pazopanib, romidepsin, sorafenib, sunitinib, toremifene, vandetanib, vemurafenib, vorinostat, cesium chloride Δ Analgesic and sedative drugs Opioids: Methadone, oxycodone Propofol Chloral hydrate Diuretics Via electrolyte changes (especially hypokalemia or hypomagnesemia) Gastrointestinal drugs Antiemetics: ondansetron, granisetron, dolasetron, droperidol (may be safe at the low doses used by anesthesiologists [0.625 to 1.25 mg]), hydroxyzine, tropisetron Promotility: cisapride (restricted availability), domperidone, metoclopramide Proton pump inhibitors: chronic use leading to hypomagnesemia Neurologic drugs Apomorphine, donepezil, fingolimod, tetrabenazine Psychotropic drugs Antipsychotics Higher risk: thioridazine, sertindole, pimozide, sulpiride, ziprasidone, quetiapine, iloperidone Lower/conditional risk: asenapine, amisulpride, flupentixol, paliperidone, zuclopenthixol, haloperidol, pipamperone, thiothixene, loxapine,