State-of-The-Art Treatment of Opioid Use Disorder

Characteristics of Methadone

Methadone Pharmacology . Methadone has a unique and complex pharmacology. It has good oral bioavailability, a gradual onset of action, and is generally long-acting. These characteristics contribute to its efficacy, but its long half-life may also lead to medication build-up and unintended toxicity. Methadone has many possible drug–drug interactions and effects on cardiac conduction; as a result, it has an FDA black box warning concerning respiratory depression and prolongation of the cardiac QT interval. Oral methadone is supplied as a solid tablet, a rapidly dissolving wafer, and a premixed liquid; these formulations are essentially bioequivalent. Methadone consists of a racemic mixture of two stereoisomers, levo( l ) -methadone and dextro ( d ) -methadone. The l -methadone enantiomer provides the majority of pharmacologic activity, and the d -methadone may contribute to side effects.

Methadone Pharmacokinetics and Pharmacodynamics : There is significant variability in methadone absorption, metabolism, and clearance both across individuals and within a given individual over time. Methadone has an average bioavailability of about 80%, but interindividual variation ranges from 41% to 95%. Absorption occurs rapidly after oral ingestion of methadone ; initial effects appear within 30 min after ingestion, but peak effects and plasma levels are achieved after approximately 4 h, with a range of 1–6 h. The average half-life of methadone is 22 h, with a wide potential range of 5–130 h. The metabolism of methadone is complex, and wide interindividual variation in enzyme activity occurs. Most available data suggests that methadone is mainly catalyzed by the liver enzyme CYP 450 3A4, but there is evidence that other enzymes including CYP2B6, CYP2D6, CYP1A2, CYP2C9, and CYP2C19 also contribute. Questions have been raised about the primary role of 3A4, with data suggesting that 2B6 may be the main enzyme responsible for methadone metabolism. Methadone has the ability to induce its own metabolism, particularly during the first month of treatment, causing reduced serum levels. The primary route of methadone elimination is renal with some eliminated in the feces. Methadone primarily acts as an agonist at the μ-opioid receptor, but, unlike most other opioids, it also antagonizes the N-methyl, d -aspartate (NMDA) receptor and blocks serotonin and norepinephrine transporters. Methadone also blocks the cardiac potassium channel, hERG, which can cause a prolonged QT interval on the ECG. Typical μ-opioid agonist effects of methadone include miosis, analgesia, sedation, possible euphoria, decrease in gut motility, and respiratory depression; like other opioids, tolerance may develop to some of these effects.

Clinical Use of Methadone

Given the complex pharmacology of methadone elucidated above, the potential for individualized responses to any given dose of methadone warrants personalized attention to clinical management. Dose conversion calculators are often inaccurate when switching patients from other opioids to methadone or vice versa. Because of methadone's long half-life, a steady-state level on a given dose is not attained for several days; dose escalation that is too rapid can lead to unanticipated medication accumulation causing adverse effects, including potentially fatal respiratory depression. The greatest risk period for overdose death occurs during the first few weeks of treatment and during periods of dose adjustments.

Though the long half-life of methadone is associated with potential adverse intoxication effects, it also makes methadone a highly effective pharmacologic intervention for OUD. For the vast majority of individuals, once-daily dosing alleviates opioid withdrawal symptoms and cravings, which are common drivers of ongoing illicit opioid use. Preclinical evidence indicates that methadone antagonism of excitatory NMDA receptors could decrease opioid tolerance, mitigating the need for repeated dose escalation over time to obtain the same effect.

Methadone Induction . The induction period after initial dosing of methadone is about two to 4 weeks to achieve a stable dose. Determination of initial induction dose, which can range from 5 to 30 mg, is partly based on knowledge of the patient's opioid use history, including recent use patterns, tolerance, and withdrawal. Thirty milligrams is the maximum allowable initial dose per federal regulations. For individuals not exposed to any opioids for three or more days prior to induction, 5–10 mg represents the most appropriate initial dose range. Age must also be considered since older individuals generally metabolize methadone less rapidly. For patients with extensive recent use of heroin or other opioids, a 30 mg initial dose typically successfully ameliorates withdrawal symptoms.

If signs or symptoms of withdrawal persist after clinical assessment two to 4 h following the initial methadone dose, additional doses of methadone to a maximum of 40 mg total on day one may be administered. If for any reason a dose higher than 40 mg on day one is considered, it must be clearly documented that additional dosing was essential to manage opioid withdrawal. If sedation or intoxication effects are observed after initial dosing, observation is warranted until effects have resolved, or, if necessary, additional measures such as naloxone administration may be initiated.

Achieving a stable dose of methadone . Given the 22-h average half-life of methadone, upward titration of methadone dosage in 5–10 mg increments every four to 5 days will yield dosages of 60–80 mg per day within 4 weeks of initiation. Induction period goals are to achieve dose stabilization such that opioid cravings and withdrawal symptoms over the 24 h following dose administration are eliminated. Additional goals include production of adequate tolerance to preclude euphoria caused by illicit opioid use, elimination of illicit opioid use as evidenced by self-report and urine drug screen, and minimization of adverse effects and intoxication symptoms that impair daily functioning. Upward titration of methadone doses in increments of 5–10 mg every five to seven days should be continued until induction goals are achieved. After the daily dose exceeds 40 mg, 10 mg dose increments are usually safe and appropriate. Evidence from clinical trials has demonstrated that daily methadone doses of 80–100 mg have significant advantages over lower doses in reducing illicit opioid use and retaining patients in treatment ; given individual variation some patients will stabilize on lower doses and others will require doses higher than 100 mg per day.

Methadone interactions with other medications . Multiple drug–drug interactions are possible with methadone given its complex metabolic pathways. Synergistic or additive effects can occur between methadone and other central nervous system depressants, such as opioids or other sedatives, including suppression of respiratory drive leading to toxicity or overdose. Methadone has a boxed warning for QT interval prolongation, so coadministration of methadone with medications that also prolong the QT interval may have additive QT prolongation effects.

Clinically significant medication interactions may occur with coadministration of medications that induce enzymes that catalyze the metabolism of methadone. Decreases in methadone serum level may trigger opioid withdrawal. Medications known to induce methadone metabolism include certain anticonvulsants, such as phenytoin and carbamazepine, the antibiotic rifampin, and antiretroviral medications including lopinavir, efavirenz, and nevirapine. Concurrent use of antiretrovirals may require substantial increases in methadone dose to manage withdrawal symptoms. Inhibitors of enzymes that catalyze methadone metabolism have the potential to elevate methadone serum levels and increase opioid effects.

Methadone-related cardiac effects : A corrected QT interval longer than 500 msec may increase the risk of a serious cardiac ventricular arrhythmia, torsades de pointes. In individuals treated with methadone, this arrhythmia has almost always been reported to occur in the context of other risk factors in addition to methadone treatment and likely occurs very rarely. Some recommendations encourage routine ECG screening for all patients on methadone, whereas others suggest ECG screening only in the presence of other risk factors, such as known structural heart disease or family history of sudden cardiac death. For patients treated with methadone with a corrected QT interval above 500 ms, consideration should be given to discontinuing other medications with QT interval prolongation effects, correcting electrolyte imbalances, or reducing the methadone dose if clinically appropriate.

Interim Methadone Maintenance . In areas of the United States where methadone treatment services are not easily accessible, interim methadone maintenance provides medication-only treatment in place of wait-lists for comprehensive treatment including ancillary services. Interim methadone provides methadone induction followed by daily dosing with no take-home doses and no services except emergency counseling. Although comprehensive methadone treatment has demonstrated superior outcomes to medication-only treatment, interim methadone compared to a wait-list control in at least three randomized controlled trials demonstrated reduced substance use and higher rates of subsequent entry into full methadone treatment services.

Characteristics of Buprenorphine

Buprenorphine Pharmacology : Buprenorphine has a unique pharmacology that confers a greater safety profile than methadone. Buprenorphine has extremely poor oral/gastric bioavailability, so several of the currently FDA approved formulations for treatment of OUD are taken by the sublingual or buccal route and absorbed via mucosa. As with methadone, buprenorphine has a gradual onset of action and generally long half-life. Buprenorphine is a partial μ-opioid agonist, rather than a full agonist (e.g., methadone), so its activity has a ceiling effect such that at some point increased doses do not lead to markedly (i.e. “lead to markedly increased effects”) increased effects. Thus, the risk of respiratory depression and overdose on buprenorphine, in the absence of concurrent central nervous system depressants, (i.e. “...and overdose on buprenoprphine, is low in healthy adults.”) is low in healthy (i.e. “in healthy adults.”) adults. Buprenorphine has fewer clinically meaningful medication interactions than does methadone, and buprenorphine appears to have smaller and fewer effects on cardiac conduction.

Buprenorphine/Naloxone : There are three transmucosal formulations of buprenorphine marketed for OUD: (1) buprenorphine sublingual tablets; (2) buprenorphine/naloxone sublingual tablets; and (3) buprenorphine/naloxone as a film for sublingual or buccal absorption. The buprenorphine/naloxone formulation is intended to deter parenteral misuse of the medication. Naloxone, a μ-opioid receptor antagonist, has minimal sublingual bioavailability; when taken by the sublingual route, insufficient naloxone is absorbed to have any clinically significant effect. However, since naloxone has very good parenteral bioavailability, attempts to crush and inject buprenorphine/naloxone result in naloxone blunting parenteral effects of buprenorphine and possibly precipitating opioid withdrawal if full agonist opioids are present. Buprenorphine/naloxone is the predominant formulation prescribed in the nation, with few problems related to parental misuse of buprenorphine.

Other buprenorphine formulations . Buprenorphine is also available as a subdermal implant that consistently releases active medication over 6 months. Implants must be surgically inserted in a brief office procedure and surgically removed after the treatment period. FDA approval was obtained in 2015 for individuals already stabilized on 8 mg or less of transmucosal buprenorphine per day. A newer monthly extended release (i.e. “monthly extended-release injectable formulation”) injectable formulation of buprenoprhine was approved in 2017 for the treatment of moderate to severe OUD in individuals who have initiated a transmucosal buprenorphine-containing product and have been stabilized on treatment for at least 7 days. The product is administered subcutaneously and deposits buprenorphine dissolved in a biodegradable delivery system (depot) that releases buprenorphine steadily as it biodegrades over time. In one study supporting its approval, the proportion of patients (N = 504) achieving treatment success (≥80% opioid-free weeks) was significantly higher in both 300 and 100 mg groups versus placebo (28.4%, 29.1%, and 2%, respectively). The approved dosing regimen is 300 mg administered subcutaneously for the first 2 months, followed by maintenance doses of 100 mg/month. It must be prescribed as part of a Risk Evaluation and Mitigation Strategy to ensure that the product is not distributed directly to patients.

Buprenorphine Pharmacokinetics and Pharmacodynamics : Absorption of buprenorphine occurs rapidly after sublingual administration. Bioavailability shows large interindividual variability but is generally around 35% for the tablet. Initial effects appear within 30 min with peak plasma levels occurring an average of 1 h after ingestion. Buprenorphine has an estimated average half-life of 32 h, although there is wide variation across studies and individuals. Most available data suggest that metabolism is primarily catalyzed by the liver enzyme CYP 450 3A4. The product of N-dealkylation is an active metabolite, nor-buprenorphine. The main route of buprenorphine clearance is fecal with lesser amounts excreted by the kidneys.

Buprenorphine serves as a partial agonist with high affinity at the μ-opioid receptor and slow dissociation and acts as an antagonist at the κ-opioid receptor. It also has agonist properties at the nociceptin/orphanin FQ (NOP) receptor (formerly known as ORL1 receptor). Buprenorphine has typical clinically observable μ-opioid agonist effects including analgesia, sedation, possible euphoria, decrease in gut motility, and respiratory depression with a ceiling on the latter effect given its partial agonist activity.