Opioid Receptor Agonists: Methadone and Buprenorphine

For more detailed discussion of this topic, see Opioid Receptor Agonist: Methadone, and Buprenorphine, Sec. 31.24, p. 3171, in Comprehensive Textbook of Psychiatry, 9th Edition.

Commonly abused opioids include heroin, hydromorphone (Dilaudid), codeine, meperidine (Demerol), oxycodone (Oxycontin), and hydrocodone (Robidone). It has long been recognized that after ongoing, regular use of opioids, a syndrome of dependence, including maladaptive use, functional impairment, withdrawal symptoms, and tolerance, may develop. The prevalence of opioid use, abuse, and dependence, particularly in regard to prescription opioids, has risen in recent years. Sustained opioid dependence is associated with several negative outcomes, including early mortality, increased rates of hepatitis, human immunodeficiency virus (HIV) infection, sexually transmitted diseases, and other health problems, as well as criminal justice system involvement. If an individual is physiologically dependent on opioids, opioid discontinuation or diminution in the amount consumed often leads to the development of an opioid withdrawal syndrome. Physical signs and symptoms that frequently occur include sweating, piloerection, yawning, rhinorrhea, sneezing, lacrimation, pupillary dilation, nausea, vomiting, abdominal cramps, diarrhea, tremor, muscle aches or cramps, agitation, dysphoric mood, fever, and sleep disturbances. Although opioid withdrawal is not considered life threatening, it is highly physically and subjectively uncomfortable, such that an individual continues to use opioids to avoid withdrawal symptoms.

Pharmacologic Actions

Methadone and buprenorphine are absorbed rapidly from the gastrointestinal (GI) tract. Hepatic first-pass metabolism significantly affects the bioavailability of each of the drugs but in markedly different ways. For methadone, hepatic enzymes reduce the bioavailability of an oral dosage by about half, an effect that is easily managed with dosage adjustments.

For buprenorphine, first-pass intestinal and hepatic metabolism eliminates oral bioavailability almost completely. When used in opioid detoxification, buprenorphine is given sublingually in either a liquid or a tablet formulation.

The peak plasma concentrations of oral methadone are reached within 2 to 6 hours, and the plasma half-life initially is 4 to 6 hours in opioid-naive persons and 24 to 36 hours after steady dosing of any type of opioid. Methadone is highly protein bound and equilibrates widely throughout the body, which ensures little postdosage variation in steady-state plasma concentrations.

Elimination of a sublingual dosage of buprenorphine occurs in two phases: an initial phase with a half-life of 3 to 5 hours and a terminal phase with a half-life of more than 24 hours. Buprenorphine dissociates from its receptor binding site slowly, which permits an every-other-day dosing schedule.

Methadone acts as pure agonists at µ-opioid receptors and has negligible agonist or antagonist activity at κ- or δ-opioid receptors. Buprenorphine is a partial agonist at µ-receptors, a potent antagonist at κ-receptors, and neither an agonist nor an antagonist at δ-receptors.

Therapeutic Indications

Methadone

Methadone is used for short-term detoxification (7 to 30 days), long-term detoxification (up to 180 days), and maintenance (treatment beyond 180 days) of opioid-dependent individuals. For these purposes, it is only available through designated clinics called methadone maintenance treatment programs (MMTPs) and in hospitals and prisons. Methadone is a schedule II drug, which means that its administration is tightly governed by specific federal laws and regulations.

Enrollment in a methadone program reduces the risk of death by 70%; reduces illicit use of opioids and other substances of abuse; reduces criminal activity; reduces the risk of infectious diseases of all types, most importantly HIV and hepatitis B and C infection; and in pregnant women, reduces the risk of fetal and neonatal morbidity and mortality. The use of methadone maintenance frequently requires lifelong treatment.

Some opioid-dependence treatment programs use a stepwise detoxification protocol in which a person addicted to heroin switches first to the strong agonist methadone; then to the weaker agonist buprenorphine; and finally to maintenance on an opioid receptor antagonist, such as naltrexone (ReVia). This approach minimizes the appearance of opioid withdrawal effects, which, if they occur, are mitigated with clonidine (Catapres). However, compliance with opioid receptor antagonist treatment is poor outside of settings using intensive cognitive–behavioral techniques. In contrast, noncompliance with methadone maintenance precipitates opioid withdrawal symptoms, which serve to reinforce use of methadone and make cognitive-behavioral therapy less than essential. Thus, some well-motivated, socially integrated former heroin addicts are able to use methadone for years without participation in a psychosocial support program.

Data pooled from many reports indicate that methadone is more effective when taken at dosages in excess of 60 mg a day. The analgesic effects of methadone are sometimes used in the management of chronic pain when less addictive agents are ineffective.

Pregnancy

Methadone maintenance, combined with effective psychosocial services and regular obstetric monitoring, significantly improves obstetric and neonatal outcomes for women addicted to heroin. Enrollment of a heroin-addicted pregnant woman in such a maintenance program reduces the risk of malnutrition, infection, preterm labor, spontaneous abortion, preeclampsia, eclampsia, abruptio placenta, and septic thrombophlebitis.

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