Summary by Claudie H. Jimenez, MD, MS
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Based on “Principles of Addiction Medicine” Chapter by Judith Martin, MD, Joan E. Zweben, PhD, and J. Thomas Payte, MD
Since 1995, there has been an enormous upsurge in nonmedical use of prescription opioids and sedatives with 1.9 million persons regularly abusing or addicted to prescription opioids in 2010 and 359,000 persons with heroin abuse or dependence. Of an estimated 2 million opioid-dependent persons in the United States, over 300,000 patients are receiving treatment in 1,166 opioid treatment programs (OTPs) offering counseling, testing, and maintenance pharmacotherapy. Since 2002, office-based maintenance using buprenorphine has been available in the United States.
HISTORY AND CONTEXT OF OMT
The modern use of opioids as a maintenance pharmacotherapy began with the use of methadone in the 1960s. Methadone maintenance has been shown to decrease mortality, reduce illicit drug use, reduce seroconversion to HIV, reduce criminal activity, and increase engagement in socially productive activities. However, there is a stigmatization of methadone as a treatment modality, and it continues to remain separate from the medical mainstream of care and is poorly understood by clinicians.
CLINICAL ISSUES IN MAINTENANCE PHARMACOTHERAPY
Goals of pharmacotherapy of opioid dependence include (1) prevention or reduction of withdrawal symptoms, (2) prevention or reduction of opioid craving, (3) prevention of relapse to use of addictive opioids, and (4) restoration to or toward normalcy of any physiologic function disrupted by chronic opioid use.
Potential agents for this treatment must have the following qualities:
1. Such medications are effective without requiring parenteral administration.
2. Such medications have a long biologic half-life (>24 hours).
3. Such medications have minimal side effects during chronic administration.
4. Such medications are safe (i.e., lacking true toxic or serious adverse effects).
5. Such medications are efficacious for a substantial proportion of persons with the disorder.
Methadone and buprenorphine generally exhibit these characteristics.
MAINTENANCE TREATMENT USING METHADONE
Methadone, regularly administered at steady state, is present at levels sufficient to maintain alertness without withdrawal symptoms, craving, or drug preoccupation throughout a 24-hour dosing interval.
The induction phase is the most critical phase of treatment. Most patients will need 80 to 120 mg/d of methadone. However, the starting dose must be much lower, and steady state is reached slowly over a period of weeks. The first several doses require careful evaluation and adjustment. Studies have reported deaths during the first 10 to 14 days of treatment, particularly when induction doses are high (more than 50 mg) and when the patient is also ingesting sedatives. About 42% of drug-related deaths during treatment occurred during the first week of OMT, and patients were reported to be 6.7 times more likely to die during induction as compared to untreated heroin users.
Federal regulations require that the initial dose of methadone is no more than 30 mg and may be lower in patients in whom low tolerance might be expected. A total dose of no more than 40 mg may be given on the first treatment day unless the program physician documents in the patient’s record that 40 mg did not suppress opioid abstinence symptoms.
Steady-state levels are reached after four to five half-lives (methadone has an average half-life of 24 to 36 hours). A significant portion of the previous dose remains in tissue stores with daily dosing. Thus, levels of methadone increase daily, even without an increase in dose.
The maintenance phase begins once a stable dose is established. Most patients receiving methadone maintenance do well on a dose range of 80 to 120 mg/d. Patients are often able to remain at their maintenance dose for years. Dose level and duration of treatment are individualized clinical decisions. Treatment should be continued as long as the patient continues to benefit from treatment, wishes to remain in treatment, remains at risk of relapse, and suffers no significant adverse effects.
In most cases, clinical observation and patient reporting are adequate to make appropriate dose determinations. Mean, random, or trough levels of methadone do not define an adequate dose. However, blood level assays can be very useful in evaluating suspected drug interactions and help identify patients who may benefit from a divided dose.
Methadone metabolism is largely a function of enzyme activity in the liver and induced or inhibited by CYP450 activity. Drugs that stimulate or induce CYP450 activity may shorten the duration and diminish the effect of methadone (such as rifampicin, phenytoin, carbamazepine, phenobarbital, nevirapine, or efavirenz) and result in onset of withdrawal symptoms. Other drugs (cimetidine, ciprofloxacin, fluconazole, erythromycin, and fluvoxamine) may inhibit this enzyme activity, slowing the metabolism and extending the duration of the drug effect.
Several case series have been published showing that methadone treatment is associated with prolongation of the QT interval and possible consequent cardiac arrhythmia (torsade des pointes or TdP). The FDA published a boxed warning in 2006 that included QT interval prolongation and risk of arrhythmia.
The increase in methadone abuse parallels the increase in prescription analgesic abuse, in particular a dramatic increase in mortality by ingestion of diverted methadone intended for pain treatment. Deaths from methadone overdoses exceeded deaths from heroin in some states by 2002. Most deaths involved multiple medications, usually including sedatives.
Levo-alpha-acetylmethadol (LAAM) was developed in 1948 and approved for treatment of opioid addiction by the U.S. Food and Drug Administration (FDA) in 1993. After several reports of the arrhythmia TdP, the FDA placed a boxed QT warning label on LAAM, and it was subsequently withdrawn from the market.
MAINTENANCE TREATMENT USING BUPRENORPHINE
Buprenorphine is a partial μ-opioid agonist approved by the FDA in 2002 for treatment of opioid dependence and is taken sublingually by patients. The buprenorphine/naloxone combination is designed to discourage injected diversion and misuse and is preferred for outpatient, office-based treatment. The buprenorphine-only formulation is used in controlled settings, such as inpatient medically supervised withdrawal, or in pregnancy.
Buprenorphine has slow onset and long duration of action, similar to methadone. As a partial μ-agonist, buprenorphine has a maximal dose–effect ceiling that is well below significant respiratory depression for most patients. This safety profile allows it to be used in office-based settings.
Since buprenorphine is a partial agonist with strong receptor affinity; its activity can be felt as the rapid onset of opioid withdrawal by the patient. Therefore, the first dose should be given when the patient is already in opioid withdrawal. The recommended first dose is 2 to 4 mg with a first-day maximum of 8 mg. The dose can be rapidly titrated over the first 3 days to control withdrawal. The average daily dose is 16 to 20 mg and usually prescribed as a single daily dose. No additional maintenance benefit is expected in doses above 32 mg/d. In cases requiring supervised dosing, it can be given every other day, or three times a week, while keeping the total weekly dose unchanged.
Buprenorphine may confer advantages when certain HIV medications are used and in cases of QT prolongation compared with methadone.
When prescribed in the office-based setting, certain restrictions are set forth in the Drug Addiction Treatment Act of 2000 (DATA 2000). Restrictions are placed on census, type of medication, and rules on storage and record keeping. In cases where buprenorphine is dispensed in the OTP, the same federal regulatory restrictions apply to both buprenorphine and methadone except that the time-in-treatment regulations that apply to take-home doses of methadone no longer apply for buprenorphine.
After the completion of a 2005 Data 2000 study, no serious adverse events have been found by use of buprenorphine/naloxone in the office-based setting. As the clinical use of buprenorphine has increased, so have reports of diversion. However, most studies have shown that patients were diverting buprenorphine to alleviate withdrawal symptoms.
Mixing benzodiazepines with opioid agonist treatment is potentially lethal. Reported rates of benzodiazepine misuse among methadone-treated patients are between 24.9% and 50.6%. For patients with therapeutic sources of benzodiazepines, careful coordination with prescribing physicians is indicated. Abrupt cessation of high doses of benzodiazepines may require medical detoxification due to risk of withdrawal seizures.
Though both medications were shown comparable in various outcomes, systematic reviews suggest that methadone is superior in retaining patients. In the United States, site of care, level of care, local availability, or cost may determine which medication is applicable for a given patient. The medications are often not equitably available, with major differences related to how and where treatment is delivered.
Patients who do well and who improve according to specified criteria set out in federal regulations can earn unsupervised dosing. The criteria include adherence to treatment, stability of home environment, involvement in productive activity, abstinence from drugs of abuse, and resolution of any legal problems. Some states have additional, more stringent regulations. The time in treatment is less for buprenorphine.
PAIN MANAGEMENT
Single daily doses of methadone control symptoms of addiction, multiple daily doses may be required for analgesia. Long-term use of methadone and possibly buprenorphine is associated with hyperalgesia. Tolerance and hyperalgesia combined means that patients in OMT who require opioids for acute pain management may need very high doses of opioids. Mixed agonist–antagonists (pentazocine, butorphanol, nalbuphine) and partial agonists (buprenorphine) must not be used in methadone-maintained patients, as these will precipitate an opioid withdrawal syndrome. Meperidine and propoxyphene should be avoided because of the risk of seizures at the higher doses required to produce analgesia in methadone-maintained patients.
Methadone-maintained patients who require opioids for acute pain management: (1) Continue maintenance treatment without interruption and use nonopioid pain treatments whenever possible; (2) provide adequate individualized doses of opioid agonists, and (3) doses should be given more frequently and on a fixed schedule rather than “as needed for pain.”
Chronic Pain
More than 30% of OMT patients report chronic, severe pain. Patients admitted to OTP for prescription opioid addiction may have higher prevalence of pain. The OTP physician can sometimes coordinate care with the patient’s primary care or pain specialist.
PREGNANCY AND OPIOID AGONIST TREATMENT
Although agonist treatment during pregnancy remains a controversial and emotionally charged topic, opioid maintenance remains the treatment of choice for pregnant, opioid-dependent patients. Breast-feeding by OMT patients is encouraged except for HIV-positive mothers. Neonatal withdrawal is a concern. However, most infants do not require treatment (55%). Methadone and buprenorphine are category C medications, though there is more experience with the use of methadone. Maternal medically supervised withdrawal during pregnancy is technically possible but should be done in the hospital with fetal monitoring.
NEEDLE-RELATED COMORBIDITY
In 2010, 60% to 70% of heroin users were injection drug users (IDUs). Infections related to needle use are a main source of comorbidity and death in the OMT population including acute skin infections, necrotizing fasciitis, botulism, and endocarditis.
Between 15% and 20% of long-term IDUs are positive for the human immunodeficiency virus (HIV). Dose adjustments may become necessary in patients on methadone or buprenorphine maintenance who begin highly active antiretroviral treatment (HAART) for HIV. Hepatitis C virus (HCV) positivity rates are reported to be 66% to 88% of all IDUs, with 77% in persons using for 1 year or less and 94% in persons who had injected drugs for at least 10 years. HCV becomes chronic in 85% of infected persons, and cirrhosis develops in 20% to 30% of patients.
PATIENTS WITH CO-OCCURRING PSYCHIATRIC DISORDERS
Common co-occurring disorders are depression, dysthymia, anxiety, and posttraumatic stress disorder. Sleep disorders are also common and appear with psychiatric disorders, chronic pain, benzodiazepine abuse, and a high methadone dose. Reports of personality disorders are common, particularly antisocial personality disorder.
PSYCHOSOCIAL INTERVENTIONS
Psychosocial interventions are considered integral to good treatment in a methadone program, and requirements for this are written into regulations even though many conflicting study results make it difficult to draw definitive conclusions. Counselors, who range widely in educational level and professional training, often serve as a case manager as well, initiating screening for medication and other program services; attending to issues concerning program rules, privileges, and policies; and providing links to other agencies. Clinics that have access to professionally trained staff may offer psychotherapy to selected patients. Utilization of multiple strategies can strengthen the physician’s and counselor’s ability to address a range of issues.
GROWTH, CONTROVERSY, AND FUTURE CHALLENGES
Stigma and access to services and community activities remain a key issue, but important conceptual advances are underway. Clinical trials of buprenorphine have shown it to be effective and safe in office-based practice as a maintenance medication. Also, work is under way on office-based use of methadone (office-based opioid treatment, or OBOT) to expand treatment capacity. OBOT with methadone currently is available and successful in several nations outside the United States, including Canada. An issue that merits attention, though there is little literature on the subject, involves individuals who use illicit opiates but who would not consider seeking treatment in the system that currently delivers OMT.
KEY POINTS
1. Opioid maintenance has been shown to decrease mortality, reduce illicit drug use, reduce seroconversion to HIV, reduce criminal activity, and increase engagement in socially productive activities.
2. In the US, opioid maintenance therapy is provided using methadone (a full agonist) or buprenorphine (a partial agonist). Methadone and buprenorphine have been shown to be comparable in efficacy.
3. Stigma and access to services and community activities remain a key issue with gaps in the availability of treatment providers. This has been helped somewhat by the availability of office-based treatment with buprenorphine, but greater access is still needed.
REVIEW QUESTIONS
1. Which of the following is NOT a goal of pharmacotherapy for opioid dependence?
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