10 - Opioid Abuse and Dependence - Acute and Chronic Treatment | Manual of Psychiatric Therapeutics: Practical Psychopharmacology and Psychiatry (Little, Browns Paperback Book Series)

Editors: Shader, Richard I.

Title: Manual of Psychiatric Therapeutics, 3rd Edition

> Table of Contents > 10 - Opioid Abuse and Dependence: Acute and Chronic Treatment

Opioid Abuse and Dependence: Acute and Chronic Treatment

Richard I. Shader

John A. Renner Jr.

Papaver somniferum, the opium-yielding poppy, is native to many parts of the world. Documentation of the use of opium for pain relief in Asia Minor can be found in writings from as early as 1500 B.C. The specific cultivation of opium began more than 2,000 years ago when settlers bordering the Mediterranean began to understand its sedative, pain-relieving, and antidiarrheal properties. Recognition of the antitussive properties of codeine and the positive role for morphine in cardiac-related pulmonary edema came later.

The opium poppy contains a number of active alkaloids, including morphine, codeine, and thebaine. Thebaine, which is usually derived from Papaver bracteatum, can be converted into codeine or a number of semisynthetic opioids, including hydrocodone (e.g., Hycodan), oxycodone (e.g., Percodan), and oxymorphone (e.g., Numorphan). Codeine is metabolized to morphine; one should note, however, that a small proportion of the overall population in the United States perhaps 10% lacks a functional hepatic microsomal enzyme (cytochrome P-450 [CYP] 2D6) necessary to carry out this catabolic step. Two highly abusable semisynthetics derived from the opium poppy are heroin, which is metabolized to morphine, and hydromorphone (Dilaudid)

Numerous synthetic opioids, such as meperidine (Demerol), methadone (Dolophine), pentazocine (Talwin), and propoxyphene (e.g., Darvon), are currently manufactured. Alfentanil (Alfenta, Rapifen) and sufentanil (Sufenta) are examples of rapidly acting synthetic opioids that are given intravenously (i.v.). Alfentanil is also available in a lollypop formulation that is designed to facilitate pain relief for small children. In this chapter, the inclusive term opioids is generally used to describe the naturally occurring opiates, the semisynthetic and synthetic compounds, and the endogenous opioids. Because of low frequency or site-specific usage, not all of the available opioids are considered in this chapter.

Knowledge about the wanted and unwanted actions of the opioid compounds and the endogenous opioids (e.g., enkephalins, endorphins, endomorphins 1 and 2) at clinical and molecular levels has expanded dramatically over the last two decades. A comprehensive review of these issues is beyond the scope of this chapter. In brief, a variety of receptors throughout both the central and peripheral nervous systems that appear to be important to the actions of endogenous, natural, and synthetic opioids has been identified. For example, -endorphin and morphine are agonists at receptors, which are named after the affinity of morphine for this receptor. They also have some agonist activity at the receptors, which are named after their presence in the vas deferens, but the met-enkephalins and leu-enkephalins are the major endogenous agonists at the latter receptors. Two receptor subtypes, ₁ and ₂, appear to exist. The ₁ subtype likely mediates the analgesic effects. The marketed antagonists, naloxone and naltrexone, are synthetic congeners of oxymorphone, and they act primarily at the receptor sites. They also have some antagonist activity at the receptors. Antagonism at the ₂ subtype is likely the basis for the reversal of the respiratory depression and for most other changes seen in opioid overdosage and withdrawal.

At least two subtypes of the receptors also exist; the receptors appear to be involved in opioid-induced sedation. Receptors, of which at least three subtypes exist, are fundamental to the agonist actions of other endogenous opioids (e.g., dynorphin), but no pure agonists are currently available for use in humans. Receptors derive their name from the agonist ligand ketazocine; they appear to mediate analgesia at the level of the spinal cord. Other opioid receptor subtypes whose functions are not fully established also have been found. Among these are the receptors, which play some role in mydriasis and possibly in delirium.

P.116

Some mixed agonist antagonists (e.g., pentazocine) act at both the and receptors, such as agonists with weak antagonism. Agonism likely plays some part in the dysphoric and psychotomimetic properties, including hallucinations, nightmares, and anxiety, that are seen with some -active synthetics (e.g., pentazocine) in abuse and overdosage. Some opioids are mixed agonists ( and ) with weak antagonist properties (e.g., butorphanol). Finally, some opioids are partial agonists¹ (e.g., buprenorphine [Buprenex], a partial agonist at the receptors). The highest concentrations of opioid receptors are found in the periaqueductal gray matter and in the thalamus, limbic cortex, locus coeruleus, caudate nucleus, and medulla.

The focus of this chapter is the accidental misuse or deliberate abuse of opioids. The dangerous complications of opioids are most commonly associated with heroin, but they apply equally to other opioids under circumstances in which they are misused or abused. In the United States, the current estimate is that 0.4% to 0.7% of adults will become dependent on heroin at some point in time. Although about one-fourth of those exposed to heroin will become dependent on it, very few patients who have been prescribed morphine or other opioids as a needed analgesia or during anesthesia will become dependent. Initial illicit or nonmedical use of any opioid is a much more significant risk factor for the development of opioid dependence than is exposure per se.

I. Acute Overdosage

A. Diagnosis

Overdosage with opioids (usually heroin or methadone) can be deliberate or accidental. The patient typically is young, and he or she generally is brought to the emergency department by police or friends. The following clinical picture of overdose is similar for most opioids: depressed respiration, depressed consciousness, pinpoint (miotic) pupils (note: the pupils may not be miotic after meperidine overdose or they may be dilated [mydriatic] if severe hypoxia is present or if the opioid was taken with other drugs), possibly hypotension, and possibly pulmonary edema (or pulmonary congestion). Venous sclerosis or track marks (old or new) are supplementary evidence of opiate use, but their absence does not refute the diagnosis, because heroin may be smoked or taken intranasally and methadone and other opioids, such as hydromorphone, may be taken orally. The presence of ice packs near the testicles or milk in the mouth may also suggest opioid use; these methods are sometimes used as street remedies for overdose. This combination of findings, together with other history that is available, usually is sufficient to establish the diagnosis; nevertheless, other causes of coma, including the intake of more than one drug, must be considered. (See Chapter 3 for a further discussion of the diagnosis and medical treatment of the comatose patient.)

B. Treatment

Emergency treatment consists of supporting or restoring vital functions and of promptly administering an opioid antagonist.

Adequacy of airway, breathing, and circulation (ABCs) should be assessed immediately. If these functions are inadequate, resuscitation should begin at once. Intubation should be performed if it is clinically indicated (see Chapter 3). If intubation is not performed, care should be taken to prevent aspiration. Support of vital functions should continue while further diagnostic and therapeutic procedures are undertaken.
A reliable i.v. route should be established. Blood should be taken for appropriate laboratory studies, including blood glucose. The serum should be screened for common drugs of abuse, including acetaminophen and aspirin. As a conservative procedure, a 50% dextrose water solution
P.117

may be injected rapidly, even when hypoglycemia is not thought to be the primary cause of the coma.
Depending on the particular clinical situation, gastric lavage may occasionally be helpful when evidence of recent ingestion of drugs is observed. This procedure should not be undertaken in a patient who has evidence of respiratory depression unless the airway has been protected by previous intubation.
Naloxone is the current short-acting antagonist of choice for the immediate reversal of the respiratory depression accompanying opioid overdosage. The usual adult dose is 0.4 to 2 mg i.v. A good response to naloxone is indicated by the reversal of the respiratory depression within one minute, followed by a lighter consciousness or level of sedation, decreased hypotension, and a widening of the pupils. Repeat doses may be given every 2 to 3 minutes, but these should be administered only if the previous dose appears ineffective. If no clinical improvement is observed after administering naloxone (up to a total of 10 mg), the clinical condition is usually not due solely to an opioid, and other causes of coma, such as trauma and other drugs, should be considered.² Because the withdrawing patient can become agitated, combative, and violent when emerging from the coma, the emergency use of physical restraints (see Chapter 26) may be required. A nonintubated patient should only be restrained in a position that minimizes the likelihood of aspiration. Naloxone does not appear to be effective, however, in relieving respiratory depression after overdosage with the partial agonist buprenorphine.
Naloxone should be administered cautiously to an opioid-dependent person, because an excess may precipitate withdrawal symptoms. When withdrawal symptoms do appear, they may be severe, but they should last only as long as the effect of the naloxone (about 30 to 90 minutes). Clonidine, a centrally acting ₂-adrenergic receptor agonist, can be administered to minimize any discomfort (see section II.C.7). Because naloxone is a pure antagonist, it should have no intrinsic pharmacologic activity in patients not taking opioids.
A syndrome of interstitial or alveolar pulmonary congestion can accompany acute overdosage. Manifestations range from asymptomatic congestion that is seen only by x-ray to severe life-threatening pulmonary edema. The heart is of normal size, and cardiac function is unimpaired. Digitalis and diuretics are of no value, and their use should not be attempted. Treatment consists of oxygen, assisted ventilation, and intubation, if necessary.
Patients should be hospitalized, preferably with continuous observation in an intensive care unit, for at least 24 hours after acute overdosage to minimize the dangers of relapse into coma and to provide for full medical evaluation, particularly when multiple-drug use is suspected.
Because most opiates have a longer duration of action than naloxone, respiratory depression and coma can recur after the initial doses of naloxone. This is particularly true with an oral methadone or propoxyphene overdose. The depressant effects may last for 24 to 48 hours after the overdose. The patient should be carefully observed, and naloxone should be readministered as required after the initial positive response.
Even after a positive response to naloxone, the physician should remember that the patient may have taken more than one drug, and monitoring should continue accordingly.

P.118

Before discharge from the intensive care unit or its equivalent, the advisability and availability of specialized follow-up medical and psychiatric care, including evaluation by a physician competent in substance abuse treatment and hospitalization in a dedicated substance abuse treatment unit, should be made clear to the patient. This is especially important, and it may enhance the chances for recovery for the patient whose overuse has been life threatening. Unless adequate attention is paid to the process of referral for aftercare and comprehensive aftercare programs are available, many opioid-addicted patients will not return for follow-up care.

II. Withdrawal

A. Diagnosis of Opioid Dependence

The diagnosis of opioid dependence is based on a history of or evidence of opioid use, followed by the abrupt cessation of use and the development of the characteristic symptoms of withdrawal (the abstinence syndrome). See Chapter 9 for a discussion of key elements in the diagnosis of physical dependence.

Heroin or morphine abstinence syndrome. The typical heroin or morphine abstinence syndrome begins approximately 8 to 12 hours after the last dose. Relatively early signs and symptoms include drug-seeking behavior, an increased respiratory rate, sweating, fever, yawning, lacrimation, rhinorrhea, gooseflesh, piloerection, tremor, anorexia, irritability, and dilated (mydriatic) pupils. More advanced signs and symptoms that occur 48 to 72 hours after the last dose include insomnia; nausea; diarrhea; weakness; abdominal cramps; vomiting; tachycardia (typically higher than 90 beats per min); hypertension (typically greater than or equal to 160/95 mm Hg in the absence of a known history of hypertension); and involuntary muscle spasms and limb movements, which were the basis for the expression kicking the habit. The syndrome subsides gradually over a period of 7 to 10 days. Some patients may have protracted withdrawal that lasts 6 to 9 months, and they may be quite troubled by mood dysregulation and greater sensitivity to life's stresses during this time.
Methadone or propoxyphene abstinence syndrome. The methadone or propoxyphene abstinence syndrome is qualitatively similar to that of morphine or heroin, but it follows a different time course. The first signs and symptoms of abstinence after regular use are seen later, generally 22 to 48 hours after the last dose. Although measuring blood concentrations of methadone typically is not part of the routine clinical assessment, data suggest that withdrawal symptoms typically appear when the blood concentrations of methadone fall below 100 ng per mL. The peak intensity appears on the third day or later. The syndrome gradually subsides, but it may continue for 3 weeks or more. Deep bone pain has been reported in the methadone abstinence syndrome. Clonidine (see section II.C.7) may relieve some of the bone pain, as may ibuprofen (600 mg every 6 hours). These patients may also experience a protracted withdrawal syndrome.
Pentazocine abstinence. This is clinically similar to abstinence from other opioids. However, it is not well antagonized by methadone substitution. Pentazocine's affinity for the receptors may explain this. Some clinicians recommend reinstituting pentazocine and then tapering the dose as the best treatment for a pentazocine abstinence syndrome.

B. Diagnosis of Opioid Dependence in the Neonate

An infant born to a heroin-dependent or a methadone-dependent mother may develop a withdrawal syndrome of hypertonicity, tremor, irritability, vomiting, fever, respiratory distress, high-pitched cry, hyperbilirubinemia, and convulsions. This typically occurs within the first 48 to 72 hours after birth (for treatment recommendations, see section II.C.12).

C. Treatment of Withdrawal (Detoxification)

Opioids should be withdrawn from a dependent person gradually, and oral methadone or buprenorphine should be given to attenuate the abstinence

P.119

syndrome. When the use of opioids is precluded, clonidine may be used instead (see section II.C.7). Optimally, detoxification should be performed in conjunction with a comprehensive treatment program to reduce the likelihood of recidivism.

The initial evaluation of a patient should include at least a complete medical and drug abuse history, a physical examination, and careful urine screening for drugs of abuse.
Attempts to establish the magnitude of a patient's habit are rarely helpful. In addition to the fact that the patient's reporting may be misleading, any formula for the conversion of bags of street heroin to a methadone dose will vary as a function of the quality of the street drug, which is usually unknown. In the last few years, the heroin available in most parts of the United States has become much more potent. More accurate estimates of the level of physical dependence can be made in the case of methadone maintenance patients who are taking a known amount of methadone. Before beginning a patient's detoxification at a given methadone level, attempting to confirm the date and amount of the last dose is important. Because patients do not always take their prescribed amounts, dividing the first day's dose to avoid accidental overdosage may be prudent. If the dose cannot be confirmed, the safest course is to follow the regimen described in section II.C.4.
Detoxification may be done on either an inpatient or outpatient basis. Some facilities reserve inpatient detoxification for patients who are dependent on more than one drug, for those who plan to enter a halfway house or a drug-free residential treatment community, for individuals who are being withdrawn from high-dose methadone maintenance, or for those who are psychotic or seriously depressed. Because of the high rate of relapse after outpatient detoxification, many facilities favor inpatient detoxification for most opioid-addicted patients. Detoxification is usually performed with long-acting opioids, such as methadone or buprenorphine. The addition of an ₂-adrenergic receptor agonist (e.g., clonidine) may help to attenuate the autonomic withdrawal symptoms and may permit a more rapid detoxification using lower doses of opiates. Patients generally prefer methadone or buprenorphine for detoxification because clonidine, when used alone, does not reduce the subjective opiate craving.
When methadone is used, an initial dose of 10 to 20 mg of oral methadone is administered after the appearance of withdrawal symptoms, such as (a) an increase in heart rate of at least 15 beats per min above baseline or a rate above 100 beats per min; (b) a diastolic blood pressure greater than 100 mm Hg, a systolic level above 160 mm Hg, or an increase in either of 15 mm Hg or more; or (c) an obvious pupillary dilatation. These determinations should be made after the patient has been observed at rest for at least 5 minutes, because some patients may use exercise to increase their heart rate and blood pressure. A single dose of methadone typically reaches peak levels in 30 to 60 minutes, and its effects on opioid withdrawal symptoms may last for 24 to 36 hours. Signs of intoxication, such as drowsiness, after the initial dose may indicate the use of too much methadone. Incremental doses of 10 mg are given over the next 24 hours when further signs of abstinence occur, but no more than 20 mg should be required in any 12-hour period, unless the patient has a documented history of tolerance to more than 40 mg of methadone per day. This first 24-hour amount is then administered as a single daily dose or in divided doses as the initial dosage strategy. Within the first few days of detoxification, the methadone dose is adjusted to reach stabilization.

Methadone is sometimes administered to outpatients in a more routine fashion that varies somewhat from program to program. Some clinicians supplement methadone with dicyclomine to relieve abdominal cramps, at a dose of 40 mg orally (p.o.) every 6 hours as needed for
P.120

48 hours and then of 20 mg every 6 hours for the next 48 hours, as needed. Other useful symptomatic medications include ibuprofen, 600 to 800 mg every 6 to 8 hours, for headache, muscle or joint pain; methocarbamol, 750 mg, for muscle spasm; lorazepam, 1 to 2 mg p.o., for anxiety; and trazodone, 50 mg p.o., for insomnia.
Once stabilization is achieved, detoxification can begin. Many schedules call for a reduction of 5 mg per day or a maximum of 20% reduction per day and complete withdrawal within 7 to 10 days; other protocols involve more gradual detoxification schedules for some patients. One well-tolerated protocol uses 5 mg per day decrements until a daily dose of 10 mg is reached; at that point, the reduction is shifted to 2.5 to 5 mg per day. Patients should be told that they may experience some mild withdrawal symptoms, which are similar to a mild case of the flu, during detoxification. During detoxification, the patients' urine should be monitored for drugs of abuse. Detoxification without a comprehensive care plan is seldom useful.
The clinician should remember that methadone metabolism can be induced by the coadministration of carbamazepine, phenobarbital, rifampin, or phenytoin, even though such drug combinations are not frequently encountered. The acute or chronic use of these medications may precipitate withdrawal or may lead to a need for higher dosages of methadone.
Clonidine can be helpful in reducing many of the distressing hyperadrenergic (autonomic) symptoms associated with withdrawal. As it has some intrinsic analgesic effects, it may also lessen bone and muscle pain. However, clonidine does not reduce subjective withdrawal symptoms or relieve opiate craving. Most patients strongly prefer detoxification protocols that use opioids. Because of the potential for hypotension and excessive sedation, clonidine administration is sometimes initiated with the patient in bed in a clinical setting for the first 24 to 36 hours, but clonidine has also been successfully used in outpatient settings. Initial amounts of 0.1 to 0.3 mg every 6 to 8 hours (not exceeding 2.5 mg per day) are given p.o., depending on the severity of the patient's symptoms. Once the symptoms are reasonably controlled, the clonidine dosage is tapered by 0.1 to 0.2 mg per day. In some clinical settings, detoxification is conducted with clonidine alone. An alternative protocol begins with oral clonidine and then adds the clonidine patch, which is continued over 3 weeks, using the 2 transdermal therapeutic system, 0.2 mg dose, (TTS-2) patches for 2 weeks and then 1 TTS-2 patch for the final week. When time and resources allow a longer detoxification strategy, the patient can first be stabilized on methadone, and clonidine can be added to alleviate any withdrawal symptoms that appear during the methadone detoxification (see section II.C.4.).

Rapid opioid detoxification, using crossover dosing of clonidine and naltrexone, has been proposed. On day 1, patients are given 0.1 to 0.2 mg of clonidine p.o. every 4 hours (up to 1.2 mg), plus naltrexone, 12.5 mg p.o.; on day 2, the clonidine dose is 0.1 to 0.2 mg p.o. every 4 hours (up to 1.2 mg), and 25 mg of naltrexone is administered p.o. The clonidine dose is tapered on day 3 (0.1 to 0.2 mg p.o. every 4 hours), with the addition of naltrexone, 50 mg p.o.

Ultrarapid detoxification protocols have been described; these involve (a) inducing and maintaining sleep with a benzodiazepine (e.g., i.v. midazolam), (b) precipitating withdrawal with naloxone while the patient is sleeping, and (c) reversing the sleep with the benzodiazepine receptor antagonist flumazenil. Little data have been published on this approach, and it should be considered highly experimental.
After detoxification, patients should be offered continued outpatient or residential rehabilitative care to prevent relapse. Many clinicians believe that patients in outpatient treatment should have daily visits for counseling and urine screens for at least 3 months.

P.121

Patients being withdrawn from methadone maintenance, especially those on doses greater than 50 mg per day, are often detoxified over a more prolonged period. These patients can be detoxified with a reduction of 5 mg per day until the level of 20 mg per day is reached. At this level, they are often detoxified more gradually. A slower methadone taper over 3 to 6 months is favored by most clinics. An alternative approach consists of adding a clonidine patch for the final 2 weeks of a gradual methadone taper and then continuing the patch for the first methadone-free week. Some facilities favor inpatient detoxification once the 20 mg level is reached. Some clinicians have advocated the combined use of clonidine and naltrexone (see sections II.C.7 and III.D.1) on an inpatient basis to ease the distress of withdrawal in patients taking modest doses of methadone.
The detoxification of patients who are dependent on both opioids and sedative-hypnotics is discussed in Chapter 9.
Some pregnant women on opioids (see also section III.B) are at high risk for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) infection. Staff involved in their care must be aware of these risks, and they should follow the appropriate procedures. Some data suggest that pregnant women in methadone maintenance programs, compared with addicted women who are not in such programs, have, on average, fewer birth complications, larger newborns, and longer pregnancies (i.e., closer to full term).
The infant born to an opioid-dependent mother should be observed for signs of withdrawal. Such signs typically occur within 72 hours after birth. Treatments include paregoric where available and phenobarbital. Breast-feeding can be carried out by women in methadone maintenance programs for the first 6 months after delivery. No data beyond 6 months are available.

III. Longer Term Treatment

Follow-up treatment for opioid use is particularly important because of the public health threat of hepatitis and HIV infection through needle sharing. It should involve efforts at rehabilitation and the prevention of recidivism. Such care should be given by experienced programs that include at least the following services:

Group and individual psychotherapy, family counseling, supplementary education, job training and placement, legal aid, and welfare assistance, as necessary;
Psychiatric treatment for comorbid psychiatric disorders because up to 70% of all opioid-dependent patients may have a mood disorder at some point in their lives;
Medical treatment for the complications of addiction;
Attempts at helping the patient to overcome the drug craving that has been described in addicts after withdrawal;
Involvement in a 12-step program, such as Narcotics Anonymous.

Drug abuse treatment programs can be categorized according to their overall approach to treatment.

A. Drug-Free Programs

These programs do not use pharmacotherapy in their treatment regimen. Instead, they try to stimulate a change in opioid-dependent patients that will allow them to remain drug free. Treatment usually begins after detoxification, and it often includes a phase of full-time residence in the program. A variety of programs exists, including therapeutic communities using peer counseling and confrontational and cognitive-behavior therapy approaches to change attitudes and behaviors and to promote drug-free living. These programs are arduous, and they require a high level of motivation and commitment to change.

Many opioid-addicted patients are treated with a staged approach. The inpatient stay includes detoxification, educational experiences, participation

P.122

in Narcotics Anonymous, psychotherapy, and relapse-prevention training. The next step frequently is placement in a halfway house for 3 to 12 months. This phase may be followed by three-quarter-way house placement. Finally, drug-free apartments are used. Patients are usually moved along as cohorts of peers, and 12-step principles and relapse-prevention training continue in all stages. Patients are told that the road to recovery is known to be difficult, and this is also reflected in staff attitudes. As the patient progresses, the level of the holding environment is gradually decreased, and the patient assumes increasing degrees of responsibility. Long-term success depends on the development of an effective support system in the community that will help the addicted person sustain a drug-free life-style after the completion of the residential phase of treatment.

Rehabilitation and a return to independent living frequently take 6 to 24 months. These programs are expensive, and they are extremely demanding on the patients and treatment staff; experience suggests that only the most highly motivated patients stay in treatment. For those who do stay in treatment, however, the outcome may include a significant enhancement of social and psychologic functioning. Many graduates of these programs later become effective workers in drug abuse programs.

B. Opiate Substitution Therapy Programs

Initially developed using methadone maintenance, opiate substitution therapy (OST) programs now provide a variety of pharmacologic options for facilitating the addiction recovery process. Oral medication methadone, levacetylmethadol (l-acetyl- -methadol [LAAM]), or buprenorphine normalizes the addicted person's altered physiologic processes and provides a foundation for other rehabilitative activities. Extensive research has demonstrated that OST reduces mortality and illicit drug use, reduces the transmission of HIV and hepatitis, and reduces both unemployment and crime. At appropriate dosage levels, these medications prevent opioid withdrawal, block the euphoric effects of illicitly used opioids, and prevent opioid craving. Patients in OST show a significant improvement in psychologic and physical health. OST has been proven most effective for those patients who have chronic histories of addiction, who have demonstrated repeated relapses after detoxication, and who have failed in drug-free treatment modalities. OST is usually provided to outpatients and is augmented by the various rehabilitative services listed earlier. Many successful programs require daily attendance for at least 3 months in which random checks of urine are conducted to detect lapses and a well-defined continuing program of group and individual counseling.

Methadone is an orally effective synthetic -opioid receptor agonist that was originally developed for the treatment of severe pain. Because of its long elimination half-life, it prevents opioid withdrawal for 22 to 36 hours and it can be administered for OST in a single daily dose. Methadone is an effective substitute for short-acting opioids. Patients maintained on methadone become tolerant to most of its effects at the maintenance dosage, and they can carry out their usual functions without any evidence of intoxication or functional impairment.

Methadone is begun without prior detoxification. Research has demonstrated that maintenance doses in the range of 60 to 80 mg per day or higher are required to block the effect of injected illicit opiates, to eliminate opiate craving, and to curtail the use of illicit opiates. Common side effects include constipation, a decreased sexual drive (libido), and excessive sweating. Most patients adapt to these side effects. Fertility is often improved in successfully maintained patients. Many patients can be successfully maintained on daily doses below 40 mg per day once they have achieved several years of stability at higher doses. Gradual detoxification from maintenance is recommended for younger addicts with briefer histories of addiction. Unfortunately, an 80% relapse rate within 12 months after detoxification is observed for even the most successful
P.123

maintenance patients. Clinicians should use great caution in recommending detoxification for chronic addicts. Opioid-addicted persons who have not achieved drug-free status by the age of 35 years rarely remain abstinent after detoxification. Indefinite OST should be recommended for such chronic and vulnerable patients.

Methadone maintenance remains the most widely applicable medical treatment available today. In the United States, federal regulations define admission standards for OST programs; describe appropriate doses; delineate the take-home supply; and specify the need for urine testing, record keeping, and supportive services. Each program must be approved before it can provide OST. In some countries (e.g., Germany), specific qualifications are needed to prescribe methadone, and all prescriptions are monitored centrally by an agency comparable with the United States Food and Drug Administration.

Some programs maintain heroin-dependent pregnant women on low doses of methadone (20 to 40 mg per day) to reduce the likelihood both of continued i.v. opioid use by the mother and of a severe withdrawal reaction in the infant. Maintaining a steady dose of methadone also protects the fetus from the changing concentrations of any opioid that the mother might abuse if she was not taking methadone. With such patients, however, ensuring that the low dose chosen is effective is important; otherwise, their craving for opioids may be increased. A concern that detoxification could terminate the pregnancy often exists. Some programs believe that very gradual detoxification and referral to a halfway house specializing in treating pregnant patients is beneficial. With the latter approach, the fetus is detoxified in utero and is born to a drug-free mother. Further studies are still needed to give more information on the optimal treatment of these patients.
Levacetylmethadol (LAAM) is a synthetic -opioid receptor agonist that is a longer-acting derivative of methadone. It is similar to methadone in its clinical efficacy, side effects, and drug interactions; but it has a slower onset of action. LAAM has two active metabolites, nor-LAAM and dinor-LAAM. Because these metabolites are eliminated more slowly than the parent drug, they produce a longer duration of action. In adequate doses, LAAM prevents opiate withdrawal for 48 to 72 hours. It is used clinically on an every other day (q.o.d.) or three times per week dosing schedule. Treatment begins with a 20 to 40 mg q.o.d regimen, with increases of 5 to 10 mg until a dose in the range of 80 to 100 mg or higher is achieved. Some clinics prefer to stabilize patients on methadone initially and then to convert them to a LAAM dose that is 1.2 to 1.3 times the methadone maintenance dose. A 30% to 40% higher dose is administered for the first 72-hour interval. Many patients prefer LAAM to methadone, reporting that they feel more normal (probably because of the longer duration of action) and that three times a week dosing is less disruptive to work and family responsibilities than is the daily dosing that is required for methadone treatment.

LAAM availability has ended in European Union countries. This action was taken because these countries concluded that LAAM had an unacceptable benefit-to-risk ratio, with the risk coming from increases in QTc intervals and, in some cases, of the ventricular tachyarrhythmia torsade de pointes. In the United States product, labeling for LAAM has been revised to include a black box warning, and it has been downgraded to non first-line therapy status. LAAM should not be prescribed for patients with preexisting QTc interval prolongation or for those taking medications that inhibit CYP 3A4. Patients should be given a 12-lead electrocardiogram before starting LAAM. Initial biweekly electrocardiographic monitoring with subsequent periodic monitoring is prudent. LAAM is not approved for use in pregnant women; those on LAAM who become pregnant must be switched to methadone.

P.124

Buprenorphine. The most recent addition to the group of medications proposed for OST is buprenorphine. This semisynthetic partial agonist has an extremely high affinity for -opioid receptors, and it is also a potent antagonist at the receptors. It dissociates slowly from these receptors, giving it a long duration of action (24 to 48 hours) and a unique safety profile that includes a reduced likelihood of withdrawal reactions.

Buprenorphine is a hybrid of the agonist etorphine and the antagonist diprenorphine. It produces subjective opioid effects after acute use, but it causes only limited dependence and mild withdrawal reactions in humans. In overdoses, an apparent ceiling effect at the receptor appears to prevent fatal respiratory depression despite the escalated intake. Like LAAM, doses can be administered three times a week. Its clinical efficacy is comparable with methadone. Addicted persons can be administered an initial dose of buprenorphine at 12 to 24 hours after their last heroin dose. Sublingual doses of 2 to 4 mg can be administered every 2 to 4 hours up to a maximum dose of 8 mg for the first day. An additional 2 to 4 mg can be added daily until the initial target maintenance dose of 12 to 16 mg per day is reached.

In addition to its use for OST, buprenorphine appears to be an effective medication for opioid withdrawal. Although a gradual 10-day to 14-day detoxification protocol is preferred, 3-day protocols have been well accepted by patients. Using the parenteral analgesic form of buprenorphine, patients have been dosed according to the following regimen: 0.3 to 0.6 mg intramuscularly three times a day on day 1, 0.15 to 0.3 mg intramuscularly three times a day on day 2, and 0.15 mg intramuscularly once or twice a day on day 3. Using the sublingual (SL) tablets, patients can be dosed with 12 mg SL (days 1 and 2) and then 6 mg SL on day 3.

In a major departure from the methadone maintenance clinic model, sublingual buprenorphine distributed as a combination tablet with naloxone has been proposed as a take-home medication for use by stable OST patients in office-based clinical practices. However, until the United States Food and Drug Administration grants final regulatory approval, this use of buprenorphine for the treatment of opioid addiction is precluded in the United States.

C. Multimodality Programs

Many drug abuse treatment programs use more than one treatment track or option. Such options might include drug-free residential treatment, OST treatment, methadone detoxification with continued outpatient treatment, or various combinations of these. All patients in these different settings have access to common social and rehabilitation services as described earlier. The growing recognition in drug-free residential programs has been that attention must be paid to the concomitant psychiatric and medical disorders, such as depression and chronic pain. Special consideration must be given to selecting nonaddicting medications for treating accompanying disorders in these so-called dual diagnosis patients.

D. Other Chemotherapy Maintenance Treatments

Naltrexone is a long-acting competitive opioid antagonist. It has little intrinsic activity, although it may produce miosis in some patients. It has minimal effects on craving and no reinforcing properties. Naltrexone acts for more than 24 hours after a single oral dose, usually of 50 mg. Some have suggested that naltrexone, which antagonizes the effects of an administered opioid, can be taken by the detoxified patient until the likelihood of a relapse to opioid use is diminished.

Naltrexone is generally administered only after a patient remains opioid free and without clinical signs of withdrawal for 5 to 10 days and then shows no signs of precipitated withdrawal after a naloxone challenge. The usual waiting period is 10 to 14 days after methadone discontinuation. The challenge procedure often involves an initial injection of 0.2 mg of naloxone i.v., followed by a second dose of 0.6 mg. Treatment
P.125

is then begun at 10 mg per day, with increases to 150 mg per day over the initial 10 days. Maintenance dosing schedules, such as 50 mg of naltrexone every 24 hours, with additional dosing (i.e., an additional 50 to 100 mg) on vulnerable days, such as weekends, are typical. Spaced dosing with larger doses (i.e., 100 to 150 mg every 2 or 3 days) sometimes helps with adherence.

Many experienced clinicians believe that naltrexone maintenance is the approach of choice when treating opioid-dependent physicians and other health care professionals. Clearly, the use of naltrexone is most successful in highly motivated patients who believe that they have a great deal to lose if treatment does not work. Less-motivated patients rarely participate in naltrexone programs. At times, legal or penal system involvement is beneficial. Considerable care must be given to educating patients about the benefits and risks of naltrexone use. They must understand that it is different from methadone; naltrexone can precipitate withdrawal in an addicted person, and this withdrawal cannot be easily overridden. The use of naltrexone in patients abusing more than one substance poses special risks.
Nalmefene is a new opioid antagonist that has shown some promise in reducing relapse in alcoholics, and it has the potential for usefulness in the treatment of opioid addiction. It appears to produce no hepatotoxicity or other serious side effects; it is also a longer-acting agent than is naltrexone.

E. Needle Exchange Programs

Needle exchange programs are one example of a harm reduction approach to the problem of opioid abuse. Many health care providers believe that, in the absence of more effective strategies and treatments to reduce recidivism rates, harm reduction is a more workable goal than is complete abstinence for some opioid abusers. Needle exchange programs have demonstrated their effectiveness in reducing the transmission of HIV and hepatitis; they may also be helpful in recruiting addicted persons into treatment programs. Currently no evidence indicates that such needle exchange initiatives encourage or spread i.v. drug use.

ADDITIONAL READING

Ball J, Ross A. The effectiveness of methadone maintenance treatment. New York: Springer-Verlag, 1991.

Barthwell A, Senay E, Marks R, et al. Patients successfully maintained with methadone escaped human immunodeficiency virus infection. Arch Gen Psychiatry 1989;46:957 958.

Bell J, Seres V, Bowron P, et al. The use of serum methadone levels in patients receiving methadone maintenance. Clin Pharmacol Ther 1988;43:623 629.

Camacho LM, Bartholomew NG, Joe GW, et al. Maintenance of HIV risk reduction among injection opioid users: a 12 month post-treatment follow-up. Drug Alcohol Depend 1997;25:11 18.

Caplhorn JRM, Ross M. Methadone maintenance and the likelihood of risky needle sharing. Int J Addict 1995;28:983 998.

Charney DS, Heninger GR, Kleber HD. The combined use of clonidine and naltrexone as a rapid, safe, and effective treatment of abrupt withdrawal from methadone. Am J Psychiatry 1986;143:831 837.

Church SH, Rothenberg JL, Sullivan MA, et al. Concurrent substance use and outcome in combined behavioral and naltrexone therapy for opiate dependence. Am J Drug Alcohol Abuse 2001;27:441 452.

Comer SD, Collins ED, Fischman MW. Buprenorphine sublingual tablets: effects on IV heroin self-administration in humans. Psychopharmacology 2001;154:28 37.

Cooper J, Altman F, Brown B, et al. Research on the treatment of narcotic addiction: state of the art. Rockville, MD: National Institute on Drug Abuse, 1983.

P.126

D'Aunno T, Folz-Murphy N, Lin X. Changes in methadone treatment practices: results from a panel study, 1988 1995. Am J Drug Alcohol Abuse 1999;25:681 699.

National Institutes of Health Consensus Development Conference. Effective medical treatment of opiate addiction. NIH consensus statement. November 17 19, 1997. 1997;15:1 38.

Geraghty B, Graham EA, Logan B, et al. Methadone levels in human breast milk. J Hum Lactation 1997;13:227 230.

Gowing L, Ali R, White J. Buprenorphine for the management of opioid withdrawal (Cochrane review). Cochrane Database Syst Rev 2000;3:CD002025.

Harding-Pink D. Methadone: one person's maintenance dose is another's poison. Lancet 1993;341:665 666.

Jasinski DR, Johnson RE, Kocher TR. Clonidine in morphine withdrawal: differential effects on signs and symptoms. Arch Gen Psychiatry 1985;42:1063 1066.

Johnson RE, Jaffe JH, Fudala PJ. A controlled trial of buprenorphine for the treatment of opioid dependence. JAMA 1992;267:2750 2755.

Joranson DF, Ryan KM, Gilson AM, et al. Trends in medical use and abuse of opioid analgesics. JAMA 2000;283:1710 1714.

Kosten TR, Kleber HD. Buprenorphine detoxification from opioid dependence: a pilot study. Life Sci 1988;42:635 641.

Ling W, Charuvastra C, Collins JF, et al. Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial. Addiction 1998;93:475 486.

Ling W, Wesson DR, Charuvastra C, et al. A controlled trial comparing maintenance in opioid dependence. Arch Gen Psychiatry 1996;53:401 407.

Maddux JF, Desmond DP. Methadone maintenance and recovery from opioid dependence. Am J Drug Alcohol Abuse 1992;18:63 74.

Mason BJ, Salvato FR, Williams LD, et al. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 1999;56:719 724.

Mello NK, Mendelson JH, Kuehnle JC. Buprenorphine effects on human heroin self-administration: an operant analysis. J Pharmacol Exp Ther 1982;223:30 39.

Metzger D, Woody G, McLellan A, et al. Human immunodeficiency virus seroconversion among intravenous drug users in- and out-of-treatment: an 18 month prospective follow-up. J Acquir Immune Defic Syndr 1993;6:1049 1056.

O'Connor PG, Carroll KM, Shi JM, et al. Three methods of opioid detoxification in a primary care setting. Ann Intern Med 1997;127:526 530.

O'Connor PG, Kosten TR. Rapid and ultra rapid opioid detoxification techniques. JAMA 1998;278:229 234.

O'Connor PG, Oliveto AH, Shi JM, et al. A randomized trial of buprenorphine maintenance for heroin dependence in a primary care clinic for substance users versus a methadone clinic. Am J Med 1998;105:100 105.

Pasternak GW. Opioid receptors. In: Meltzer H, ed. Psychopharmacology: the third generation of progress. New York: Raven, 1987:281 288.

Peachy JE. The role of drugs in the treatment of opioid addicts. Med J Australia 1986;145:395 399.

Rosen MI, Kosten TR. Buprenorphine: beyond methadone? Hosp Comm Psychiatry 1991;42:347 349.

Rounsaville BJ, Kleber HD. Untreated opiate addicts. Arch Gen Psychiatry 1985;42:1072 1077.

Sees KL, Delucchi KL, Masson C, et al. Methadone maintenance vs 180-day psychosocially enriched detoxification treatment of opioid dependence. JAMA 2000;283:1303 1310.

Senay EC. Methadone maintenance treatment. Int J Addict 1985;20:803 821.

Umbricht A, Montoya ID, Hoover DR, et al. Naltrexone shortened opioid detoxification with buprenorphine. Drug Alcohol Depend 1999;56:181 190.

Ward J, Hall W, Mattick RP. Role of maintenance treatment in opioid dependence. Lancet 1999;353:221 226.

Woods JH, Winger G. Opioids, receptors, and abuse liability. In: Meltzer H, ed. Psychopharmacology: the third generation of progress. New York: Raven, 1987:1555 1564.

Zweben JE. Counseling issues in methadone maintenance treatment. J Psychoactive Drugs 1991;23:177 190.

¹Although more than one definition of the term partial agonist may exist, here it refers to a receptor ligand that binds to a receptor and elicits a response that is submaximal when compared with a full agonist for the same receptor. By occupying the receptor in this manner, a coadministered full agonist cannot bind as well to its receptor; the net result is that the partial agonist functions as an antagonist to the full agonist.

²Although the authors have not found documentation in the literature, the authors have received an anecdotal report of rare cases of apparently massive methadone overdoses that seemed to require further doses of naloxone to produce an initial response (W. Leigh Thompson, M.D., personal communication).