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DOI: 10.1176/appi.books.9781585623440.351947
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Chapter 20. Opioid Maintenance Treatment
OPIOID MAINTENANCE TREATMENT: INTRODUCTION
Opioid dependence (i.e., dependence on opiate or opiate-like drugs) is a chronic and severe
psychiatric disorder associated with substantial risk of mortality, medical and other psychiatric
morbidity, and adverse social, vocational, familial, and legal consequences. As with other chronic
and severe medical or psychiatric disorders, the goals of treatment are to prevent or reduce the
adverse medical, psychiatric, and other consequences of the disorder and to improve the patient’s
functioning, quality of life, and overall well-being.
Since its development in the 1960s as a treatment for opioid dependence, opioid agonist
maintenance treatment, initially with methadone and more recently with L- -acetyl-methadone
(LAAM) or the partial agonist buprenorphine, has proven to be the most effective treatment for
opioid dependence. This treatment greatly reduces the risk of mortality, morbidity, and other
adverse consequences of the disorder. Methadone or other opioid agonist maintenance treatment
generally refers to a comprehensive treatment approach that includes the continuing
administration of opioid medications under medical supervision in combination with drug
counseling, behavioral monitoring and intervention, and provision of other psychiatric, medical, and
vocational services as clinically indicated. Medically supervised provision of methadone
maintenance alone, in the absence of counseling or other services (referred to as interim
methadone maintenance in the United States), however, may still lead to substantial benefits
compared with not providing methadone maintenance (Schwartz et al. 2007). Although other
treatments (e.g., medically supervised withdrawal followed by opioid antagonist maintenance
treatment or long-term residential therapeutic community treatment) are efficacious for some
patients, the widespread patient appeal of opioid agonist maintenance treatment, high treatment
retention, substantial reductions of illicit drug use and criminal activity, and improvement in
medical, social, family, and vocational functioning during opioid agonist maintenance treatment
combine to make it the most effective approach for individuals meeting eligibility requirements for
Nevertheless, the rationale for methadone or other opioid agonist maintenance treatment is often
misunderstood; social and political opposition to methadone maintenance treatment limits its use
in many regions of the world and within the United States; access to the treatment is often limited
by inadequate treatment resources (lack of programs or treatment “slots”) and reimbursement;
and methadone or other opioid agonist maintenance treatment is often suboptimal and provided
without adhering to research-based principles that are known to improve its efficacy.
In this chapter, I review the rationale for opioid agonist maintenance treatment and the clinical
pharmacology, medication interactions, and adverse effects of methadone; the research supporting
the efficacy and effectiveness of methadone maintenance treatment overall and the efficacy of
specific components of treatment (dose, counseling, duration of treatment); special treatment
issues (comorbid other substance use, psychiatric disorders, and medical disorders; pain
management; pregnancy); federal rules governing opioid agonist maintenance treatment; and
opioid agonist maintenance treatment in primary care clinics and physician offices.
The clinical pharmacology of buprenorphine, the third medication approved by the U.S. Food and
Drug Administration (FDA) for opioid agonist maintenance treatment, is reviewed in Chapter 21,
“Buprenorphine Maintenance,” in this volume.
OPIOID DEPENDENCE: EPIDEMIOLOGY AND NATURAL HISTORYPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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Recent studies point to an increase in illicit opioid use and dependence in the United States during
the past decade and indicate that approximately 2 million adults are dependent on heroin or
nonmedically prescribed prescription opioids (SAMHSA 2006). Initiation of illicit opioid use most
often begins in late adolescence and early adulthood and is generally preceded by use of cigarettes,
alcohol, and other drugs. The latency period for the transition from occasional use to dependence is
variable and may last only a few weeks to several years or more. The number of new users of
nonmedically prescribed opioids (by oral, intranasal, or injection routes) has increased in the
United States from an estimated 600,000 individuals in 1990 to 2.2 million individuals in 2006 and
has become the drug category with the largest number of new users each year (SAMHSA 2007).
The availability of high-purity heroin, which may be used by nasal insufflation or smoking, may also
have lowered the threshold for initial experimentation with heroin and attracted many new users
(Bach and Lantos 1999).
Heroin continues to be used primarily by injection in many regions in the United States, but in some
regions of the country most patients addicted to heroin entering treatment now report noninjection
routes of administration (National Institute on Drug Abuse 2005). Although these other routes of
administration reduce the risk of infectious diseases (e.g., HIV, hepatitis, endocarditis), the risk of
transition from nonmedically prescribed opioids to heroin and from noninjection to injection use is
high—one study estimated that 15% of intranasal heroin users convert to injection use each year
(Neaigus 1998)—and the incidence of infectious diseases increases dramatically following
transition to injection use. Drug overdose is also a significant risk with insufflation or smoking of
heroin or with oral, intranasal, or injection use of prescription opioids, although many users are not
aware of this risk.
The transition from heroin use to dependence carries a dire prognosis, with a risk of dying of
approximately 2% per year, and sustained remission is difficult to achieve. A little more than 30
years after admission to compulsory drug abuse treatment in California, nearly half of the 581
heroin-addicted men followed up on in one cohort study had died (Hser et al. 2001). At the time of
admission, most of these heroin-addicted men were in their 20s and 30s, and the results of this and
other studies indicate that, in comparison with peers matched for age, gender, and socioeconomic
status, the annual risk of dying for a heroin-addicted person is increased 6- to 20-fold. Most of the
excess mortality is due to drug overdose, suicide, violence, accidents, infection, or chronic liver
disease. Only 23% of the original cohort of addicted men in California were not currently using
illicit opiates 33 years after admission; the rest were currently using (9%), refused to provide a
urine specimen for toxicology testing (4%), were in prison (6%), were not interviewed (10%), or
were dead (49%). Notably, only about one out of six of those who were continuing to use 20 years
after admission and about the same proportion of those who had been abstinent for less than 5
years at that time point were abstinent 10 years later. One-quarter of those who had been
abstinent for more than 15 years at the 20-year follow-up also relapsed over the next 10 years.
These findings point to the persistence of the disorder and the high risk of relapse even after long
periods of remission. Less than 10% of the cohort participated in methadone maintenance
treatment in any given year, but heroin use was reduced in those who participated in this
treatment. As has been so vividly demonstrated in the results of this and other long-term follow-up
studies (Vaillant 1973), after its onset, the course of heroin or other opioid dependence is chronic
and persistent, marked by periods of abstinence that are often followed by relapse, and associated
with a severe risk of death or disability.
CLINICAL PHARMACOLOGY OF METHADONE AND LAAM
Methadone is a synthetic, long-acting, orally available opioid that acts primarily as a high-affinity
agonist at and opiate receptors; methadone also acts as an N-methyl-D-aspartate (NMDA)
antagonist (Gutstein and Akil 2001). After oral administration, methadone is rapidly and nearly
completely (85%–90%) absorbed in the intestine. Absorption can be delayed by reductions in
gastric emptying caused by food, by hypertonic sucrose solutions often used to dissolve methadone
(in order to deter its injection), or by methadone itself. Peak plasma levels of methadone occur 2–6
hours after oral administration. Methadone is highly lipophilic, has a large volume of distribution,Print: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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and accumulates in high concentrations in solid organs (liver, kidney, lungs, and brain) (Wolff et al.
1997).
Generally administered as a racemic mixture, R-methadone has substantially higher affinity and
efficacy at and opioid receptors and lower protein binding in plasma compared with the
S-enantiomer. S-methadone is not inactive, however, and has comparable NMDA antagonist activity
to R-methadone and, compared with R-methadone, is associated with an opposite profile of effects
on mood (negative mood states) and withdrawal symptoms (increased rather than relieved),
especially at higher daily doses of the racemic mixture (Mitchell et al. 2004). Methadone undergoes
N-demethylation to a highly unstable compound, which undergoes rapid and spontaneous
cyclization and dehydration to the major inactive methadone metabolites. The major route of
methadone metabolism is through cytochrome P450 (CYP) enzymes, predominantly involving the
CYP3A4 pathway but also involving CYP2B6, CYP2C19, CYP2D6, CYP2C9, and possibly also CYP1A2
and CYP2C8 (Crettol et al. 2006); methadone also inhibits CYP2D6 (Eap et al. 2001). After oral
administration, methadone and its metabolites are excreted in approximately equal amounts in
urine, and urinary excretion accounts for about 50% of the dose.
The long plasma half-life of methadone (averaging 24 hours, with a range of 13–50 hours) after
repeated daily dosing results in part from accumulation of methadone in organ systems, and
achievement of steady-state plasma levels may take 5–10 days. Its long half-life permits
once-a-day methadone dosing during maintenance treatment. During maintenance treatment,
peak-to-trough plasma ratios generally range from 2:1 to 4:1 (Foster et al. 2001). Trough
concentrations exceeding 200 ng/mL are usually sufficient to prevent withdrawal, although some
studies suggest that an increased rate of decline, associated with more rapid metabolism of
methadone, even with adequate trough levels, also may be associated with withdrawal symptoms
(Dyer et al. 1999). There are considerable interindividual differences in methadone metabolism,
which may be mediated by genetic polymorphisms affecting the activity of CYP isoforms as well as
by medications that induce or inhibit these enzymes or by liver disease. Although clinically
significant diurnal alterations in mood state are not observed or reported during methadone
maintenance treatment for most patients, mood changes associated with changes in methadone
plasma concentration have been observed after administration of a sensitive assessment measure,
the Profile of Mood States. These changes are more pronounced before patients have developed full
tolerance to their daily dose and in patients who report experiencing withdrawal symptoms even
while taking a stable methadone dose compared with patients who do not report withdrawal (Dyer
et al. 2001). As a result, some patients with very rapid methadone metabolism may benefit from
methadone dosing two times a day (split dosing).
LAAM, a methadone derivative also approved by the FDA for opioid agonist maintenance treatment,
has a longer half-life than methadone (2 days) and is metabolized by CYP enzymes (primarily
CYP3A4) to two active metabolites with half-lives of 2 days (nor-LAAM) and 4 days (dinor-LAAM)
(Neff and Moody 2001). Like methadone, LAAM acts as a full agonist at opiate receptors and is
absorbed from the gastrointestinal tract after oral administration, with initial effects appearing
within 1 or 2 hours. Because LAAM is slowly metabolized to two active metabolites, which are
somewhat more potent than LAAM, steady-state levels of LAAM and its active metabolites and its
full effects are achieved after 1–3 weeks. Daily dosing can lead to excessive accumulation of active
medication and metabolites, and Monday-Wednesday-Friday dosing is recommended. The longer
period required to achieve a full maintenance dose is thought to be responsible for the greater
early attrition from treatment found during induction onto LAAM compared with methadone. The
abuse liability of LAAM is comparable with that of methadone, and consequently, use of LAAM is
restricted to approved narcotic treatment programs, which diminished its appeal to patients.
Reports of clinically significant prolongation of the QT interval and torsades de pointes associated
with LAAM led to its removal from the European Union and a black box warning in the United
States, and LAAM is no longer being marketed in the United States.
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Knowledge of possible interactions between opioid agonist medications used for maintenance
treatment and other prescribed or herbal medications or use of other substances is essential to
ensure the safety and efficacy of methadone dosing and dosing with other medications. Medication
interactions with methadone have been more thoroughly evaluated than with buprenorphine or
LAAM, and interaction effects with LAAM are complicated because its major metabolites are active.
Methadone metabolism may be increased substantially by concomitant administration of
medications that induce CYP hepatic enzymes (e.g., carbamazepine, phenytoin, rifampicin,
efavirenz, nevirapine, ritonavir, nelfinavir, phenobarbital, dexamethasone, spironolactone, and
possibly risperidone), and initiation of treatment with any of these medications may lead to
withdrawal symptoms in a methadone-maintained patient (Rainey 2002). Initiation of risperidone
treatment during methadone maintenance also has been associated with precipitation of opioid
withdrawal, possibly through induction of methadone metabolism, interference with methadone
absorption, or a direct effect of risperidone on opioid receptors (Wines and Weiss 1999).
Methadone also induces its own metabolism during the first 2–3 weeks of administration, and the
elimination half-life of methadone early in treatment is considerably longer (median 128 hours)
than after patients have been treated for more prolonged periods (median 48 hours) (Wolff et al.
2000). Initiation of St. John’s wort, which induces CYP3A4, was reported to reduce methadone
trough plasma concentrations substantially (19%–60%) in four patients and to lead to withdrawal
symptoms in two of the patients (Eich-Höchli et al. 2003).
Medications that inhibit CYP enzymes, including some macrolide antibiotics (e.g., erythromycin or
azithromycin), fluoroquinolones (e.g., ciprofloxacin), azole antifungals (e.g., ketoconazole or
voriconazole), and some selective serotonin reuptake inhibitors (e.g., sertraline, fluoxetine, or
fluvoxamine), may cause inhibition of methadone metabolism and symptoms associated with
increased methadone plasma levels, including sedation, confusion, or possibly respiratory
depression. The effects can be quite severe, as illustrated by a case report of a 42-year-old woman
treated with 140 mg/day of methadone for 6 years who experienced sedation, confusion, and
respiratory depression when treated for recurrent urinary tract infections with ciprofloxacin, a
potent inhibitor of CYP1A2 and CYP3A4 (Herrlin et al. 2000). Concurrent treatment with
venlafaxine (or on one occasion with fluoxetine), cigarette smoking, and acute infection may have
contributed to the severity of her symptoms. Fluoxetine and fluvoxamine, inhibitors of CYP2D6 and
CYP1A2, respectively, as well as paroxetine and fluconazole cause delayed metabolism and
increases in plasma methadone half-life (Begre et al. 2002). Grapefruit juice also inhibits CYP3A4
and may lead to modest increases in peak and 24-hour area-under-the-curve plasma methadone
concentrations. Increases in methadone plasma levels due to inhibition of methadone metabolism
are most likely to cause clinically significant symptoms at the onset of methadone treatment (when
patients have the lowest tolerance) and in patients with underlying liver disease. Methadone
treatment also affects the metabolism of other medications and causes increased plasma levels of
desipramine, amitriptyline, and zidovudine. Table 20–1 shows some of the reported and possible
medication interactions with methadone.
TABLE 20–1. Medication interactions with methadone
May reduce
plasma
methadone
May increase
plasma
methadone
Methadone may
increase plasma
levels of
Methadone may
decrease plasma
levels of
May increase risk of
arrhythmia if used
with methadone
Abacavir Amiodarone Amitriptyline Didanosine
Ca++ channel blockers
Amprenavir Cimetidine Desipramine Stavudine Class I, II
antiarrhythmics
Carbamazepine Ciprofloxacin Zidovudine Haloperidol, possibly
other neuroleptics
Efavirenz Erythromycin
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May reduce
plasma
methadone
May increase
plasma
methadone
Methadone may
increase plasma
levels of
Methadone may
decrease plasma
levels of
May increase risk of
arrhythmia if used
with methadone
Lopinavir +
ritonavir
Fluconazole
Possibly laxatives
Nelfinavir Fluoxetine
Possibly tricyclic
antidepressants
Nevirapine Fluvoxamine
Phenobarbital Saquinavir
Phenytoin Sertraline
Rifampin Voriconazole
Risperidone
Ritonavir
St. John’s wort
Note. The effects of medication interactions are further complicated by the need to take into consideration
the effects of medication discontinuation. For example, discontinuation of a medication that inhibits
methadone metabolism, such as fluoxetine, can lead to increased methadone metabolism and the occurrence
of withdrawal symptoms, craving, or relapse in a previously asymptomatic and stable patient receiving
methadone maintenance treatment.
Methadone interactions with antiretroviral medications and with medications used to treat hepatitis
C are of particular interest because of the high prevalence of HIV and hepatitis C infection among
injection drug users (Rainey 2002). Although protease inhibitors are potent inhibitors of CYP3A4,
nelfinavir causes substantial decreases (40%) in plasma methadone, which can be associated with
withdrawal symptoms, possibly as a result of also inducing CYP enzymes or increasing the free
(unbound) fraction of methadone in plasma. Methadone inhibition of the glucuronidation of
zidovudine increases the plasma concentrations of this medication and the potential for
dose-related toxicity. Methadone-induced decreased gastrointestinal motility, however, leads to
increased gastrointestinal degradation of stavudine and didanosine and significant decreases in
plasma concentrations of these medications. No significant interactions have been found between
methadone and either peg interferon or ribavirin, both of which are used to treat hepatitis C
(Sulkowski et al. 2005).
RATIONALE FOR OPIOID AGONIST SUBSTITUTION TREATMENT WITH
METHADONE
The main, planned, and desired pharmacological effects of methadone, LAAM, or buprenorphine
when used for opioid agonist maintenance treatment are to prevent withdrawal and craving and to
block or attenuate the euphoric or other rewarding effects of heroin or other illicit opioid use. Oral
methadone dosages of 20–40 mg/day are generally sufficient to prevent or at least greatly
attenuate opiate withdrawal symptoms. Because craving for opiates is one of the earliest and most
powerful hallmarks of withdrawal, preventing withdrawal greatly reduces craving or the urge to
use illicit opioids. Preventing withdrawal also eliminates the repeated negative reinforcement that
occurs when heroin or other illicit opioids are self-administered to relieve withdrawal. Chronic
administration of higher doses of methadone, buprenorphine, or LAAM may directly reduce craving
(possibly by preventing more subtle manifestations of withdrawal) and also induce dose-dependent
tolerance to the effects of street doses of heroin and other illicit opioids, so that individuals
receiving sufficiently high doses experience little or no direct reinforcement from illicit opioid use
(Donny et al. 2002, 2005).
Additional advantages of the medications used for opioid agonist maintenance treatment are that
all of them have long-lasting effects on opiate receptors and substitute a less dangerous and lessPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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reinforcing method of administration (oral or sublingual) for more dangerous and reinforcing
routes (injection, smoking, nasal insufflation). Unlike the fluctuations in mood and consciousness
associated with repeated illicit administration of heroin and other short-acting opioids,
administration of long-acting maintenance medications during maintenance treatment normalizes
most neuroendocrine alterations found with use of short-acting opioids and does not substantially
alter mood or alertness throughout the day (Kreek and Koob 1998). Oral or sublingual routes of
administration lead to a relatively slow rate of increase in plasma (and brain) levels and are thus
less euphorigenic and inherently less reinforcing than routes associated with faster rates of
increase. During maintenance treatment, patients develop tolerance to the effects of their daily
methadone dose and generally experience no or only very limited and transient effects of their
daily dose. By preventing withdrawal, attenuating euphoric effects of illicit opioid use, reducing
illicit opioid use, and stabilizing mood, opioid agonist substitution treatment also provides a stable
medication platform facilitating provision of drug abuse counseling and other effective
rehabilitation services.
SAFETY AND TOXICITY
More than 40 years of clinical experience with methadone maintenance treatment, involving
hundreds of thousands of patients worldwide, has established the overall safety of methadone
when used for opioid agonist maintenance treatment. When used for maintenance treatment,
methadone has not been found to produce any long-term damage to heart, lung, kidney, liver,
brain, or other organ systems (Kreek 2000). Heroin and other opioid dependence is associated with
alterations of hypothalamic-pituitary-adrenal (HPA) axis and immune system functioning, whereas
methadone maintenance treatment generally leads to normalization of most measures of HPA axis
and immune system functioning and overall improvement in health status, although some
alterations of corticotropin releasing factor responsivity and other neuroendocrine measures may
persist (Schluger et al. 2003). The most commonly reported adverse effects of methadone when
used for maintenance treatment include constipation, which may be quite severe; sweating; and
urinary retention. Additionally, methadone maintenance treatment may be associated with
lymphocytosis and increased prolactin, albumin, and globulins. Adverse effects of methadone early
in treatment may also include nausea and vomiting, lightheadedness, hypotension, dizziness,
anorexia, and dry mouth. Methadone dose-related orgasm dysfunction (anorgasmia or delayed
orgasm) has recently been reported in men receiving methadone maintenance treatment, but other
measures of sexual dysfunction were not more prevalent in this population of men than in the
general population (Brown et al. 2005). Decreased respiratory sensitivity to carbon dioxide and
sleep apnea have also been reported for patients receiving methadone maintenance treatment, but
cigarette smoking may represent an important confound (Greenwald 2004). Similarly, low bone
density has also been reported among methadone-maintained patients, but a variety of (potentially
treatable) underlying medical conditions and dietary factors may account for this (Kim et al. 2006).
Although methadone is generally quite safe for maintenance treatment, methadone overdose can
cause severe sedation, respiratory depression, and death (Wolff 2002). Signs of methadone
overdose include drowsiness or coma, limpness, depressed respiratory rate and depth, loud
snoring, pin-point pupils, hypotension, and bradycardia. Methadone overdose may also lead to
pulmonary edema or aspiration. Overdose is particularly a problem with regard to accidental
ingestion by children, use by nondependent opioid users who experiment with methadone or
self-administer it, or at the initiation of methadone maintenance treatment if the initial doses are
too high or the methadone dose increased too rapidly. There are reports of apnea and coma in
children after ingestion of 5 mg of methadone and of death following ingestion of 10 mg of
methadone, although prompt treatment of overdose has led to complete recovery in children after
ingestion of much higher doses. Because of its long elimination half-life and the possibility of
delayed absorption, methadone overdose requires prolonged treatment.
Death has been reported to occur more than 24 hours after ingestion (and several hours after
discontinuation of naloxone treatment). Several studies report increased mortality rates during the
initial 2 weeks of methadone maintenance treatment compared with mortality rates later inPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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methadone maintenance treatment, with much of the increased mortality attributed to overdose
deaths. Methadone dosages in excess of 40–50 mg/day at the onset of methadone maintenance
treatment, when methadone has not yet induced its own metabolism and its elimination half-life is
quite prolonged, may lead to methadone accumulation and overdose death even in individuals who
report large heroin habits but who are not fully tolerant to the full effects at both and receptors
of methadone. Fatalities may occur after several days of dosing if the methadone dose is started
too high or increased too rapidly (Buster et al. 2002). The risk of methadone overdose is increased
by concomitant use of medications interfering with methadone metabolism (e.g., medications that
inhibit CYP3A4) or use of alcohol or sedating drugs (e.g., benzodiazepines, chloral hydrate).
Individuals with reduced methadone metabolism due to genetic factors or liver disease and
individuals with underlying pulmonary, cardiac, liver, or renal disease may also be at increased risk
for overdose (Corkery et al. 2004). Recent guidelines for induction onto methadone maintenance
treatment recommend starting dosages of no more than 30–35 mg/day and gradual dosage
increases (5–10 mg no more frequently than every 2–3 days). Considerably lower starting dosages
may be advisable for patients at higher risk for overdose, including patients with underlying severe
respiratory or liver disease, patients treated with sedating medications or medications inhibiting
CYP3A4, or patients with lower baseline tolerance to opioids (Srivastava and Kahan 2006).
Recent reports indicate an association between methadone and cardiac conduction defects
(prolonged QTc interval) and torsades de pointes (Krantz et al. 2002), an association previously
noted for LAAM. A black box warning about these effects was added to the prescribing information
for methadone in December 2006. Methadone may also induce bradycardia through its effects on
calcium channels, as illustrated in a recent case report of bradycardia associated with methadone
administration to a patient dependent on both opioids and benzodiazepines (Ashwath et al. 2005).
Clinically significant prolongation of the QTc interval (>500 ms) during methadone treatment has
been reported in association with high methadone doses (mean ± SD 231 ± 201 mg in one review
of cases; Justo et al. 2006), but 29% of cases reported to the FDA were in patients treated at
dosages of 60–100 mg/day (Pearson and Woosley 2005). The incidence of clinically significant
prolongation of the QTc interval among methadone-maintained patients has not been sufficiently
studied; one small study found it in 2 of 83 methadone-maintained patients (Maremmani et al.
2005), whereas another study in a program using higher methadone dosages found it in 3 of 138
patients (Peles et al. 2006). Additional risk factors for prolongation of the QTc interval in
methadone-maintained patients include concomitant use of other medications causing QTc
prolongation or arrhythmias (e.g., haloperidol, class I or II antiarrhythmics, tricyclic
antidepressants, or calcium channel blockers), inhibiting methadone metabolism, or causing
electrolyte disturbances (e.g., diuretics); hypokalemia; liver dysfunction; heart disease; or cocaine
use. Methadone effects on the QTc interval may result from blockade of ionic current through
potassium channels composed of subunits expressed by the human ether-a-go-go–related gene.
These considerations suggest the need for caution and possibly repeat electrocardiogram testing
when prescribing higher dosages of methadone (e.g., greater than 120 mg/day) and when
prescribing methadone for patients with prolonged QTc intervals or with other risk factors for QTc
prolongation or cardiac arrhythmias, including, for example, cardiac hypertrophy (Deamer et al.
2001).
Although methadone causes sedation in individuals who have not developed tolerance, methadone
maintenance treatment is generally not associated with significant sedative effects once patients
have developed tolerance to their daily methadone dose, nor is it associated with alterations of
neuropsychological functioning. With regard to driving, an evidence-based review of methadone
maintenance effects on driving performance concluded that there is relatively strong and consistent
evidence that the driving ability of patients stabilized on long-term opioid treatment is not impaired
by their regular doses of opioid medication (Fishbain et al. 2003). Patients should be advised not to
drive if they feel sedated, not to drive after using alcohol (or illicit drugs), and to be particularly
cautious if they are using medications that may increase sedation (e.g., antihistamines,
benzodiazepines) or after a dose increase. A range of neuropsychological impairments has been
reported in heroin- or other opioid-dependent individuals, however, including problems inPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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executive functioning (impulse control, planning, and decision making), verbal and visual memory,
attention, processing speed, and response inhibition. These deficits may persist after prolonged
periods of abstinence from illicit opioid use and may reflect preexisting deficits or result from
alcohol or drug abuse. Notably, however, stabilized patients receiving methadone maintenance
treatment with no evidence of illicit drug use for the preceding 18 months do not differ in measures
of neuropsychological functioning from former heroin users abstinent from illicit drug use for the
past 18 months (Prosser et al. 2006). During methadone induction or before patients have
developed tolerance to their methadone dose, methadone dose administration may be associated
with some effects on mood and cognition, including some impairment of delayed verbal recall
(Curran et al. 2001). One recent study documented significant improvement from pretreatment
baseline after 2 months of methadone maintenance treatment on measures of learning, memory,
and psychomotor performance (Gruber et al. 2006). The underlying cognitive impairments of
opioid-dependent patients (including memory and attention deficits) suggest the importance of
carefully tailoring drug counseling to the cognitive abilities of the patient, especially at the
beginning of methadone maintenance treatment, when these deficits may be most pronounced.
EFFECTIVENESS OF OPIOID AGONIST MAINTENANCE TREATMENT
The effectiveness of methadone and other opioid agonist maintenance treatments for reducing
illicit drug use, reducing mortality and morbidity, and improving social, vocational, and legal
functioning has been established in randomized, controlled clinical trials and quasi-experimental
and observational studies and has been validated in several recent meta-analyses (Institute of
Medicine Committee on the Prevention of HIV Infection Among Injecting Drug Users in High Risk
Countries 2006). Mortality rates are reduced substantially during methadone maintenance
treatment, although they remain somewhat higher than for the general population because of the
impaired health of many patients at treatment entry (e.g., HIV infection, hepatitis C). The risk of
new infection with HIV is substantially reduced in patients receiving methadone maintenance
treatment compared with untreated heroin-addicted patients in the same geographic setting, and
the risk decreases in association with the length of time continuously treated with methadone
maintenance (Metzger et al. 1993). Criminal activity decreases during treatment and has been
found to increase substantially among individuals discharged from treatment because of the closing
of public methadone programs after financial cutbacks (Anglin et al. 1989). Follow-up data from
the National Treatment Outcome Study confirm the findings of previous national studies of drug
abuse treatment regarding the effectiveness of methadone maintenance treatment for reducing
illicit drug use and criminal activity (Hubbard et al. 1997).
Most studies of the long-term effects of treatment are based on methadone maintenance, but
shorter-term studies (generally lasting up to 6 months) suggest that the effectiveness of
maintenance treatment with LAAM or buprenorphine is comparable with that with methadone. Early
attrition from LAAM compared with methadone has been a problem in some studies (Clark et al.
2002), but results for methadone, buprenorphine, and LAAM, when provided at sufficient doses,
were comparable (and significantly better than the results for a group treated with low-dose
methadone) in a large, double-blind clinical trial (Johnson et al. 2000). Recent meta-analyses
suggest that methadone may be associated with somewhat better overall reductions in illicit opiate
use compared with buprenorphine maintenance, although sufficient doses of both methadone and
buprenorphine are more efficacious than low maintenance doses of either medication (Mattick et
- 2004). Advantages of buprenorphine compared with methadone, including a decreased risk of
respiratory depression, led to buprenorphine being classified as a Schedule III narcotic and thus
permitted to be prescribed by specially certified physicians in office-based practices, whereas
methadone is a Schedule II narcotic and may only be dispensed for methadone maintenance
treatment in specialized narcotic treatment programs.
Despite the overwhelming scientific evidence establishing the efficacy and effectiveness of opioid
agonist maintenance treatment, misunderstanding of, prejudice toward, and political opposition to
methadone treatment persist and continue to interfere with efforts to increase access to and
availability of this treatment modality in the United States and elsewhere in the world. At present,Print: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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only about 240,000 of the estimated 2 million individuals dependent on heroin or other opioids in
the United States are enrolled in opioid agonist maintenance treatment. When methadone
maintenance treatment has been made widely available, free or at low cost, and publicized, 90% or
more of the heroin-addicted population have been attracted into treatment (Hartgers et al. 1992).
Economic factors, including medical insurance coverage (or the lack of coverage) for methadone
maintenance treatment, affect both entry and retention in methadone maintenance treatment. In
Oregon, 1-year retention in methadone maintenance increased from 28% to 51% when managed
care picked up the costs, whereas exclusion of methadone coverage from Medicaid led to decreased
entry into methadone maintenance treatment (Deck and Carlson 2005; Deck et al. 2006). These
findings indicate that the low market penetration of methadone maintenance treatment results
primarily from the lack of its availability in many geographic areas and the long waiting lists and
costs of treatment even in areas where programs are available, rather than from a lack of potential
need, interest, or demand for treatment.
Considerable program-to-program variability in how treatment is provided and in the effectiveness
of agonist maintenance treatment (as measured by the prevalence of continued illicit drug use
during treatment and other outcome measures) has drawn attention to identifying the key
components of methadone maintenance treatment (e.g., dose, duration of treatment, counseling,
program structure) and improving the quality of treatment programs (Ball and Ross 1991). The
most recent national survey of methadone treatment practices found that substantial progress had
been made in improving treatment practices compared with earlier surveys but still pointed to
continuing problems with inadequate methadone doses in many programs (D’Aunno and Pollack
2002).
METHADONE DOSE AND TREATMENT DURATION
The efficacy and effectiveness of maintenance treatment with methadone, as with LAAM and
buprenorphine, are dose dependent, and effective dosages generally fall within a targeted range of
60–120 mg/day or higher for methadone, 8–16 mg/day or higher for buprenorphine, and 80–140
mg three times per week for LAAM. The optimal dosage for a given patient, however, should be
based on the patient’s response to treatment.
Early observational studies pointed to the dose-dependent efficacy of methadone for maintenance
treatment, and more recent randomized, double-blind clinical trials and experimental studies
confirmed the earlier observations with regard to methadone and established the dose-dependent
efficacy of buprenorphine and LAAM. Although methadone dosages of 20–30 mg/day lead to
greater retention in treatment compared with placebo doses, illicit opioid use is dose-dependently
reduced at moderate (60–75 mg) daily doses and reduced even more at higher (100 mg) daily
doses (Strain et al. 1993, 1999). In experimental studies, dosages of 30 mg/day and 60 mg/day
are sufficient to suppress most withdrawal symptoms for more than 48 hours, but full attenuation
of the subjective and reinforcing effects of heroin (up to 20 mg/70 kg) occurs only with a higher
methadone dosage (100–150 mg/day) (Donny et al. 2002, 2005). Increased craving for opiates has
been observed 24 hours after a 25% reduction in the daily methadone dose, consistent with clinical
observations and patient reports of withdrawal-related discomfort and increased risk for
resumption of illicit opioid use following a missed daily methadone dose (Greenwald 2002).
Clinically, patients who continue illicit opioid use at a given daily methadone dose often reduce or
eliminate illicit opioid use when the daily methadone dose is increased gradually over several
weeks to a sufficiently high dose. Several studies suggest that some poor responders to methadone
dosages of 80–100 mg/day have increased metabolism of methadone and suboptimal trough
plasma methadone levels or increased rates of clearance; increasing the methadone dose to
achieve trough levels greater than 200 ng/mL, or providing methadone in split doses to prevent
trough levels from declining too rapidly or below this target, can help to reduce or eliminate
continued illicit opiate use (Dyer et al. 2001).
Duration of treatment is also a critical factor, and premature discontinuation of methadone
treatment leads to relapse. In one randomized clinical trial, tapering of methadone dose to zeroPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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over 60 days (methadone detoxification) after 4 months of methadone maintenance treatment led
to accelerated attrition from treatment and significant increases in illicit opioid use in the test
group compared with a group assigned to continued methadone maintenance treatment (Sees et al.
2000). Substantial and sustained changes in vocational or social functioning and lifestyle may take
years to achieve for many patients (Gunne et al. 2002). Even then, the risk of relapse after
discontinuation of methadone maintenance remains high even for patients who have been receiving
methadone maintenance treatment for prolonged periods and have made substantial changes in
lifestyle and achieved stable recovery while receiving treatment. Because of the difficulties
experienced by many patients who attempt tapering and detoxification (Calsyn et al. 2006), the
high risk of relapse after discontinuing methadone maintenance treatment, and the very high risk
of severe adverse consequences associated with relapse, many patients may benefit optimally from
lifetime maintenance. Decisions about whether or when to discontinue methadone treatment for
patients who are benefiting from it should always be made collaboratively and with the patient’s
fully informed and voluntary consent.
Taken together, the results of observational studies, experimental human laboratory studies, and
randomized clinical trials are compelling: methadone maintenance dose-dependently decreases
illicit opioid use; its beneficial effects on health and social and vocational functioning may occur
gradually over prolonged periods; and the effectiveness of methadone maintenance treatment
diminishes substantially when methadone doses are lowered or discontinued, even when patients
can continue to receive enhanced psychosocial services.
DRUG COUNSELING AND BEHAVIORAL COMPONENTS OF AGONIST
MAINTENANCE TREATMENT
As with many other medical or psychiatric disorders, the effectiveness of medication treatment can
be greatly enhanced by combining medication administration with counseling aimed at promoting
treatment adherence and lifestyle change. The seminal study establishing the treatment effects of
counseling evaluated treatment outcomes for 92 patients randomly assigned to one of three levels
of services (minimal counseling, standard drug counseling, or standard drug counseling plus
enhanced vocational, legal, and medical services) (McLellan et al. 1993). All patients received
identical standard daily methadone doses. The prevalence of continued illicit opioid use and of
cocaine use was substantially higher among patients in the minimal counseling group, who
received only brief contact with a counselor once per month, compared with patients in the
standard counseling group, who received weekly or more frequent counseling until achieving
sustained abstinence, or the enhanced services group. By the end of 12 weeks, 69% of the patients
in the minimal counseling group had triggered the criteria for protective transfer (unremitting drug
use, as evidenced by 8 consecutive weeks of illicit opiate or cocaine use or three emergency
situations requiring immediate health care interventions), whereas 41% of those receiving
standard counseling and 19% of those receiving enhanced services met the criteria. Although
enhanced services led to the best outcomes overall, standard drug counseling was found to be the
most cost-effective approach.
Subsequent studies have found no overall advantage for requiring an intensive day treatment
program at program entry compared with weekly drug counseling, and some patients (e.g., those
with social anxiety) may benefit more from weekly individual drug counseling than from day
treatment (Avants et al. 1998, 1999). A variety of different types of counseling approaches,
including cognitive and behavioral treatment, the community reinforcement approach, 12-step
facilitation counseling, and counseling combining the different approaches, can be effective as long
as they are performed consistently and with a high degree of competence. In addition to the
specific counseling provided, behavioral monitoring (e.g., urine toxicology testing) during
treatment and consistent behavioral responses to patient’s behavior (e.g., providing take-home
methadone to patients who become abstinent or increasing the frequency and intensity of required
counseling for patients with continued illicit drug use) contributes greatly to improved treatment
outcomes (Brooner et al. 2007).
Although effective counseling improves outcomes for many patients, it is unclear whether allPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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patients require counseling to benefit from treatment, and the optimal frequency, intensity, and
duration of counseling have not been well established. Recent randomized clinical trials have
shown substantial benefits of providing methadone maintenance in the absence of any counseling
services, compared with waiting list control groups, with regard to reductions in illicit drug use and
subsequent enrollment in a full-service methadone maintenance treatment program (Schwartz et
- 2006, 2007; Yancovitz et al. 1991). Interim methadone maintenance is permitted for up to 120
days under federal regulations in the United States that were designed to improve access to
methadone maintenance treatment in areas that have long waiting lists for entering full-service
narcotic treatment programs.
CO-OCCURRING PSYCHIATRIC DISORDERS
The prevalence of co-occurring substance use and other psychiatric disorders among
opiate-dependent individuals entering methadone maintenance treatment greatly exceeds the
prevalence found in the general population, even controlling for age, gender, socioeconomic status,
and other factors, as has consistently been shown in studies conducted over the past 25 years in
several different geographic areas (Brooner et al. 1997; Rounsaville et al. 1982). Left untreated,
many of these disorders are associated with an adverse prognosis and an overall poorer response
to methadone maintenance treatment. Thus, careful psychiatric assessment of patients entering
methadone or other agonist maintenance treatment and early institution of treatment interventions
for co-occurring disorders are essential.
A high prevalence of co-occurring alcohol abuse or dependence was noted in early studies of
patients receiving methadone maintenance treatment, and several studies suggested that
treatment with disulfiram administration (after detoxification, if necessary) supervised at the time
of methadone ingestion, led to improvement of alcohol dependence, illicit drug use, and social
functioning. Marijuana use is also very common among patients receiving opioid agonist
maintenance treatment, but the clinical significance of marijuana use in this population is a matter
of some controversy. Some studies suggest that marijuana use is not associated with other illicit
drug use during opioid agonist maintenance treatment, but marijuana use still may interfere with
full participation in treatment and rehabilitation (Nirenberg et al. 1996; Saxon et al. 1993).
Beginning in the early 1980s, cocaine abuse and dependence became epidemic among
opioid-dependent individuals. Although the prevalence of cocaine abuse and dependence has
declined substantially in the general population since then, these problems have remained endemic
among opioid-dependent individuals. The reported prevalence of cocaine abuse or dependence
among new admissions to methadone treatment ranges from 15% to 40% or more in the United
States. Although the prevalence of frequent cocaine use decreases substantially during opioid
agonist maintenance treatment (from 36% at treatment entry to 22% after 1 year in the Treatment
Outcome Prospective Study; Fairbank et al. 1993), continued cocaine abuse is associated with
continued illicit opiate use, injection drug use, increased risk of HIV and other infectious diseases,
increased risk of cardiac toxicity, and criminal activity.
Promising treatment interventions for cocaine abuse during opioid agonist maintenance treatment
include behavioral treatments such as contingency management, in which vouchers with a
monetary value are used to reward cocaine-free urine tests (Schottenfeld et al. 2005). Notably, in
this study, patients randomly assigned to methadone (60–90 mg/day) reduced illicit opiate and
cocaine use significantly more than patients assigned to buprenorphine (12–16 mg/day). Several
studies suggest that supervised administration of disulfiram also reduces cocaine use during
methadone or buprenorphine maintenance treatment (George et al. 2000; Petrakis et al. 2000),
independent of its effects on reducing alcohol use, but this is not an FDA-approved indication for
disulfiram. The potential severity of disulfiram-alcohol-cocaine interactions in patients who use
both cocaine and alcohol while taking disulfiram, as well as the potential risks of
disulfiram-induced hepatotoxicity or neuropathy, raise safety concerns about its use for this
indication. Recent preclinical and clinical studies suggest that increasing the methadone dose may
decrease cocaine as well as illicit opioid use. High-dose methadone is reported to block conditionedPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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place preference to cocaine and both spontaneous and cocaine-precipitated cocaine seeking in rats
(Leri et al. 2006), and some earlier clinical studies reported greater reductions in cocaine use with
higher compared with lower methadone doses (Stine and Kosten 1992).
Benzodiazepine abuse and dependence are also a problem for a high proportion (generally
comparable with the prevalence of cocaine abuse) of individuals receiving opioid agonist
maintenance treatment. As with concurrent cocaine abuse and dependence, benzodiazepine abuse
and dependence are associated with continued heroin or other illicit drug use, injection drug use,
increased risk of infection, and continued involvement in drug subcultures (Darke et al. 1993).
Benzodiazepine abuse also increases the risk of oversedation and respiratory depression in patients
receiving methadone maintenance treatment. Benzodiazepine use during agonist maintenance
treatment poses a difficult challenge for psychiatrists and treatment programs because many
patients experience anxiety disorders that could be treated with benzodiazepines, but
benzodiazepines are frequently misused by patients receiving opioid agonist maintenance
treatment (Spiga et al. 2001). Approximately one-third of the benzodiazepine-using patients in one
study reported taking higher benzodiazepine doses than prescribed, and many took very high doses
around the time of ingesting their daily methadone to boost the methadone effects (Stitzer et al.
1981). Gradual tapering and then discontinuation of benzodiazepines may be possible on an
ambulatory basis, but many patients require inpatient treatment to complete detoxification
successfully. Substitution with a longer-acting benzodiazepine, such as clonazepam, followed by
gradual tapering and discontinuation may offer some advantages. In one study comparing
clonazepam tapering and discontinuation with clonazepam maintenance, clonazepam maintenance
was associated with better retention and decreased benzodiazepine abuse (assessed by self-report
only) (Weizman et al. 2003). Clonazepam may also be administered under direct observation at the
time of methadone dispensing to reduce its potential for abuse or diversion.
Mood disorders, anxiety disorders, and personality disorders, which are also considerably more
prevalent among opioid agonist–maintained patients than in the general population, also may
adversely affect response to agonist maintenance treatment. Treatment of current depression,
found in approximately 15%–25% of those entering treatment, may lead to improvements in mood
and other depression outcome measures and also to reductions in illicit drug use (Nunes et al.
1998, 2004). Treatment of anxiety disorders in agonist-maintained patients is complicated by the
high abuse liability of benzodiazepines in this population. Cognitive and behavioral treatments for
anxiety disorders either alone or, when indicated, in combination with medications with little or no
abuse liability (e.g., buspirone, citalopram) can be beneficial for patients. A recent clinical trial
found no beneficial effect of buspirone for reducing anxiety symptoms in patients receiving
methadone maintenance treatment, however, although depressive symptoms were reduced in
these patients (McRae et al. 2004). Antisocial personality disorder, found in approximately 25% of
patients, has in some but not all studies been associated with a relatively less optimal response to
methadone maintenance treatment (Alterman et al. 1996).
CO-OCCURRING MEDICAL DISORDERS AND PROVISION OF MEDICAL CARE
Patients receiving opioid agonist maintenance treatment may experience health problems
associated with opioid dependence (e.g., AIDS, hepatitis B or C, tuberculosis) or common in the
general population (e.g., hypertension, diabetes, heart and lung disease), and the stabilizing
effects of maintenance treatment on patients’ overall functioning facilitate implementation of
effective medical treatment for these health problems and preventive health services. A study
conducted by the Centers for Disease Control and Prevention among 1,717 injection drug users
entering treatment in six cities in the United States found that 50%–81% had evidence of hepatitis
B, 66%–93% had hepatitis C, and infection with HIV ranged from 3%–5% in cities in the Midwest
and West to 28%–29% in the Northeast (Murrill et al. 2002). The prevalence of infection with
hepatitis B, hepatitis C, or HIV was significantly higher for older injection drug users than for
younger users. With the advent of effective treatments for HIV and hepatitis C, it is essential to
screen patients for these conditions at admission and at regular intervals during opioid agonistPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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maintenance treatment and to refer patients with these disorders for treatment. Several recent
studies have shown the safety and efficacy of peg interferon and ribavirin treatment for patients
with hepatitis C receiving methadone maintenance treatment. Peg interferon does not alter
methadone metabolism or pharmacokinetics, and patients receiving methadone maintenance
treatment show good virologic response to treatment (Mauss et al. 2004; Sulkowski et al. 2005).
Coordination of addiction treatment and medical treatments can improve medication adherence,
adherence to medical treatment recommendations, and response to medical treatment. Several
studies suggest that provision of onsite primary care medical services improves primary care
attendance and initial retention in methadone maintenance treatment (Saxon et al. 2006).
Treatment for hepatitis C can be integrated into methadone maintenance programs (Litwin et al.
2005) and is cost-effective (Sheerin et al. 2004). Interactions between opioid agonist maintenance
medications and some medications to treat medical conditions may necessitate dose adjustments
or consideration of alternative medication treatments, as noted earlier in this chapter in the section
“Medication Interactions.” Other preventive health services that benefit patients include
immunizations (e.g., for hepatitis B, for antibody- and antigen-negative patients who are at risk for
infection; for tetanus; and for pneumococcal pneumonia) as well as testing for tuberculosis and
syphilis and treatment for those with evidence of infection. Adherence to medical treatment, such
as prophylactic isoniazid treatment, can also be improved through directly observed treatment at
the time of methadone dispensing.
Because of the extremely high prevalence of cigarette smoking among opioid-dependent
individuals, health problems associated with cigarette smoking (e.g., emphysema, cancer,
cardiovascular disease) are common among patients receiving opioid agonist maintenance
treatment. Smoking cessation interventions may lead to considerable health benefits for patients
receiving methadone maintenance treatment, and many such patients are interested in stopping
smoking. Some studies suggest that smoking cessation is difficult to achieve or sustain for many of
these patients, and at present few methadone treatment programs offer smoking cessation
treatment (Nahvi et al. 2006; Richter et al. 2004).
PAIN MANAGEMENT DURING OPIOID AGONIST MAINTENANCE
TREATMENT
Pain is an important clinical problem among patients receiving methadone maintenance treatment,
and appropriate management and treatment of pain is essential for optimal care. A recent survey of
patients receiving methadone maintenance treatment in two methadone programs found that 37%
of patients experienced chronic pain (i.e., lasting 6 months or longer) of moderate or greater
severity, most often involving the musculoskeletal system (back or leg pain) or headache.
Two-thirds of these patients reported that pain interfered substantially with their functioning, and
many reported using illicit drugs to treat pain during the preceding 3 months (Rosenblum et al.
2003). In one study, opioid-dependent patients with chronic pain at entry into methadone
maintenance treatment had comparable retention and drug use outcomes as patients without
chronic pain, but they continued to have problems with pain and worse psychological functioning,
compared with patients without chronic pain, even after 1 year of methadone maintenance
treatment (Ilgen et al. 2006).
Treatment of acute or chronic pain among patients receiving methadone maintenance treatment is
complicated by the difficulties, common to both opioid-dependent patients and patients without any
history of drug abuse, of assessing pain severity objectively, diagnosing underlying etiologies of
painful conditions, and prescribing optimal treatment regimens that reduce pain and improve
patient functioning and well-being with the fewest adverse effects. These difficulties are further
complicated in patients receiving methadone maintenance treatment by the effects of methadone
maintenance on pain sensitivity and tolerance to opioid analgesia as well as by concerns about the
potential abuse liability of opioids prescribed for analgesia to patients with a history of drug abuse.
Because methadone is used for the treatment of chronic pain, some physicians mistakenly assume
that patients receiving methadone maintenance treatment do not require opioid analgesicPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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medications in addition to their daily methadone dose to treat either acute or chronic painful
conditions. To the contrary, such patients develop tolerance to the analgesic effects of their daily
dose and may also become cross-tolerant to the analgesic effects of morphine or other opioids
administered for pain relief (Athanasos et al. 2006). Additionally, acute or chronic opioid
administration may lead to increased sensitivity to pain. Increased pain sensitivity has been found
in association with administration of heroin, morphine, methadone, and other opioids, possibly
through up-regulation of spinal dynorphin (Gardell et al. 2002), and has also been reported in
patients receiving methadone maintenance treatment (Compton et al. 2001).
Some physicians may be reluctant to prescribe opioid analgesics to patients receiving methadone
maintenance treatment because of concerns about precipitating relapse to illicit drug use.
Administration of opioid analgesics to these patients for the treatment of acute pain has not been
found to lead to relapse or even to the need for higher methadone doses after the painful condition
has resolved (Kantor et al. 1980). Recommendations for managing acute pain in a patient receiving
methadone maintenance treatment include continued provision of the patient’s regular daily
methadone dose and administration of additional analgesic medications, including non-opioid
analgesics or short-acting opioids, as clinically indicated (Alford et al. 2006; Mehta and Langford
2006). During methadone maintenance treatment, results of positron emission tomography studies
suggest that methadone occupies 19%–32% of the opioid receptor, leaving a substantial
proportion of unoccupied receptors available for analgesic response to opioid medications (Kling et
- 2000). When opioid analgesics are required, patients receiving methadone maintenance
treatment may require even higher doses or more frequent administration of opioid analgesic
medications to ameliorate pain than do patients who are not opioid dependent or receiving
methadone maintenance treatment. In a recent study, patients receiving methadone maintenance
treatment undergoing liver transplantation needed higher doses of intraoperative and
postoperative opioid analgesia than did other liver transplant recipients (Weinrieb et al. 2004).
When opioid analgesics are required for such individuals, it is important to use only medications
that act as full (rather than partial) agonists at opioid receptors; administration of a partial agonist
(e.g., pentazocine or buprenorphine) may precipitate withdrawal.
PREGNANCY AND OPIOID DEPENDENCE
Opioid dependence during pregnancy has adverse health effects on the pregnant woman, fetus, and
neonate, resulting from a combination of direct drug effects, withdrawal, infections associated with
injection drug use and addiction, the detrimental effect of addiction on nutrition, and the possible
exposure to violence. Opiate withdrawal during pregnancy, especially when it occurs without
medical treatment or supervision, causes significant fetal stress and is associated with spontaneous
abortion and fetal demise (Archie 1998). Early studies found that methadone maintenance
treatment led to substantial reductions in opiate use and improvements in nutrition, health status,
and participation in prenatal care for heroin-dependent pregnant women and also to improved fetal
growth and perinatal outcomes in their offspring. These findings led to the recommendation to
provide comprehensive methadone treatment to heroin-dependent pregnant women, with services
including prenatal and obstetrical treatment, nutritional supplementation, and counseling in
addition to methadone maintenance medications (Kaltenbach et al. 1998).
Determination of the optimal methadone dose during pregnancy requires recognition of the effects
of pregnancy on methadone metabolism and disposition and careful balancing between the risks of
continued illicit opiate use, if the methadone dose is too low, and the risks of the neonatal
abstinence syndrome (NAS), which may be associated with higher methadone doses. Methadone
plasma elimination rate is increased and its plasma half-life is decreased substantially during
pregnancy, most likely as a result of increased volume of distribution and increased liver
metabolism and placental and fetal metabolism. Consequently, methadone doses may need to be
increased and administered more frequently (two or three times per day) during pregnancy in
order to prevent withdrawal and craving and to obtain optimal reductions of illicit opioid use. In
one study, mean methadone trough plasma levels were approximately 0.3 mg/L in pregnant
women who did not experience withdrawal symptoms and significantly lower (0.175 mg/L) inPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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pregnant women who did experience withdrawal symptoms, despite somewhat higher daily
methadone doses administered to women who experienced withdrawal (Drozdick et al. 2002).
Methadone doses of 50–150 mg, or occasionally even higher, and split dosing may be needed in
pregnant women who experience withdrawal symptoms, in order to achieve methadone trough
levels of 0.2–0.4 mg/L, which are likely to suppress withdrawal and reduce illicit opioid use.
Opiate dependence and opioid agonist maintenance treatment during pregnancy are both
associated with NAS. NAS is characterized by central nervous system irritability and disturbances of
gastrointestinal, respiratory, and autonomic nervous system function. Features of NAS may include
high-pitched crying, yawning, sneezing, tremors, increased muscle tone, feeding difficulties,
diarrhea, rapid respiratory rate or periods of apnea, and seizure (Kaltenbach et al. 1998). Findings
regarding the relationship between maternal methadone dose and the incidence of NAS have been
inconsistent, and continued heroin or other illicit opioid use among patients treated with lower
methadone doses may complicate analysis of the relationship. In one study, methadone dose and
heroin use during the pregnancy were both significantly correlated with NAS. Continuing heroin use
during pregnancy was found in 31% of the women; 68% of the neonates of women who continued
to use heroin during pregnancy required treatment for withdrawal, whereas 35% of the neonates
of women with no evidence of illicit opioid use required treatment. The correlation between
methadone dose and NAS remained significant, however, even when controlling for heroin use
(Dashe et al. 2002). In that study, approximately 12% of the neonates born to mothers who were
treated with less than 20 mg/day of methadone required treatment for withdrawal, whereas 90%
of those born to mothers receiving 40 mg/day or more of methadone required treatment. A more
recent study found that approximately half of the neonates born to mothers treated with
methadone doses greater than 100 mg/day, and a comparable proportion of those born to mothers
treated with less than this daily dose, required treatment for NAS (McCarthy et al. 2005). In this
study, pregnant women were maintained at a full range of dosages (14–190 mg/day), titrated to
prevent craving and withdrawal. Illicit opioid or other drug use was relatively low during
treatment; 18% of the newborns tested positive for illicit drugs at delivery. Higher maternal
methadone doses, although not associated with NAS, were associated with less illicit drug use.
Differences among studies in the symptom thresholds for initiating treatment and differences in the
rates of continuing illicit opioid use may account for differences in the rates of neonates needing
treatment for withdrawal.
Methadone is secreted into breast milk, and it is estimated that breastfed infants may absorb
approximately 2%–3% of the maternal methadone dose (Begg et al. 2001). There is some
controversy regarding the risks and benefits of women breastfeeding during methadone treatment.
The “Patient Information” section on methadone published by the U.S. Food and Drug
Administration states that methadone “passes through your breast milk and may harm your baby”
(U. S. Food and Drug Administration 2007). The advisory sheet regarding maintenance treatment
for pregnant women published by the Substance Abuse and Mental Health Service Administration,
however, reaffirms earlier guidelines (Center for Substance Abuse Treatment 2005) that in most
situations the benefits of breastfeeding outweigh the potential risks of the small amounts of
methadone contained in breast milk (SAMHSA 2007). The risks to the baby are likely to be greatest
if very high dosages of methadone are prescribed for pain management or the baby was not
exposed to methadone in utero and has not developed tolerance to it. Despite the overall favorable
safety and efficacy profile of methadone maintenance during pregnancy and after childbirth, illicit
or harmful substance use (including abuse of opioids, cocaine, benzodiazepines, marijuana,
cigarettes, and alcohol) during methadone maintenance treatment may reduce some of the
beneficial effects of methadone maintenance treatment during pregnancy or after childbirth on
maternal health and well-being as well as on fetal growth, perinatal outcome, and child
development. These considerations have led to some calls for a reappraisal of the role of
methadone maintenance treatment during pregnancy (Brown et al. 1998), but high rates of
continued illicit opioid use in some studies may reflect less than optimal methadone dosing.
Carefully supervised medical withdrawal of an opioid-dependent pregnant woman may be
considered for women who request medical withdrawal and can maintain abstinence from illicitPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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opioids without maintenance treatment (e.g., women treated in residential programs) or when
opioid agonist maintenance treatment is not available. Some studies suggest that opiate
detoxification can be performed safely during pregnancy under careful medical supervision (Dashe
et al. 1998, 2002). Of course, withdrawal during pregnancy reduces the likelihood of neonatal
abstinence and other perinatal complications only if the pregnant woman remains abstinent
following completion of withdrawal and adheres to other medical and nutritional recommendations.
FEDERAL RULES GOVERNING OPIOID AGONIST MAINTENANCE
TREATMENT
Many aspects of opioid agonist maintenance treatment, including patient eligibility criteria,
medications that can be used for opioid agonist maintenance treatment, medication dispensing, and
program guidelines, are tightly regulated by federal and state rules and guidelines. Although
physicians may prescribe opioids for analgesia according to the usual guidelines for prescribing
controlled substances, methadone may only be dispensed for opioid detoxification or maintenance
treatment in accordance with federal and state regulations. With the exception of patients
hospitalized for conditions other than opioid dependence or during emergency periods of up to 3
days pending admission for more definitive treatment of addiction, methadone may only be
dispensed for opioid detoxification or maintenance treatment by opioid treatment programs that
have been certified by the Substance Abuse and Mental Health Services Administration and
approved by the appropriate state agency. The regulations are designed to ensure appropriate use
of this treatment modality, maintain effectiveness by encouraging optimal treatment and program
structure, and limit diversion of prescribed medications to illicit use. Recent revisions in federal
regulations regarding maintenance treatment with methadone have introduced quality assurance
monitoring and program certification requirements and also have made changes in the provisions
for take-home medications (U.S. Department of Health and Human Services 2001). The current
regulations define the required administrative and organizational structure of the program,
including the need for a medical director, and require the availability of counseling and medical
services and referral for other service needs. Eligibility for maintenance treatment with methadone
generally remains restricted to individuals ages 18 years or older who have been dependent on
opioids for a minimum of 1 year before admission. The 1-year history of dependence may be waived
for pregnant or previously treated patients or following prison release. Individuals younger than
age 18 years may be admitted if they have a history of repeated treatment failure (two or more
documented attempts at short-term detoxification or drug-free treatment within past 12 months);
parent or guardian consent is required for individuals younger than age 18 years. Depending on
their response to treatment, patients may receive up to a 6-day supply of take-home medications
by the end of the first year in treatment, up to a 2-week supply after 1 year in treatment, and a
maximum of a 1-month supply after 2 years in treatment.
An amendment to the Controlled Substances Act (Drug Addiction Treatment Act of 2000) enables
qualified physicians meeting defined training and certification criteria to prescribe office-based
opioid agonist detoxification or maintenance treatment using Schedule III, IV, or V medications
that have been approved for these indications by the FDA. In October 2002, buprenorphine became
the first Schedule III narcotic to be approved for these indications (Drug Enforcement
Administration 2002) and is now available through office-based prescription by physicians. The
current regulations governing narcotic treatment programs also permit office-based physicians to
become part of the medical staff of a narcotic treatment program or to obtain a license as a
satellite medication dispensing unit and thereby provide a form of office-based prescription of
methadone maintenance treatment. Individual physicians also may obtain a special narcotic
treatment program license, but the requirements for obtaining the license and operating as a
narcotic treatment program are considered too cumbersome by many physicians to make use of
this mechanism.
OFFICE-BASED OPIOID AGONIST MAINTENANCE TREATMENT
Historically, opioid agonist maintenance treatment in the United States was provided almost
entirely to patients enrolled in licensed narcotic treatment programs, whereas physicianPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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office-based treatment is widely available in Canada, England, France, and other countries. Despite
the laudable goals of restricting opioid agonist maintenance treatment to specially licensed narcotic
treatment programs (e.g., facilitating quality improvement goals and adherence to patient
eligibility criteria and decreasing the likelihood of diversion of prescribed opioid agonist
medications to illicit use), the restriction contributes to the lack of availability and difficulties in
gaining access to this treatment. Recent studies suggest that some opioid-dependent individuals
refrain from enrolling in narcotic treatment programs because of concerns about being recognized
by others in the program and identified as an addicted person and the possibility that this might
jeopardize his or her employment, family, or social situation. Additionally, some patients who have
achieved sustained recovery from illicit drug use during opioid agonist maintenance treatment
indicate a strong preference for “medical maintenance” by an office-based physician in order to
move away from continuing contact in clinics with many active drug users, to reduce the perceived
stigma of continuing attendance in a narcotic treatment program, and to gain greater flexibility in
prescribing and dispensing procedures (Fiellin et al. 2001).
The effectiveness of medical maintenance for stable patients receiving methadone maintenance
treatment has been evaluated in several studies, and many patients who have been abstinent from
illicit drugs for prolonged periods are able to make the transition to medical maintenance
successfully (Fiellin et al. 2001; King et al. 2002) and remain stable in medical maintenance for
prolonged periods (Harris et al. 2006; King et al. 2006; Merrill et al. 2005). One of the main
limitations noted in most of the studies is that only a small proportion of patients in methadone
maintenance treatment programs meet the stability criteria for medical maintenance, suggesting
that this approach will lead to only a modest increase in treatment capacity by freeing up treatment
slots in narcotic treatment programs (Fiellin et al. 2001; Rich et al. 2005). In one study that used
hair toxicology testing, a surprisingly high prevalence of previously undetected, recent illicit drug
use was found among patients meeting clinical criteria for medical maintenance (Fiellin et al.
2001). Patients with recent illicit drug use were substantially more likely than documented
abstinent patients to use illicit drugs in the next 6 months, but the likelihood of illicit drug use did
not differ between patients randomly assigned to medical maintenance in a physician’s office and
patients receiving continued treatment in the narcotic treatment program.
Qualified physicians who obtain special Drug Enforcement Administration registrations can now
provide office-based buprenorphine maintenance treatment for new admissions to maintenance
treatment, but relatively few studies have evaluated this setting and approach in the United States.
The initial studies of buprenorphine maintenance in a primary care clinic support the feasibility and
potential efficacy of this approach and suggest that many patients may benefit from
physician-prescribed buprenorphine maintenance and relatively brief weekly nurse-administered
counseling (Fiellin et al. 2006). Adherence to buprenorphine was quite variable, however, and
better adherence was associated with greater reductions in illicit drug use and retention in
treatment. The success of this approach for office-based opioid agonist maintenance treatment
raises important questions about the feasibility and potential efficacy of providing methadone
maintenance in these settings, although the potential abuse and diversion liability of methadone
limits dispensing options. As we enter an era of expanded access to opioid agonist maintenance
treatment and approval of new medications, settings, and dispensing options for this treatment, it
will be essential to evaluate the counseling requirements and the treatment protocols and
treatment algorithms that lead to optimal outcomes for patients (Kakko et al. 2007).
METHADONE MAINTENANCE TREATMENT IN PRISONS AND JAILS
The prevalence of opioid dependence and other substance use disorders among individuals
incarcerated in prisons or jails is substantially higher than in the general population in the United
States and throughout the world (Fazel et al. 2006). Additionally, although methadone
maintenance treatment reduces criminal activity, patients receiving methadone maintenance
treatment who become incarcerated experience significant difficulties. Surveys of jails indicate that
only about 1 in 4 contact the methadone program to verify the patient’s dose; very few continue
methadone maintenance while the patient is in jail; and many do not provide any efficaciousPrint: Chapter 20. Opioid Maintenance Treatment http://www.psychiatryonline.com/popup.aspx?aID=351951&print=yes…
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medical treatment to manage withdrawal (Fiscella et al. 2004a, 2004b). Despite the high risk of
relapse to heroin after incarceration, the surveys also suggest that few prisons or jails refer
inmates at the time of release for drug abuse treatment. Methadone maintenance treatment during
incarceration may improve postrelease entry and retention in community-based methadone
treatment programs and possibly lower reincarceration rates (Magura et al. 1993). Additionally,
despite efforts to prevent drug use during incarceration, drug use and injection drug use may
occur. The potential for HIV or hepatitis C or B transmission associated with injection drug use in
prisons or jails is particularly high, because inmates may share needles and injection equipment in
an attempt to minimize the risk of being detected for possessing injection equipment (Calzavara et
- 2003; Macalino et al. 2004; Zamani et al. 2006). The potential benefits of methadone
maintenance treatment during incarceration for reducing the risks both during periods of
incarceration and after release have led to the development of methadone treatment programs in
prisons in a number of countries. In one randomized clinical trial of methadone maintenance in
prison, heroin use and HIV and hepatitis C risk behaviors were significantly reduced in prison
inmates assigned to methadone maintenance treatment in prison compared with a waiting list
control (Dolan et al. 2003). The costs of providing methadone maintenance in prison and its
cost-effectiveness were comparable with the costs and cost-effectiveness of methadone
maintenance in community programs (Warren et al. 2006).
KEY POINTS
More than 40 years of clinical research and clinical experience with methadone maintenance treatment have
established the efficacy and effectiveness of this treatment for reducing illicit opioid use and for reducing the
mortality and morbidity associated with opioid dependence. Based on a thorough and critical review of the
literature, a recent Institute of Medicine committee concluded that the scientific evidence supports the
effectiveness of methadone maintenance treatment for reducing heroin and other illicit opioid use, retaining
patients in treatment, and reducing criminal activity, mortality, drug-related HIV risk behaviors, and the risk
of HIV transmission associated with heroin dependence (Institute of Medicine Committee on the Prevention of
HIV Infection among Injecting Drug Users in High Risk Countries 2006).
Critical factors determining the effectiveness of methadone maintenance treatment include treatment
duration, methadone dose, and provision of counseling and other services. The Institute of Medicine
committee also concluded that longer-term maintenance treatment is more effective than shorter-term
treatment and that the effectiveness of methadone maintenance is improved when sufficient daily methadone
dosages are provided and when patients receiving methadone maintenance treatment are provided drug
counseling and ancillary vocational, medical, or other needed services.
Clinical challenges during methadone maintenance treatment include co-occurring other substance use and
psychiatric or medical disorders. These co-occurring disorders respond to specific treatments, and treatment
for co-occurring disorders is facilitated by integrating or coordinating it with methadone maintenance
treatment.
From a public health standpoint, the most important challenge is to improve the availability and accessibility
of methadone or other opioid agonist maintenance treatment so that all heroin- or other opioid–dependent
patients can receive this treatment for as long as needed.
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SUGGESTED READING
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detoxification for treatment of opioid dependence: a randomized controlled trial. JAMA 283:1303–1310, 2000
Treatment Improvement Protocols developed for the Center on Substance Abuse Treatment:
http://www.treatment.org/Externals/tips.html
Copyright © 2008 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Opioid Maintenance Treatment
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Understanding Opioid Addiction
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History and Evolution of Opioid Maintenance Treatment
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Core Principles of Opioid Maintenance Treatment
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Opioid Maintenance Treatment Basics Quiz
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Key Components of an Effective Treatment Program
Understanding Pharmacological Therapies in Opioid Maintenance
Implementing Patient-Centered Treatment Plans
Advanced Strategies for Monitoring and Adjusting Treatment
Best Practices and Ethical Considerations in Opioid Maintenance
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