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Opioid Dependence: Rationale for and Efficacy of Existing and New Treatments

Article in Clinical Infectious Diseases · January 2007

DOI: 10.1086/508180 · Source: PubMed

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 SUPPLEMENT ARTICLE

Opioid Dependence: Rationale for and Efficacy

of Existing and New Treatments
David A. Fiellin,1 Gerald H. Friedland,1 and Marc N. Gourevitch2
1
Yale University School of Medicine, New Haven, Connecticut; and 2New York University School of Medicine, New York, New York

Opioid dependence is a chronic and relapsing medical disorder with a well-established neurobiological basis.
Opioid agonist treatments, such as methadone and the recently approved buprenorphine, stabilize opioid
receptors and the intracellular processes that lead to opioid withdrawal and craving. Both methadone and

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buprenorphine have been proven effective for the treatment of opioid dependence and can contribute to a
decreased risk of human immunodeficiency virus (HIV) transmission. In addition, a buprenorphine/naloxone
combination appears to have a decreased potential for abuse or diversion, compared with that associated with
methadone. Largely because of these properties, recent legislation now affords an unprecedented opportunity
for general physicians to offer opioid agonist treatment through their offices. This review focuses on the
neurobiological basis of opioid dependence, the rationale for methadone and buprenorphine treatments, and
issues in prescribing these medications to patients with HIV infection.

DIAGNOSTIC CRITERIA FOR OPIOID NEUROBIOLOGICAL ASPECTS OF OPIOID

DEPENDENCE DEPENDENCE

Opioid dependence, as defined by the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV), is characterized by physical dependence on
opioids (e.g., tolerance and withdrawal) and loss of
control over opioid use (table 1). Commonly referred
to as “opioid addiction,” the characteristic of loss of
control over opioid use is the distinguishing feature of
the diagnosis. In contrast to patients who have physical
dependence on opioids as the result of receiving long-
term opioid treatment for relief of a painful condition,
patients with opioid dependence (addiction) as defined
by DSM-IV criteria must also manifest loss of control
over opioid use, resulting in adverse consequences (e.g.,
employment, legal, or social complications).
Reprints or correspondence: Dr. David A. Fiellin, Yale University School of
Medicine, 333 Cedar St., PO Box 208025, New Haven, CT 06520-8025 (david
.fiellin@yale.edu).
Clinical Infectious Diseases 2006; 43:S173–7
 2006 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2006/4312S4-0002$15.00
The neurobiological pathways of many addictive dis-
orders have been elucidated over the past 20–30 years,
leading to an enhanced understanding of these diseases
and allowing targeted treatment strategies [1, 2]. Long-
term exposure to opioids affects neurologic pathways
in regions of the mesolimbic forebrain—specifically, the
ventral tegmental area and the nucleus accumbens. Re-
peated exposure to short-acting opioids can have a pro-
found and lasting impact on opioid receptor kinet-
ics, transmembrane signaling, and postreceptor signal
transduction. With chronic exposure to opioids, there
are adaptations in the G protein–coupled receptors that
mediate the reinforcing action of opioids and the up-
regulation of the cyclic adenosine monophosphate
(cAMP) second-messenger pathway. Preliminary evi-
dence indicates that these alterations are mediated in
the locus ceruleus and nucleus accumbens, at least in
part at the level of gene expression [3]. For instance,
2 gene transcription factors (cAMP response element
binding protein and DFosB) located in the nucleus ac-
cumbens, a major portion of the reward system of the
brain, are affected by chronic activation of opioid re-

Opioid Dependence Treatment • CID 2006:43 (Suppl 4) • S173

Table 1. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for substance dependence.

Substance dependence: a maladaptive pattern of substance use leading to clinical impairment or distress, manifested within a
12-month period by ⭓3 of the following:
Tolerance, defined by either increased amounts of the substance used to achieve intoxication or other desired effect or diminished
effects with continued use of the same amount of the substance
Withdrawal, manifested by the characteristic withdrawal syndrome, or use of the substance to relieve or avoid withdrawal symptoms
Use of substance in larger amounts or over a longer period of time than intended
Persistent desire or unsuccessful attempts to cut down or control substance use
Great deal of time spent obtaining the substance, using the substance, or recovering from the effects of substance use
Loss of interest in social, occupational, or recreational activities
Substance use despite knowledge of physical/psychological problems

ceptors and mediate tolerance, dependence, and symptoms of
withdrawal and craving [4, 5].
RATIONALE FOR OPIOID AGONIST TREATMENT
The neurobiological changes resulting from opioid exposure
hort of patients, with the prevalence of weekly heroin use de-
creasing from 89% before treatment to 28% at the end of 1
year [16]. Methadone treatment has also been associated with
decreases in criminal behavior [13], HIV risk behavior, and
HIV seroconversion among injection drug users [17–20]. For

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help to provide insight into the chronic and relapsing nature
of opioid dependence and the failure of detoxification strategies
[6–9], and they provide a rationale for specific pharmacother-
apies, such as long-acting opioid agonists, that are aimed at
stabilizing these complex systems.
Opioid agonist maintenance treatment stabilizes brain neu-
rochemistry by replacing short-acting opioids—such as heroin
or oxycodone, which can create rapid changes in opioid levels
in the serum and brain—with a long-acting opioid that has
relative steady-state pharmacokinetics, such as methadone or bu-
prenorphine. Opioid agonist maintenance treatment is designed
to have a minimal euphoric effect, blocks the euphoria associated
with administration of exogenous opioids (competitive antago-
nism), eliminates the risk of infection associated with injection
drug use, and prevents the phenomenon of opioid withdrawal.
METHADONE AND L-a-ACETYLMETHADOL
(LAAM)
The first research demonstrating the effectiveness of methadone
for the treatment of opioid dependence was published 30 years
ago [10]. Methadone hydrochloride is a synthetic medication
that is a long-acting agonist at the m-opioid receptor. Peak levels
in blood occur 2–6 h after oral ingestion, and peak levels in
serum remain within a 2-fold range over 24 h. Methadone at
higher doses can effectively block the euphoric effects of ex-
ogenous opioids [11].
The efficacy of methadone has been demonstrated empiri-
cally in a number of experimental and observational studies
[10, 12–15]. In an observational study of 633 subjects, involving
6 methadone treatment programs in New York, Philadelphia,
and Baltimore, there was a decrease in the prevalence of in-
jection drug use among the 388 patients who continued to
receive treatment, from 81% at admission to 29% at 4 years
[13]. These findings have been replicated in a recent large co-
example, one study of injection heroin users demonstrated HIV
seroconversion in 22% of the 103 subjects not receiving treat-
ment, compared with 3.5% of the 152 subjects receiving meth-
adone maintenance treatment over an 18-month period [18].
The methadone dose used can determine the efficacy of the
drug. Methadone doses have increased because of an increase in
heroin purity and an increase in the number of patients entering
methadone treatment programs as a result of misuse of potent
prescription opioids. Despite the significant variability seen in
methadone dosages and outcomes in community-based meth-
adone programs [21, 22], dose-ranging studies have demon-
strated that retention in treatment programs and abstinence from
illicit opioid use is improved with doses 150 mg [23–26]. One
study revealed fewer opioid-positive urine samples in patients
receiving 80–100 mg of methadone than in those receiving 40–
50 mg (53% vs. 62%; P ! .05). LAAM is a long-acting opioid
agonist with pharmacologic properties and efficacies that are
similar to those of methadone, but its use has been discontinued
in the United States because of concerns about episodes of QT-
interval prolongation and torsades de pointe.
The provision of methadone in the United States is highly
regulated and is functionally restricted to opioid treatment pro-
grams overseen by a federal agency, the Center for Substance
Abuse Treatment of the Substance Abuse and Mental Health
Services Administration. Federal regulations dictate treatment
practices, including frequency of medication dispensing, coun-
seling services, and urine toxicology testing in the 1900 programs
in the United States [27]. The concentration of heroin use over
the past 40 years in the larger urban regions of the West, East,
and Southeast has resulted in the preferential distribution of
treatment programs in these areas, to the exclusion of rural and
less-populated areas. Efforts to provide methadone in an office-
based setting have been successful [28–33], but implementation
has been limited because of federal regulations [27].

S174 • CID 2006:43 (Suppl 4) • Fiellin et al.

BUPRENORPHINE
Buprenorphine hydrochloride, a partial agonist at the m-opioid
receptor, has efficacy in the treatment of opioid dependence
and was approved for this indication by the US Food and Drug
Administration in late 2002. Buprenorphine is a Schedule III
narcotic, according to the Drug Enforcement Administration,
and, therefore, on the basis of the Drug Addiction Treatment
Act of 2000, can be prescribed by certified physicians in office-
based settings [34]. There is a ceiling to the opioid agonist
effects of buprenorphine, which leads to a lower potential for
abuse of the drug, compared with full opioid agonists. The
most commonly prescribed formulation is one that incorpo-
rates naloxone, which is designed to deter misuse of the prep-
aration by the injection route. Buprenorphine is reasonably well
absorbed sublingually, whereas naloxone is not well absorbed
sublingually. Therefore, sublingual administration of buprenor-
phine/naloxone allows for adequate absorption of the bupre-
norphine with minimal absorption of the naloxone. The nal-
oxone serves as a deterrent, however, to those who would take
the medication and attempt to inject it, because this would
result in precipitated opioid withdrawal due to immediate oc-
cupation of the opioid receptor by naloxone. The lack of ap-
preciable naloxone absorption with sublingual administration
of this drug combination results in no adverse effects.
Clinical trials have demonstrated the efficacy of buprenor-
phine over placebo in decreasing illicit opioid use. In addition,
daily and alternate-day buprenorphine dosing is possible and
effective [35–37].
Clinical trials comparing buprenorphine and methadone
have demonstrated similar treatment retention and decreases
in illicit opioid use, compared with those associated with low
doses (20–30 mg) of methadone [38, 39]. Comparisons with
more-adequate doses (35–90 mg) of methadone have yielded
mixed results. One trial demonstrated improved efficacy [40],
another demonstrated reduced [41] efficacy, and a third dem-
onstrated equivalent reductions in opioid use for the bupre-
norphine and high-dose methadone groups [42]. Dose-ranging
studies with buprenorphine have demonstrated improved treat-
ment outcomes with doses of 6–16 mg/day, compared with
doses of 1–4 mg/day [41, 43].
MEDICATION INTERACTIONS
Methadone. Methadone interacts with medications metabo-
lized by the cytochrome P450 pathway, and levels in plasma
can be increased by concomitant administration of such med-
ications as cimetidine, erythromycin, ketoconazole, and flu-
voxamine [44]. Induction of hepatic microsomal enzymes leads
to decreased levels of methadone in plasma and to withdrawal
resulting from interactions with alcohol, barbiturates, pheny-
toin, carbamazepine, isoniazid, rifampin [44, 45], ritonavir
[46], nevirapine [47], and, potentially, efavirenz [48].
Buprenorphine. Although the data on drug interactions
between methadone and HIV medications are more extensive,
the literature on drug interactions between buprenorphine and
the pharmacotherapies utilized in antiretroviral regimens is lim-
ited [49]. Many medications used to treat HIV infection are
metabolized via the cytochrome P450 3A4 system, the same
pathway as buprenorphine.
A study of the interaction between buprenorphine and the
nucleoside reverse-transcriptase inhibitor zidovudine found that
buprenorphine did not increase zidovudine concentrations and,
therefore, was less likely to lead to zidovudine toxicity, as op-
posed to methadone, which had been found to increase zi-
dovudine levels [50, 51]. In contrast, one in vitro study of
interactions between buprenorphine and the HIV protease in-
hibitors ritonavir, indinavir, and saquinavir revealed significant
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inhibition of the metabolism of buprenorphine by these HIV
medications, which could, potentially, lead to significant in-
creases in buprenorphine levels [46]. Although it is important
to monitor patients for clinical sequelae, this interaction is of
less concern with buprenorphine, given the ceiling to its agonist
effects and the decreased likelihood of such adverse events as
respiratory depression or coma. Similarly, one of the less fre-
quently used nonnucleoside reverse-transcriptase inhibitors,
delavirdine, is a cytochrome P450 3A4 inhibitor and thus, in
theory, increases buprenorphine levels. The remainder of the
medications in this class are considered to be inducers and
could, theoretically, decrease buprenorphine levels. A study ex-
amining patients receiving buprenorphine and the nonnucleo-
side reverse-transcriptase inhibitor efavirenz (an inducer) con-
cluded that these patients did not develop opioid withdrawal
syndrome during the administration of efavirenz, despite hav-
ing decreased levels of buprenorphine in serum [52].
In addition, because of the ceiling to the analgesic properties
of buprenorphine and the ability of the drug to block the effects
of other opioids used for pain relief, patients receiving long-
acting opioids for chronic severe pain may not be good can-
didates for buprenorphine treatment. This phenomenon has
significant implications for patients with HIV infection. Pain
disorders are more common among patients with HIV disease
than among other primary care patients, with the prevalence
of painful syndromes ranging from 30% to 97% [53]. In ad-
dition, pain is frequently undertreated in patients with HIV
infection or AIDS, particularly in those individuals with a his-
tory of substance abuse [54, 55].
Clinicians should be knowledgeable about potential medi-
cation interactions when managing patients who are receiving
concurrent treatment for opioid dependence and HIV infec-
tion. Awareness of potential drug interactions between bu-
prenorphine and HIV antiretroviral medications is important
Opioid Dependence Treatment • CID 2006:43 (Suppl 4) • S175
for optimizing outcomes by avoiding drug interactions that
may lead to suboptimal levels of the HIV medication or bu-
prenorphine, as well as for minimizing adverse events such as
toxicity or overdose, although there is a lack of known clinically
significant interactions from rigorous clinical studies. In ad-
dition, as efforts continue with the goal of integrating bupre-
norphine into HIV care, further studies will be needed to con-
firm these interactions.
CONCLUSION
The clinical manifestations of opioid dependence are caused by
neurobiological changes resulting from repeated exposure to
opioid compounds. These changes are stabilized by long-acting
noneuphorigenic medications, such as methadone and bupre-
norphine, that bind to m-opioid receptors, thereby preventing
withdrawal and blocking the effects of exogenous opioids. These
medications are effective in promoting treatment retention, de-
creasing illicit opioid use, decreasing the risk of HIV transmission,
and promoting prosocial activities among opioid-dependent pa-
tients. Buprenorphine can serve an important role in the care of
HIV-infected, opioid-dependent patients, on the basis of its less-
regulated distribution and the current lack of known interactions
with antiretroviral medications.
Acknowledgments
Supplement sponsorship. This article was published as part of a supple-
ment entitled “Buprenorphine and HIV Primary Care: New Opportunities
for Integrated Treatment,” sponsored by the National Institute on Drug
Abuse, National Institutes of Health, Public Health Service, US Department
of Health and Human Services.
Potential conflicts of interest. All authors: no conflicts.
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