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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 The neurobiological pathways of many addictive dis-
Statistical Manual of Mental Disorders, Fourth Edition orders have been elucidated over the past 20–30 years,
(DSM-IV), is characterized by physical dependence on leading to an enhanced understanding of these diseases
opioids (e.g., tolerance and withdrawal) and loss of and allowing targeted treatment strategies [1, 2]. Long-
control over opioid use (table 1). Commonly referred term exposure to opioids affects neurologic pathways
to as “opioid addiction,” the characteristic of loss of in regions of the mesolimbic forebrain—specifically, the
control over opioid use is the distinguishing feature of ventral tegmental area and the nucleus accumbens. Re-
the diagnosis. In contrast to patients who have physical peated exposure to short-acting opioids can have a pro-
dependence on opioids as the result of receiving long- found and lasting impact on opioid receptor kinet-
term opioid treatment for relief of a painful condition, ics, transmembrane signaling, and postreceptor signal
patients with opioid dependence (addiction) as defined transduction. With chronic exposure to opioids, there
by DSM-IV criteria must also manifest loss of control are adaptations in the G protein–coupled receptors that
over opioid use, resulting in adverse consequences (e.g., mediate the reinforcing action of opioids and the up-
employment, legal, or social complications). 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,
Reprints or correspondence: Dr. David A. Fiellin, Yale University School of
Medicine, 333 Cedar St., PO Box 208025, New Haven, CT 06520-8025 (david 2 gene transcription factors (cAMP response element
[email protected]). binding protein and DFosB) located in the nucleus ac-
Clinical Infectious Diseases 2006; 43:S173–7
 2006 by the Infectious Diseases Society of America. All rights reserved.
cumbens, a major portion of the reward system of the
1058-4838/2006/4312S4-0002$15.00 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 hort of patients, with the prevalence of weekly heroin use de-
withdrawal and craving [4, 5]. creasing from 89% before treatment to 28% at the end of 1
year [16]. Methadone treatment has also been associated with
RATIONALE FOR OPIOID AGONIST TREATMENT decreases in criminal behavior [13], HIV risk behavior, and
The neurobiological changes resulting from opioid exposure HIV seroconversion among injection drug users [17–20]. For

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

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

BUPRENORPHINE toin, carbamazepine, isoniazid, rifampin [44, 45], ritonavir
[46], nevirapine [47], and, potentially, efavirenz [48].
Buprenorphine hydrochloride, a partial agonist at the m-opioid
Buprenorphine. Although the data on drug interactions
receptor, has efficacy in the treatment of opioid dependence
between methadone and HIV medications are more extensive,
and was approved for this indication by the US Food and Drug
the literature on drug interactions between buprenorphine and
Administration in late 2002. Buprenorphine is a Schedule III
the pharmacotherapies utilized in antiretroviral regimens is lim-
narcotic, according to the Drug Enforcement Administration, ited [49]. Many medications used to treat HIV infection are
and, therefore, on the basis of the Drug Addiction Treatment metabolized via the cytochrome P450 3A4 system, the same
Act of 2000, can be prescribed by certified physicians in office- pathway as buprenorphine.
based settings [34]. There is a ceiling to the opioid agonist A study of the interaction between buprenorphine and the
effects of buprenorphine, which leads to a lower potential for nucleoside reverse-transcriptase inhibitor zidovudine found that
abuse of the drug, compared with full opioid agonists. The buprenorphine did not increase zidovudine concentrations and,
most commonly prescribed formulation is one that incorpo- therefore, was less likely to lead to zidovudine toxicity, as op-
rates naloxone, which is designed to deter misuse of the prep- posed to methadone, which had been found to increase zi-
aration by the injection route. Buprenorphine is reasonably well dovudine levels [50, 51]. In contrast, one in vitro study of
absorbed sublingually, whereas naloxone is not well absorbed interactions between buprenorphine and the HIV protease in-
sublingually. Therefore, sublingual administration of buprenor- hibitors ritonavir, indinavir, and saquinavir revealed significant

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phine/naloxone allows for adequate absorption of the bupre- inhibition of the metabolism of buprenorphine by these HIV
norphine with minimal absorption of the naloxone. The nal- medications, which could, potentially, lead to significant in-
oxone serves as a deterrent, however, to those who would take creases in buprenorphine levels [46]. Although it is important
the medication and attempt to inject it, because this would to monitor patients for clinical sequelae, this interaction is of
result in precipitated opioid withdrawal due to immediate oc- less concern with buprenorphine, given the ceiling to its agonist
cupation of the opioid receptor by naloxone. The lack of ap- effects and the decreased likelihood of such adverse events as
preciable naloxone absorption with sublingual administration respiratory depression or coma. Similarly, one of the less fre-
of this drug combination results in no adverse effects. quently used nonnucleoside reverse-transcriptase inhibitors,
Clinical trials have demonstrated the efficacy of buprenor- delavirdine, is a cytochrome P450 3A4 inhibitor and thus, in
phine over placebo in decreasing illicit opioid use. In addition, theory, increases buprenorphine levels. The remainder of the
daily and alternate-day buprenorphine dosing is possible and medications in this class are considered to be inducers and
effective [35–37]. could, theoretically, decrease buprenorphine levels. A study ex-
Clinical trials comparing buprenorphine and methadone amining patients receiving buprenorphine and the nonnucleo-
have demonstrated similar treatment retention and decreases side reverse-transcriptase inhibitor efavirenz (an inducer) con-
in illicit opioid use, compared with those associated with low cluded that these patients did not develop opioid withdrawal
doses (20–30 mg) of methadone [38, 39]. Comparisons with syndrome during the administration of efavirenz, despite hav-
more-adequate doses (35–90 mg) of methadone have yielded ing decreased levels of buprenorphine in serum [52].
mixed results. One trial demonstrated improved efficacy [40], In addition, because of the ceiling to the analgesic properties
another demonstrated reduced [41] efficacy, and a third dem- of buprenorphine and the ability of the drug to block the effects
onstrated equivalent reductions in opioid use for the bupre- of other opioids used for pain relief, patients receiving long-
norphine and high-dose methadone groups [42]. Dose-ranging acting opioids for chronic severe pain may not be good can-
studies with buprenorphine have demonstrated improved treat- didates for buprenorphine treatment. This phenomenon has
ment outcomes with doses of 6–16 mg/day, compared with significant implications for patients with HIV infection. Pain
doses of 1–4 mg/day [41, 43]. disorders are more common among patients with HIV disease
than among other primary care patients, with the prevalence
MEDICATION INTERACTIONS of painful syndromes ranging from 30% to 97% [53]. In ad-
dition, pain is frequently undertreated in patients with HIV
Methadone. Methadone interacts with medications metabo- infection or AIDS, particularly in those individuals with a his-
lized by the cytochrome P450 pathway, and levels in plasma tory of substance abuse [54, 55].
can be increased by concomitant administration of such med- Clinicians should be knowledgeable about potential medi-
ications as cimetidine, erythromycin, ketoconazole, and flu- cation interactions when managing patients who are receiving
voxamine [44]. Induction of hepatic microsomal enzymes leads concurrent treatment for opioid dependence and HIV infec-
to decreased levels of methadone in plasma and to withdrawal tion. Awareness of potential drug interactions between bu-
resulting from interactions with alcohol, barbiturates, pheny- prenorphine and HIV antiretroviral medications is important

Opioid Dependence Treatment • CID 2006:43 (Suppl 4) • S175

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