Review

Opioid dependence treatment:

options in pharmacotherapy
Angela L Stotts†, Carrie L Dodrill & Thomas R Kosten
†University of Texas Medical School at Houston, Texas, USA
1. Opioid dependence treatment:
options in pharmacotherapy The development of effective treatments for opioid dependence is of great
2. Agonist medications for opioid importance given the devastating consequences of the disease.
dependence Pharmacotherapies for opioid addiction include opioid agonists, partial
3. Partial agonist medications for agonists, opioid antagonists, and alpha-2-adrenergic agonists, which are
opioid dependence targeted toward either detoxification or long-term agonist maintenance.
Agonist maintenance therapy is currently the recommended treatment for
4. Alpha-2-adrenergic agonist
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Waterloo

opioid dependence due to its superior outcomes relative to detoxification.

medications for opioid
detoxification
Detoxification protocols have limited long-term efficacy, and patient dis-
comfort remains a significant therapy challenge. Buprenorphine’s effective-
5. Antagonist medications for
ness relative to methadone remains a controversy and may be most
opioid dependence
appropriate for patients in need of low doses of agonist treatment.
6. Conclusion Buprenorphine appears superior to alpha-2 agonists, however, and office-
7. Expert opinion based treatment with buprenorphine in the USA is gaining support. Studies
of sustained-release formulations of naltrexone suggest improved effective-
ness for retention and sustained abstinence; however, randomized clinical
trials are needed.
For personal use only.

Keywords: heroin, opiate, opioid, pharmacotherapy

Expert Opin. Pharmacother. (2009) 10(11):1727-1740

1.  Opioid dependence treatment: options in pharmacotherapy

Annual prevalence estimates of heroin dependence in the USA remain stable at

about 0.14%, although some recent indicators suggest a decrease  [1]. In other
countries, prevalence rates are higher, e.g., 2% of the population in South East
and South West Asia are heroin-dependent. Prevalence of non-medical use of
opioid pain relievers has increased significantly, with > 2 million people in the
USA abusing prescription opioids  [1]. While these rates are low relative to other
substances of abuse, such as alcohol and marijuana, the burden of disease is sub-
stantial, with high rates of morbidity and mortality; disease transmission; increased
healthcare, crime and law enforcement costs; as well as the less tangible costs of
family distress and lost productivity  [2].
Clinically, there are two general treatment paths from which to choose: opioid
maintenance treatment or detoxification. Most opioid-dependent individuals
engage in both, probably multiple times, during the course of their drug-using
careers. Agonist and partial agonist medications are commonly utilized for both
maintenance and detoxification purposes; alpha-2-adrenergic agonist medications
are primarily used to enhance detoxification outcomes. Antagonist medications
are used to accelerate the detoxification process and prescribed post-detoxification
to assist in preventing relapse. Success of the various treatment approaches and
combinations of treatments is assessed in a number of ways with the primary
outcomes of interest being retention in treatment, and opioid and other drug use.
Secondarily, HIV risk behaviors, legal/crime involvement, psychiatric symptoms,
and morbidity are also used as indicators of treatment success. With regard to
detoxification, there are undoubtedly differences between individuals withdrawing
from illicit opioid use and those withdrawing from methadone or buprenorphine

10.1517/14656560903037168 © 2009 Informa UK Ltd ISSN 1465-6566 1727

All rights reserved: reproduction in whole or in part not permitted
 Opioid dependence treatment: options in pharmacotherapy

maintenance and the contexts in which these occur; however, Methadone dose reduction schedules have ranged from
due to limited prospective, comparative data this distinction 2 – 3 weeks to as long as 180 days, with longer time periods
is not highlighted for purposes of this review. The review of generally associated with better outcomes  [12]. Studies have
pharmacotherapy options for opioid dependence derives indicated that the more rapid the reduction, the worse the
from Medline, PubMed, and systematic reviews from the treatment retention and heroin use outcomes, although the
Cochrane Databases. optimal timeframe has yet to be clearly delineated  [12,13].
There is some evidence that higher doses of methadone are
2.  Agonist
medications for associated with more severe withdrawal symptoms during
opioid dependence detoxification  [14]. A recent review of the evidence concludes
that the use of long-acting opioids, such as methadone, and
2.1  Methadone slow tapering, accompanied by medical supervision, ancillary
Methadone is a full mu-opioid receptor agonist, typically used medications, and psychosocial treatment, can reduce with-
as a replacement therapy for heroin or other opioid depen- drawal severity and improve outcomes  [2]. Unfortunately,
dence. Methadone’s slow onset of action when taken orally the vast majority of patients tend to relapse to heroin or
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and long elimination half-life (24 – 36 h) allows it to be used other opiates during or post-detoxification, which is not
as either a maintenance therapy or detoxification agent  [3]. wholly surprising given the chronic and relapsing nature of
opioid  dependence.
2.1.1  Maintenance
Methadone has been used as a substitution for heroin or 2.2  Levomethadyl acetate
other opiates and, through the mechanisms of tolerance and Levomethadyl acetate (LAAM), a longer-acting derivative of
cross-tolerance, prevents opioid intoxication and withdrawal. methadone and full mu-opioid agonist substitute, was
Adequate dosing ranges from 80 – 150  mg, typically begin- approved by the US FDA for maintenance therapy in 1993.
ning with a daily dose of 20 – 30  mg with increases of 5 or LAAM’s longer-acting properties allow for thrice-weekly
10 mg until the optimal dose is reached. Methadone mainte- dosing – a significant advantage over the required daily dos-
For personal use only.

nance treatment (MMT) is associated with retention in treat- ing of methadone. Oral LAAM typically is administered on
ment, and reductions in i.v. drug use, criminal activity, and a Monday–Wednesday–Friday schedule, starting at a daily
HIV risk behaviors and mortality  [4-7]. It is currently the most 20-mg dose with every-other-day increments to a maximum
successful treatment for chronic opioid dependence, although alternate day dosing of 130/130/180 or 100/100/140  [15].
not without fairly substantial financial and personal costs to As with methadone, stabilization doses vary widely across
individuals participating in this therapy  [8]. patients, in the range of 40 – 140  mg.
Several recent studies have found methadone to be associated Several clinical trials comparing LAAM to methadone
with significant cardiac effects; specifically, a prolonged suggest LAAM to be at least comparable and occasionally
QT interval in the electrocardiography (ECG) of methadone superior on primary outcomes such as retention in treatment
patients. One study found a 16.2% rate of QT prolonga- and frequency of opiate-positive urine screens  [15,16]. Regardless,
tion in hospitalized methadone maintained patients, LAAM was not embraced by opioid treatment providers in
compared with 0% in non-methadone maintained, drug- the USA, probably for varied and complex reasons  [17]. The
injecting patients  [9]. Another study found that methadone most cited reason, however, was concern over prolongation
dose was related to a longer QT interval of 0.140 ms/mg in of the QT interval and report of several deaths in the USA
a cross-sectional study of daily methadone users in free drug and in Europe  [18,19]. Although methadone has recently been
treatment clinics in Copenhagen  [10]. Thus, while patients associated with cardiac side effects in some patients, and despite
in MMT may need closer medical supervision than is cur- direct comparison data indicating few differences in LAAM
rently in practice, methadone has been used safely in the and methadone on cardiac measures, Roxane Laboratories has
treatment of opioid dependence for a number of  years. discontinued the sale and distribution of LAAM. The well-
established benefits of methadone and reluctance of opiate
2.1.2  Detoxification treatment providers to shift to new treatment paradigms
Methadone dose tapering or detoxification is controversial have reduced viable and perhaps superior treatment options
given the relative effectiveness of MMT and the low rates to the opiate-dependent  population.
of detoxification success  [2]. Regardless, detoxification is an
important component of any comprehensive opioid treat- 3.  Partial
agonist medications for
ment program  [11], particularly because the demand for opioid dependence
methadone often outstrips community resources, at least in
the USA. Wait-lists are long and patient financial con- 3.1  Buprenorphine
straints result in the premature termination of a substantial In October of 2002, sublingual buprenorphine and
number of patients by their opiate treatment providers. buprenorphine/naloxone tablets for the management of opiate
Effective detoxification regimens are sorely  needed. dependence were approved by the FDA in the USA. Prior

1728 Expert Opin. Pharmacother. (2009) 10(11)

 Stotts, Dodrill & Kosten

to this, buprenorphine had been used successfully in many in the treatment of opioid dependence. Kakko and co-
European countries as well as Australia  [20,21]. Of significance workers  [43] suggest a stepped care approach in which
in the USA, buprenorphine is designated as a Schedule III buprenorphine is the first-line treatment, with patients
drug, making it legal for qualified US physicians to prescribe escalated to methadone when needed. In a letter to the editor
it for opioid dependence. Unlike methadone and LAAM, regarding Kakko and colleagues’ recommendation, Byrne
which are full opioid agonists, buprenorphine is a partial and Wodak [44] claim that the data do not support buprenor-
agonist of mu-opioid receptors. It has a slow onset and long phine as a first-line treatment because almost two-thirds
duration of action, allowing for alternate-day dosing  [22-24]. (65%) of their study patients were transferred to methadone
Its partial agonist properties reduce the risk of unintentional due to illicit drug use or cravings. Neither age, gender, duration
overdose relative to full agonist medications. The disadvan- of heroin use, nor Addiction Severity Index aggregate scores
tage, however, is that the partial agonism may also limit predicted who stayed on buprenorphine/naloxone versus
buprenorphine’s maximum efficacy  [25,26]. The recommended switched to methadone. Although much more research is
maximum sublingual dose is 24 or 32 mg, which is equivalent needed to make definitive conclusions, it has been recom-
to 60 – 70  mg of methadone. Many patients undergoing mended that higher dependence severity indicates placing
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Waterloo

methadone maintenance are on higher doses, with some on patients on the full agonist methadone over buprenorphine.
much higher doses (150+ mg). Buprenorphine has also been However, it is unclear as to the best way in which to mea-
combined with naloxone at a 4:1 ratio for the purpose of sure dependence severity for this purpose. Researchers have
reducing abuse liability. The 4:1 ratio was chosen based on suggested that patients who require doses of more than
results from several clinical pharmacology studies  [27-29] 30 – 40 mg of methadone daily would be unlikely to expe-
which suggested that this ratio results in negligible absorption rience success with buprenorphine  [25,37]. A subcutaneous
of naloxone when used sublingually (no significant with- buprenorphine implant has also been tested, but no results
drawal symptoms), but when crushed and injected it will have been published, and no studies are currently ongoing
result in opioid receptor antagonism. Commercially available (Titan Pharmaceuticals, 2008). Establishing effective
buprenorphine/naloxone is typically either a 2/0.5 or 8/2 buprenorphine regimens is an important research goal, par-
For personal use only.

mg combination, both of which are much lower than the ticularly in light of findings from a recent review which
maximum dose and may limit the use of this product with suggests a lower mortality rate with buprenorphine relative
patients at higher levels of opioid dependence. More recent to methadone maintenance  [45]. Further research is needed
studies have suggested that 8/2 and 32/8 mg buprenorphine/ to delineate patient and perhaps setting characteristics which
naloxone are well-tolerated and more effective in reducing indicate the prescribing of one drug over the  other.
the reinforcing and subjective effects of heroin, relative to
the 2/0.5 mg dose  [30]. 3.1.2  Buprenorphine detoxification
There is growing interest in using buprenorphine as a way
3.1.1  Buprenorphine maintenance of managing opioid withdrawal. Because of the partial agonist
Outcome data from several studies have established the properties, buprenorphine is expected to produce fewer
superiority of buprenorphine maintenance over placebo [31-35]. withdrawal symptoms as it is withdrawn, relative to full
Results from studies comparing buprenorphine and metha- agonist therapies  [46]. As with methadone, detoxification
done, however, have been mixed, and dependent on several outcomes are likely to depend on a complex interaction of
factors such as dose level and flexibility  [36-41]. Overall, it factors including dependence severity, opioid used, dose
appears that decreased illicit opiate use and increased retention taken, duration of use, taper schedule, social/environmental
are seen with both higher doses of methadone (> 60 mg) circumstances, and psychological factors such as fear of
and higher doses of buprenorphine (> 8 mg), although withdrawal, depression, and anxiety about life without
methadone appears superior to buprenorphine in retaining drugs  [47,48]; and to date, success rates have not been high.
patients when using flexible dosing approaches  [30]. There is Gowing and colleagues  [49] reviewed four studies comparing
some evidence to suggest that inducting patients too slowly the efficacy of buprenorphine and methadone detoxification
onto buprenorphine may contribute to poorer retention protocols  [42,50-52]. Overall, the data suggest that buprenor-
rates  [36,42]; however, the lesser opioid effect and possibly phine and methadone have similar efficacy for detoxification
mild withdrawal symptoms when transferring from heroin purposes, although withdrawal via buprenorphine may be
to buprenorphine cannot be discounted. Also for consideration, somewhat faster  [53]. Buprenorphine has repeatedly been
a meta-analysis by West and colleagues  [41] indicated that found superior to the alpha 2 adrenergic agonist clonidine
buprenorphine tended to be more effective in studies with in reducing symptoms of withdrawal, retaining patients in a
patients who reported prior methadone maintenance experi- withdrawal protocol, and in treatment completion  [54-58].
ence, compared with studies that included subjects who had Contrary to expectations, several studies found little dif-
no prior experience with methadone. ference in the severity of withdrawal when tapering from
Given the mixed results regarding buprenorphine’s effec- buprenorphine compared with methadone  [42,51]. However,
tiveness relative to methadone, controversy exists as to its role the pattern of withdrawal symptoms may indeed be different.

Expert Opin. Pharmacother. (2009) 10(11) 1729

 Opioid dependence treatment: options in pharmacotherapy

Petitjean and co-workers  [42] reported that while patients opioid-dependent patients  [68-70]. Buprenorphine treatment
withdrawing from methadone experienced a gradual increase also has reduced various infectious diseases related to
in withdrawal symptoms, peaking at the end of the taper, intravenous drug use  [71,72].
buprenorphine patients reported higher withdrawal symptoms Following four initial US studies on buprenorphine
earlier in the taper followed by a rapid decline. Similar findings effectiveness  [58,73-75], recent studies also have supported
were reported by Seifert and colleagues  [51]. Detoxification office-based buprenorphine treatment efficacy by investigating
outcomes may be influenced by the rate of dose reduction, longer retention intervals and additional settings (Table 1) [76-78].
with several studies suggesting that gradual tapering of The 79% retention rate found by Fiellin and colleagues  [73] in
buprenorphine results in higher completion rates relative to a private office setting was followed by similar evidence from
rapid tapering  [59,60], and several studies indicating no reliable Cunningham and co-workers  [76] of 71% retention in an
differences (e.g.,  [61,62]). Many buprenorphine detoxification urban community health center setting. Buprenorphine is
studies have been conducted on an in-patient basis and were effective for treatment of both injection and oral opioid
targeting withdrawal from heroin rather than methadone. users, but results have been mixed over whether buprenorphine
The extent to which results will generalize to the out-patient can be said to be clearly more successful for one particular
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setting and to methadone users is not fully known. Ling and route of administration over  another.
co-workers  [63], however, conducted a multicenter randomized Some patients may desire to transfer from methadone to
trial of buprenorphine–naloxone and found superior results primary care-based buprenorphine maintenance. At pres-
for buprenorphine in both the in-patient and out-patient ent, data regarding precipitation of withdrawal when
arms relative to the clonidine. Although retention rates were switching from methadone or LAAM to buprenorphine are
similar in the in-patient versus out-patient settings, success limited, particularly for doses of methadone > 30 mg daily.
rates were about double for in-patients. Caution must be Additionally, buprenorphine is quite expensive relative to
used in interpreting these data, however, as patients were methadone, making it available mainly to individuals with
not randomly allocated to the two settings. The few studies adequate  resources.
of managed methadone withdrawal using buprenorphine
For personal use only.

have reduced the methadone dose to ≤ 30 mg prior to begin- 4.  Alpha-2-adrenergic agonist medications for
ning buprenorphine and have delayed the first dose 24  h opioid detoxification
after the last dose of methadone  [64,65]. The transition from
methadone to buprenorphine has been found to precipitate Several alpha-2-adrenergic agonist medications have been
withdrawal  [66], and must be approached carefully. investigated and found to facilitate positive opioid with-
To date, buprenorphine has not surpassed methadone in drawal outcomes. One process underlying opioid withdrawal
its effectiveness for managed withdrawal; however, there is is noradrenergic hyperactivity  [79]. Alpha-2-adrenergic ago-
significant potential. Additionally, there has been limited nists moderate the symptoms of noradrenergic hyperactivity
research on post-detoxification outcomes, leaving it unclear by acting centrally. Clonidine was the first alpha-2 agonist
as to whether one medication is superior to the other in the discovered to ameliorate some signs and symptoms of with-
long term  [67]. Much research is needed to identify the optimal drawal. Because it is not a drug of abuse or dependence,
conditions under which buprenorphine can succeed for clonidine has gained widespread use as a non-opioid alterna-
detoxification purposes, including optimal duration, setting, tive for managing withdrawal  [80]. Unfortunately, clonidine
route of administration, severity of dependence, and whether is associated with significant hypotension, which has limited
patients are withdrawing from heroin or methadone. its use. This finding led to a search for alternative alpha-2
agonist medications without significant side effects.
3.1.3  Buprenorphine in the primary care setting Lofexidine, guanfacine, and guanabenz acetate have been
In the USA, the ability of primary care physicians to prescribe investigated to varying extents  [81]. Of these, lofexidine has
buprenorphine for opioid dependence presents an important been the most frequently studied  [82-87], and results suggest
and far-reaching opportunity to improve access and quality that it may not have the hypotension side effect that plagues
of treatment, as well as reduce social harm. Positive effects clonidine. It is likely to replace clonidine as the leading opi-
have been documented in many countries. European, Asian, oid withdrawal treatment in this drug  class.
and Australian data suggest that opioid-related deaths and Initial studies of clonidine reported reduction or elimination
drug injection-related medical morbidity have decreased of lacrimation, rhinorrhea, muscle pain, joint pain, restlessness,
with the introduction of buprenorphine. In France, national and gastrointestinal symptoms  [88,89], suggesting significant
surveys conducted annually in treatment facilities for drug- potential for managing opiate withdrawal. Clonidine is
dependent individuals suggested that widespread initiation typically administered orally, in three or four doses per day
of office-based buprenorphine treatment in 1996 was up to a maximum of 1 mg/day. Dizziness, sedation, and
associated with a decline of heroin use among opiate lethargy attributed to orthostatic hypotension and dry
users from 74% in 1995 to 25% in 1997, as well as mouth were the primary adverse side effects. Lofexidine can
with improvements in the social and medical status of be prescribed up to about 2 mg/day and appears to be

1730 Expert Opin. Pharmacother. (2009) 10(11)

 Stotts, Dodrill & Kosten

Table 1. Studies of buprenorphine in primary care settings.

Authors Comparison drugs Assessment Percent retained Percent negative urine

time points screens

Maintenance
Cunningham et al., None 3 months 71% 76%
2008
Fiellin et al., 2002 None 13 weeks 79% 75%
Fiellin et al., 2008 None 5 years 38% 91%
Fiellin et al., 2006; None 24 weeks 43% overall; 59% of prescription 41% overall; 75% of
Moore et al., 2007 only users, 30% of heroin only, prescription only users,
38% who used both 52% of heroin only,
48% who used both
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Fudala et al., 2003 Bup only, 4 weeks 82% 21%

Bup + Naloxone, Placebo 75% 18%
69% 6%
Mintzer et al., 2007 None 6 months 100% 54%
O’Connor et al., 1996 None 6 months 71% 80%
O’Connor et al., 1998 None 12 weeks 78%, 52% 43%, 13%
Detoxification
O’Connor et al., 1997 Clonidine; Clonidine + 8 days 60% for Bup, 65% for Clonidine, 81% for Bup, 65% for
Naltrexone 54% for Clonidine, 81% for
For personal use only.

Clonidine + Naltrexone Clonidine + Naltrexone

Wright et al., 2007 Dihydrocodeine 15 days, Completed 15 day detox: 32% for 21% for Bup, 3% for
3 months, 6 Bup, 13% for Dihydrocodeine Dihydrocodeine;
months At 3 months: 37%
for Bup, 17% for
Dihydrocodeine;
At 6 months: 32%
for Bup 16% for
Dihydrocodeine

associated with fewer adverse effects. Completion rates of trial, confirmed that lofexidine significantly decreases the
managed withdrawal assisted with clonidine and other signs and symptoms of opioid withdrawal. Retention was
alpha-2-adrenergic agents versus methadone have been also higher in the lofexidine condition. Three studies compar-
comparable  [90-92], with at least one study finding poorer ing the efficacy and tolerability of lofexidine to clonidine
outcomes for clonidine  [93]. Withdrawal symptoms, while suggested comparable efficacy in reducing withdrawal symp-
reasonably similar in intensity, demonstrate a difference in toms, with an advantage for lofexidine due to smaller
time course. Symptoms occur much earlier in the withdrawal hypotensive effect. Interestingly, Bearn and co-workers  [90]
period for clonidine and lofexidine than for methadone, reported that an accelerated 5-day lofexidine regimen resulted
which perhaps has implications for length of time in treatment. in faster attenuation of withdrawal symptoms relative to a
In a few studies specifically reporting duration of treatment, more conventional 10-day lofexidine  schedule.
subjects receiving reducing doses of methadone remained in As stated earlier, buprenorphine appears to be somewhat
treatment longer than those receiving alpha-2 agonists  [92,94]. more effective in facilitating opioid withdrawal than cloni-
In the UK, lofexidine has had a product license for dine  [63,95]. Of the two open-label trials comparing lofexidine
treatment of opiate detoxification since 1992, and the extent and buprenorphine, one found the two treatments to be
of use has increased steadily since that time. Lofexidine equivalent in effectiveness  [84], while the other found
treatment is typically initiated at 0.2 mg twice daily, increasing buprenorphine to result in less severe withdrawal symptoms
daily by 0.2 – 0.4 mg with a recommended final dose of 2.4 in a large portion of subjects  [86]. Thus, the alpha-2-adrenergic
mg/day. Doses required to effectively manage withdrawal agonists are of significance given the paucity of medications
symptoms, however, vary for each patient depending on the approved for opioid detoxification and relapse prevention
amount, frequency, and duration of opioid used. Yu and purposes, particularly non-opioid medications; arguably,
colleagues  [87], in a Phase III randomized, placebo-controlled however, alpha-2 agonists may not be the best ‘first-line’

Expert Opin. Pharmacother. (2009) 10(11) 1731

 Opioid dependence treatment: options in pharmacotherapy

treatment for opioid detoxification. Further research is after missing naltrexone doses especially likely to drop
needed to determine optimal dose, duration and perhaps out  [110]. For example, Rothenberg and colleagues  [111]
combinations of medications to improve upon the typically reported that only slightly more than half of participants
poor detoxification  outcomes. completed 4 weeks of a 24-week naltrexone-behavior therapy
protocol. Greenstein and co-workers  [112] reported that 47%
5.  Antagonist
medications for of opiate-dependent patients dropped out of treatment in
opioid dependence the first few weeks. Further, Tennant and colleagues  [113]
reported that over a quarter of their patients dropped out
Naltrexone is an oral, long-acting opioid antagonist with high after only a few days. Rothenberg’s study  [111] also reported
affinity to mu-opioid receptors. A daily dose of naltrexone even lower retention for patients using methadone at base-
(50 mg) will block the pharmacologic effects of 25  mg i.v. line: 39% completed 1 month, and no patients completed
heroin for as long as 24  h, and increasing the dose extends the full 6 months of treatment. These data suggest that tran-
its duration of action to 48  h with 100  mg and 72  h with sition from long-acting opioids to naltrexone may be especially
150 mg  [96]. Neither tolerance nor dependence develops difficult and portend the need for improved methods for
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Waterloo

with naltrexone  [97,98]. Oral naltrexone is approved for transitioning to antagonist treatment.

relapse prevention of alcohol and opioid dependence in
several countries, although its effectiveness for the latter 5.1  Sustained-release formulations of naltrexone
remains in question  [99]. Due to poor rates of adherence  [109], sustained-release
In general, clinical research on naltrexone over the past formulations of naltrexone are being developed in the
few decades indicates that it is safe, associated with few side hope of improving outcomes, and are currently the focus
effects, and clearly blocks the reinforcing properties of heroin of much research. Although nine different sustained-release
and other opiates. Original fears that naltrexone would cause formulations are available, none is approved for opioid
hepatotoxicity or elevate liver function tests appear unwar- dependence in the USA, Europe or Australia. Three depot
ranted  [100-102]. It remains common practice, however, to injection formulations are being investigated and deliver thera-
For personal use only.

evaluate liver function prior to administering naltrexone and peutic doses (blood levels of 1 – 2 ng/ml) for ≤ 4 weeks [114,115].
refrain from prescribing if liver function tests are three to Comer and colleagues  [116] has conducted the only pub-
five times normal levels. Failure to prescribe naltrexone to lished, randomized, controlled clinical trial investigating
patients with less elevation in LFTs is unfortunate, as a injectable, sustained-release naltrexone in 60 heroin-dependent
significant proportion of the opiate-using population has patients. Following an initial in-patient detoxification and 3
liver disease such as hepatitis B or C  [103,104]. Naltrexone has consecutive days of oral naltrexone, patients were randomized
in fact been associated with improvements in LFTs due to to receive placebo, 192 or 384  mg of depot naltrexone
reductions in alcohol/opiate use  [105,106]. Further, naltrexone (Depotrex; BIOTEK, Inc., Woburn, MA, USA). A second
has few additional side effects. The most commonly injection of the same dose was administered after week 4 of
reported symptoms are headache, nausea, and abdominal the 8-week study. Retention in treatment was superior for
pain, as well as dysphoria, and depression in a subgroup of the two naltrexone conditions (60 and 68% remaining at
patients  [107,108]. end of study in the 192- and 384-mg groups, respectively)
Although naltrexone has theoretically ideal properties, relative to placebo (39% remaining). A significant dose–response
only weak support exists for its effectiveness in clinical settings. relationship was found on time to dropout, with the higher
A recent meta-analysis  [99] reviewing 10 studies (N = 696) naltrexone group remaining in treatment the longest.
concluded that naltrexone maintenance combined with psy- Significant effects on opiate use across the study were also
chosocial therapy was, in fact, more effective than placebo found, favoring the naltrexone groups over placebo.
in reducing heroin use and reincarceration rates during treat- Treatment-related side effects were relatively mild (e.g., fatigue,
ment. However, results of studies using naltrexone alone did injections site induration, and injection-site pain), although
not differ from placebo, and, in the majority of studies, five participants (one in the placebo and four in the 192-mg
retention, side effects and relapse rates were all similar to groups) were discharged from the study for injection-site
placebo. Most researchers would agree, and there are data [109] redness or induration. Injection-site problems have been
demonstrating that the primary problem with naltrexone is reported in other studies of alcohol and opioid-dependent
low adherence to the medication and poor retention in patients, and found at significantly greater frequency with
treatment. Presumably because naltrexone has no reinforcing naltrexone relative to placebo  [117-119].
properties of its own, blocks reinforcement from occasional Although it is premature to conclude sufficient effectiveness,
lapse to opiates, and has no associated withdrawal syndrome sustained-release depot naltrexone formulations appear to
encouraging its continued use, acceptance of the treatment hold significant promise in improving retention, and pre-
by patients is low relative to agonist-based treatments. Many sumably decreasing opiate use, in opioid-dependent patients.
studies have reported large numbers of dropouts in the first Subcutaneous naltrexone implants are also being used in
few weeks of treatment, with those lapsing to opiate use the treatment of opioid dependence, particularly in Russia

1732 Expert Opin. Pharmacother. (2009) 10(11)

 Stotts, Dodrill & Kosten

and China. Data on implants of 1.1, 2.2, and 3.3 g naltrexone alpha-2-adrenergic agonist, has been investigated as a method
have been reported. A recent study by Ngo and col- for rapid opiate detoxification (ROD) and has been pur-
leagues  [120] concluded that a 3.3-g implant provided longer ported to shorten the duration of withdrawal without sig-
therapeutic coverage compared to the 1.1-g implant, but nificantly increasing patient discomfort  [128]. Another benefit
was not significantly different from the 2.2-g implant. The to ROD is the reduced time between opioid use and the
primary difficulty in evaluating the effectiveness of sustained- commencement of naltrexone treatment. Controlled studies
release naltrexone is the lack of clinical trials, although a comparing naltrexone plus clonidine to clonidine alone or
clinical trial has been presented showing superior treatment to methadone tapering have found that the former approach
retention with a naltrexone implant compared with oral was well tolerated and reduced the withdrawal period while
naltrexone and a placebo implant (College on Problems of improving retention  [13,58,129,130]. ROD completion rates
Drug Dependence, June 2007, Quebec City, Canada). In using naltrexone and clonidine are in the range of 75 – 81%,
that study, 190 detoxified opiate addicts were randomized to compared with 40 – 65% for methadone or clonidine
the three treatment groups, and at the end of 6 months alone  [58,131]. Lofexidine has been shown to have equal effi-
45% of patients of the naltrexone implant group had cacy with clonidine when combined with naltrexone and has
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Waterloo

relapsed compared with about 85% in the other two groups fewer side effects  [132], perhaps making it a more suitable
(p < 0.001). Cohort studies have been reported and results detoxification medication, particularly in out-patient set-
are quite favorable. For example, Foster and co-workers  [121] tings. Gowing and Ali  [11], however, based on their review of
reported 74 – 79% opiate abstinence rates 12  weeks after seven studies, report that it is still unclear whether with-
implantation. Fifteen percent had local tissue reactions that drawal induced by opioid antagonists in combination with
were mild with no regional lymphadenopathy, resolving adrenergic agonists actually facilitates the transfer to sus-
without surgical treatment. tained naltrexone treatment beyond 10 – 14  days, and
Recent reports of serious adverse events associated with thereby improving effectiveness, relative to adrenergic
naltrexone implants have surfaced, however. A retrospective agonists alone.
chart review of ER patients referred to Drug and Alcohol Buprenorphine and methadone have also been used in
For personal use only.

Consultation/Liaison services in two teaching hospitals in combination with naltrexone. Umbricht and colleagues  [133]
Sydney, Australia reported 12 patient admissions in a 1-year stabilized patients on buprenorphine prior to detoxification
period with implant-related presentations  [122]. Six of 12 with naltrexone and clonidine and found the treatment to
admissions were for severe dehydration and opiate with- be safe, with an even shorter duration of detoxification rela-
drawal secondary to rapid opioid detoxification and naltrex- tive to patients stabilized on methadone or using heroin (1 day
one implantation in the prior 24 – 48  h. Opioid overdose vs 3 days of detoxification). Gerra and co-workers  [134] con-
deaths have also been reported  [123]. Conversely, longitudinal ducted an observational study suggesting potential benefit
cohort data collected prospectively in Australia indicate an from the combination of lower doses of buprenorphine (4
absence of mortality associated with naltrexone implant mg) and naltrexone as a detoxification and subsequent main-
treatment  [124]; and, further, naltrexone implantation has tenance strategy to counteract the protracted opioid absti-
been associated with long-term reductions in opioid-related nence syndrome common after detoxification (dysphoria
hospital morbidity  [125]. Davoli and co-workers  [126] report and somatic symptoms). Another uncontrolled study of
that overall, overdose mortality risk while in opioid treat- 3-day ROD using one dose of 50 mg naltrexone with meth-
ment is significantly lower than when out of treatment, with adone maintenance patients reported a shortened withdrawal
the first month post treatment being a considerably risky syndrome (managed by symptom-relief meds)  [135]. Two
time. Thus, although more research is needed, initial data phases of symptoms were reported: i) a first withdrawal
on naltrexone implants indicate significant improvements in phase, seen in most patients, characterized by common
adherence and retention, and perhaps increased effectiveness symptoms and probably naltrexone-induced; and ii) a sec-
for relapse prevention. Careful participant selection and ond phase experienced by fewer patients (aches, insomnia
close clinical management is clearly warranted, however, to and loss of appetite worsened), probably attributable to
prevent serious adverse outcomes. declining methadone  concentrations.
Ultra-rapid opiate detoxification (UROD) is an extension
5.2  Rapid and ultra-rapid opiate detoxification of ROD with the use of anesthetics. UROD is highly con-
While gradual dose reduction of methadone or buprenor- troversial due to the medical risks and mortality associated
phine is perhaps the most straightforward way in which to with anesthesia relative to the painful, yet nonfatal, risks of
manage opiate detoxification, this method is time-consum- untreated opiate withdrawal. At least one death during the
ing and plagued by high dropout rates. Alpha-2-adrenergic recovery period of this intervention has been reported  [136].
agonists, such as clonidine and lofexidine, assist in reducing Further, while withdrawal severity following anesthesia-assisted
some of the symptoms of opiate withdrawal; however, they withdrawal did not differ, Collins and colleagues  [137]
do not alter the duration of withdrawal  [127]. Use of the reported three life-threatening adverse events in the anesthe-
opioid antagonist naltrexone, typically combined with an sia group, but none in the buprenorphine or clonidine

Expert Opin. Pharmacother. (2009) 10(11) 1733

 Opioid dependence treatment: options in pharmacotherapy

groups. Effectiveness relative to alternative detoxification readiness for complete withdrawal  [141]. For these reasons,
procedures is difficult to evaluate, as most studies have not experts understandably have recommended agonist maintenance
included longer-term follow-up data or randomization to a treatment over detoxification. However, long-term methadone
comparison condition. Some studies report relatively high maintenance treatment is not without adverse consequences.
rates of abstinence  [138,139], while others report worse outcomes Methadone, like other opioids, produces sustained constipation
with UROD  [140]. in some individuals, which if left untreated can lead to toxic
In sum, ROD with naltrexone and clonidine is safe and megacolon. The only fatalities from methadone unrelated to
effective in the management of opiate withdrawal. While the overdose have been caused by this side effect. Methadone
duration of detoxification is shortened, effectiveness in also elevates serum prolactin and lowers testosterone levels,
facilitating continued use of antagonist treatments post which can impair sexual functioning. Further, under many
detoxification has yet to be established. UROD remains circumstances, such as lack of financial resources to initiate
controversial with regard to safety and is also quite expensive, or continue maintenance treatment, detoxification of opioid-
thus significantly limiting its  use. dependent patients is essential. Thousands of patients each
year (at least in the USA) are terminated from opiate treatment
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Waterloo

6.  Conclusion programs for failure to pay and other ‘non-therapeutic’

reasons  [142]. Without effective detoxification protocols,
Given the burden of disease, the development of effective individuals lacking resources will inevitably continue or
treatments for opioid dependence is of great significance. return to illicit opiate use and, consequently, the myriad of
Methadone maintenance is currently the gold standard of associated psychosocial and health problems.
treatment, as it is associated with reductions in intravenous Various pharmacotherapies and dose-reduction protocols
drug use, crime, HIV risk behaviors and mortality, and is have been tested to improve detoxification outcomes. Alpha-2-
well established in community treatment programs around adrenergic agonist medications, such as clonidine and lofexidine,
the world. New and evolving opioid treatments are held to have gained widespread use because they are a non-opioid
this standard. Yet even when comparing favorably to methadone alternative. Their effectiveness as single agents is inferior to
For personal use only.

(e.g., LAAM), new pharmacotherapies may be viewed with managed withdrawal using buprenorphine, however, they have
reluctance, which can have the untoward effect of prematurely had more patient acceptance as adjunctive agents during
limiting use and availability. Cardiac side effects have been buprenorphine tapering. Naltrexone, a long-acting opioid
documented for both LAAM and methadone, though, and antagonist, seems an ideal candidate medication for the prevention
patients should be carefully monitored for such. In recent of relapse to opiates, but is associated with unacceptably low
years, buprenorphine has emerged as a potential first-line adherence and retention rates. Sustained-release formulations
treatment for opioid dependence and may be ideal for have been developed, with strong support for naltrexone
patients needing lower doses of agonist medications. implants from mostly uncontrolled studies, although questions
Buprenorphine has a reduced risk of overdose relative to full regarding safety have yet to be answered. Further research
agonist therapies, and in combination with naloxone, has attending to issues of both efficacy and safety is needed to
reduced abuse liability. Office-based buprenorphine treatment rigorously test this promising  treatment.
has the potential to expand the reach of opioid treatment
thereby improving the social and medical status of increasing 7.  Expert opinion
numbers of opioid dependent patients. Further research is
needed to identify patient and setting characteristics best Opioid pharmacotherapy faces a significant challenge because
suited to comparing buprenorphine with methadone. the most rapidly growing populations needing treatment in
Opioid detoxification remains a critical area of focus. the USA are adolescents and young adults. Prescription opioids
There is no consensus on the most effective pharmacological have become the most commonly abused illicit drug during
strategy to achieve complete abstinence from all opiates. the last 5  years among these young abusers  [1,143]. In the
Relapse either during or after detoxification occurs in the treatment of young abusers, it is necessary to recognize that
majority of patients, and, for those who have the resources, developmental processes are ongoing and hormone levels are
return to maintenance treatment is common. Despite the changing and influencing growth in many organs, including
dismal rates of success, a minority of patients are able to the brain. This developmental perspective must inform any
detoxify successfully from methadone, heroin, and other pharmacotherapy decision, and a decision to simply provide
opiates. Research has yet to determine, however, who will withdrawal treatment and no ongoing relapse prevention
succeed and who will fail. In a recent manuscript reporting treatment is simply untenable in this era of infectious diseases
on a 6-month LAAM detoxification study in which almost such as HIV and hepatitis C, which are frequent comorbidities
every participant returned to opioid use (methadone of opioid abuse and dependence  [144].
maintenance or illicit opioids), Grabowski and colleagues Chronic opioid agonist treatments are the gold standards
(under review) concluded that neither patients nor clinical for efficacy, but providers and parents have significant reluctance
researchers are adequately equipped to determine a patient’s to enroll adolescents in a sustained program of maintenance

1734 Expert Opin. Pharmacother. (2009) 10(11)

 Stotts, Dodrill & Kosten

on methadone, and the usual treatment for opioid-addicted hormonal perturbations range from growth retardation and
youth is detoxification and counseling. Extended medication- affective instability to increased fertility in adolescent girls,
assisted therapy may be more helpful, and a different attitude leading to pregnancy when effective birth control is not
may be developing for buprenorphine, particularly as an used. In summary, current pharmacotherapies have great
office-based therapy. A recent study at six community programs potential, but have associated risks in our growing population
evaluated the efficacy of continuing buprenorphine-naloxone of young opioid abusers.
for 12  weeks versus detoxification for opioid-addicted A very attractive, more cost-effective alternative has been
youth  [145]. They enrolled 152  patients aged 15 – 21  years potential therapeutic vaccination or even monoclonal
who were randomized to 12  weeks of buprenorphine or a immunotherapy  [147]. These immunotherapies are very
14-day taper detoxification. The patients in the detoxification appealing because they have no direct effects on the brain,
group had higher proportions of opioid-positive urine tests endocrine system or any other organs. Their mechanism of
at weeks 4 and 8; by week 12, only 21% remained in treatment, action is simply that the antiopioid antibody binds to the
compared with 70% of those maintained on buprenorphine. abused opioid and thereby holds the opioid in the blood-
Thus, continuing treatment with buprenorphine improved stream, preventing its entry into any of these organs  [148].
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Waterloo

outcome compared with short-term detoxification, which As this opioid antibody complex passes through the liver,
encourages further research into the efficacy and safety of longer- the opioid is extracted and converted into inactive metabo-
term treatment with buprenorphine for young individuals with lites that are then excreted in the bile and kidney. Vaccina-
opioid dependence. tion-induced antibody levels remain high enough to block a
The antagonist naltrexone seems an ideal treatment for specific opiate for about 8 – 12 weeks, after which a booster
these reluctant young patients, since we have developed is needed to get the antibody levels back for 2 – 3 months.
long-lasting depot formulations, such as Vivitrol® (Alk- This vaccine approach has been quite feasible for both
ermes, MA, USA) and naltrexone implants, that can over- nicotine and cocaine in human vaccines  [147,149]. A signifi-
come these patients’ poor adherence to taking daily cant challenge to this approach has been the wide range of
medications  [116,117,121]. Starting naltrexone requires initial abused prescription opioids. Because antibodies are highly
For personal use only.

withdrawal treatment, however, and our treatments have had specific for the chemical structures of the various opioids,
limited efficacy using clonidine. Lofexidine availability in an antibody to morphine will not be effective for oxy-
the USA is expected to improve upon clonidine-assisted codone, codeine, or fentanyl, or for many other abused
withdrawal treatments, as it has in many European coun- opioids. Making vaccines or monoclonal antibodies to the
tries. Lofexidine may have a second important role during wide range of opioids is possible, but a logistic challenge
naltrexone maintenance, as stress-induced relapse may be that seems still more than 5  years in the future as we
reduced by several months of sustained treatment with understand how to provoke stronger immune responses to
lofexidine after detoxification is completed. Nevertheless, a haptens like these drugs and to produce monoclonals more
problem for commercial depot naltrexone products such as cost-effectively. Thus, new options are evolving in pharma-
Vivitrol is that its FDA approval is limited to alcoholism, cotherapy of opioid dependence, and the increased safety
thereby making its use for opioid dependence ‘off label’ and and efficacy of these options will be particularly important
potentially a medical and economic risk. The economic risk as we target these abusers early in their addiction careers in
is that depot naltrexone is relatively expensive, at about five order to avoid the major life-threatening complications that
times the cost of oral naltrexone. Since opioid dependence is arise from sustained abuse of these  drugs.
not an approved FDA indication, insurance carriers may not
reimburse its substantial cost of about $10,000 for a year’s Declaration of interest
treatment. The medical risk involves these antagonists’ sig-
nificant hormonal effects on increasing cortisol, growth hor- T Kosten has worked as a consultant for Reckitt Benckiser,
mone, luteinizing and follicle-stimulating hormones (LH who make Suboxone®. The other authors declare no conflicts
and FSH)  [146]. The unintended consequences of these of interest.

Expert Opin. Pharmacother. (2009) 10(11) 1735

 Opioid dependence treatment: options in pharmacotherapy

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Affiliation
For personal use only.

Angela L Stotts†1 PhD, Carrie L Dodrill1 PhD &

Thomas R Kosten2 MD
†Author for correspondence
1University of Texas Medical School at Houston,

Department of Family and Community

Medicine,
6431 Fannin, JJL 324,
Houston, TX 77030, USA
Tel: +1 713 500 7590 ; Fax: +1 713 500 7606;
Email: [email protected]
22002 Holcombe, VA Hospital Bldg 110,

Rm 229, Houston, TX 77030, USA

Tel: +1 713 794 7032; Fax: +1 713 500 7606;
E-mail: [email protected]

1740 Expert Opin. Pharmacother. (2009) 10(11)