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The place of detoxification in treatment of opioid dependence

Linda R. Gowinga,b and Robert L. Alia,b

Purpose of review Introduction


This review summarizes current research on the Dependent opioid users seek detoxification for a range of
management of opioid withdrawal and considers the reasons. Some seek brief respite from the illicit drugs
selection of the approach in different situations. lifestyle; some want to regain control over their drug use,
Recent findings intending to continue using opioid drugs in smaller
The recent publication of three controlled trials makes firm amounts and at a lower cost; some come with the incen-
conclusions about the relative effectiveness of newer tive of impending legal action, hoping to impress the
approaches (antagonist-induced withdrawal under court with their intention to change; and some come
anaesthesia or with minimal sedation; buprenorphine) to the under pressure from family and friends. Many express
management of opioid withdrawal possible. a wish to be abstinent but with considerable ambivalence
Summary about their ability to cope with life without drugs. Given
Antagonist-induced withdrawal under anaesthesia should the diversity in reasons for seeking detoxification and
not be pursued as it has an increased risk of life-threatening ambivalence towards abstinence, it is perhaps not surpris-
adverse events and has no additional benefits relative to ing that rates of completion of detoxification are low, and
antagonist-induced withdrawal under minimal sedation. rates of relapse to opioid use following detoxification are
Antagonist-induced withdrawal with minimal sedation is high [1–3]. This in turn is the basis for views that
feasible and may be suitable for those who intend to enter detoxification alone does not constitute treatment for
antagonist-maintenance treatment with a clear commitment opioid dependence [4,5].
to abstinence and good support. Buprenorphine is suitable
for quick withdrawal, supports transition to naltrexone Nonetheless, detoxification is an important component
maintenance treatment, is safe and effective in outpatient of a comprehensive treatment system. Detoxification
settings and can be extended into maintenance treatment if remains the first step required for many forms of longer
the detoxification attempt is unsuccessful. Adrenergic term treatment. It may represent the end point of an
agonists (clonidine and lofexidine) remain an effective extensive period of substitution treatment such as metha-
option for those who do not want to use an opioid and do done maintenance, or it may be the first point of contact
not intend to transfer to naltrexone maintenance treatment, between a user and the treatment services. Either way,
with lofexidine being preferable for outpatient settings. effective management of the detoxification episode may
Through appropriate choice of approach, detoxification can be critical to the future engagement of the user in longer
be a gateway to multiple, long-term treatment options. term abstinence-oriented treatment.

Keywords For many years, routine procedures for opioid detoxifica-


antagonist-induced withdrawal, buprenorphine, tion involved suppression of withdrawal with methadone
detoxification, opioid dependence and gradual reduction of the methadone dose. Ambiva-
lence towards the use of a drug of dependence to treat
Curr Opin Psychiatry 19:266–270. ß 2006 Lippincott Williams & Wilkins. opioid dependence, government restrictions on the pre-
scription of methadone and consumer dislike for the
a
Drug and Alcohol Services South Australia and bUniversity of Adelaide, Adelaide,
South Australia, Australia
protracted nature of methadone withdrawal have, to some
extent, limited the use of methadone in this way.
Correspondence to Linda R. Gowing, Discipline of Pharmacology, Level 5, Medical
School, University of Adelaide, Adelaide, SA 5005, Australia Discovery of the capacity of the a2-adrenergic agonist,
Tel: +61 8 8303 8055; fax: +61 8 8303 8059; clonidine, to ameliorate some signs and symptoms of
e-mail: linda.gowing@adelaide.edu.au
withdrawal led to widespread use of this drug as a non-
Current Opinion in Psychiatry 2006, 19:266–270 opioid alternative for managing withdrawal [6]. The use
Abbreviation of clonidine, however, has been hampered by adverse
95% CI 95% confidence interval effects of sedation and hypotension. Dissatisfaction with
methadone and clonidine has led to a sustained explora-
ß 2006 Lippincott Williams & Wilkins tion of a variety of alternative approaches. This research
0951-7367 effort has come to fruition with the results of three
significant controlled trials being published in the past
year: de Jong et al. [7] compared antagonist-induced
withdrawal under anaesthesia or minimal sedation;

266

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Detoxification and opioid dependence Gowing and Ali 267

Collins et al. [8] compared detoxification assisted by Data from these four studies indicate that buprenorphine
anaesthesia, buprenorphine and clonidine; and Ling et al. has similar capacity as methadone to suppress withdrawal
[9] conducted two separate multicentre, controlled signs and symptoms, a finding that is consistent with
trials: one in inpatient and the other in outpatient findings in relation to maintenance treatment [11]. It is
settings, both comparing buprenorphine and clonidine however possible that patterns of withdrawal may differ
for the management of opioid withdrawal. With the with buprenorphine and methadone. In particular, it
results of these trials, it is becoming possible to draw appears that the majority of individuals treated with
firmer conclusions about the effectiveness of the newer reducing doses of buprenorphine do not experience
detoxification approaches relative to the more traditional rebound withdrawal after cessation of buprenorphine,
approaches of tapered methadone or clonidine-plus- whereas peak withdrawal occurs 1–2 days after the
symptomatic medications. This review summarizes the end of the methadone dose taper [12]. Overall, more
state of current research evidence and the clinical information is required on the relative patterns of with-
implications in terms of the selection of detoxification drawal associated with buprenorphine compared with
approach in different situations. methadone [10].

Relative effectiveness of newer The limited data available suggest a marginally shorter
detoxification approaches time in treatment when withdrawal is managed with
Newer approaches involve the use of buprenorphine to buprenorphine rather than with methadone, and that this
ameliorate withdrawal symptoms and opioid antagonists reflects quicker completion of treatment. It appears that
to induce withdrawal. neither buprenorphine nor methadone is associated with
significant adverse effects and rates of the completion of
Buprenorphine compared with clonidine withdrawal are similar.
In a systematic review [10], we identified 10 controlled
trials (including the studies by Ling et al. [9] and Collins Antagonist-induced withdrawal: anaesthesia or
et al. [8]) comparing buprenorphine and clonidine for minimal sedation?
the management of opioid withdrawal. These 10 studies The study by de Jong et al. [7] is one of the only two
indicate that controlled studies comparing different levels of sedation
in conjunction with antagonist-induced withdrawal [13].
(1) buprenorphine is more effective than clonidine in The treatment regimes for these two studies were quite
ameliorating the signs and symptoms of opioid with- different but the findings were similar in two aspects.
drawal; First, the findings of both studies indicate that the level of
(2) buprenorphine is associated with greater retention sedation does not affect the intensity and duration of
in treatment, as indicated by a longer mean duration withdrawal, although it is possible that the duration of
of treatment, particularly in outpatient settings [stan- anaesthesia may influence withdrawal severity. Second,
dardized mean difference: 0.82; 95% confidence these studies indicate that the risk of adverse events is
interval (95% CI): 0.57, 1.06; P < 0.001] – partici- significantly greater with heavy sedation than light seda-
pants treated with buprenorphine remain in treat- tion (relative risk: 3.21; 95% CI: 1.13, 9.12; P ¼ 0.03). De
ment for 1 or 2 days longer, relative to clonidine, for Jong et al. [7] found that the level of sedation had no
each week of scheduled treatment; effect on the completion of detoxification or abstinence at
(3) data on adverse effects are limited, but it appears that 1-month postdetoxification.
with buprenorphine there are fewer adverse effects
and fewer premature withdrawals due to adverse Anaesthesia-assisted, antagonist-induced withdrawal
effects; compared with conventional treatment
(4) completion of withdrawal treatment is significantly The study of Collins et al. [8] is one of the three studies
more likely when withdrawal is managed with bupre- comparing antagonist-induced withdrawal under anaes-
norphine rather than with clonidine, in either an thesia with conventional approaches. In a study by
inpatient (relative risk: 2.06; 95% CI: 1.03, 4.14; Krabbe et al. [14], the comparison was with tapered
P ¼ 0.04) or an outpatient setting (relative risk: methadone; in the study by McGregor et al. [15], the
1.46; 95% CI: 1.07, 1.99; P ¼ 0.02). comparison was with inpatient detoxification managed
with clonidine and symptomatic medications, whereas
Buprenorphine compared with methadone Collins et al. used buprenorphine and clonidine in com-
Data comparing buprenorphine with methadone for the parisons.
management of opioid withdrawal are somewhat sparse –
our systematic review [10] identified only four controlled Collins et al. [8] found no significant difference in
studies that compared buprenorphine and methadone for withdrawal severity following anaesthesia-assisted with-
the management of opioid withdrawal. drawal compared with withdrawal managed with either

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
268 Addictive disorders

buprenorphine or clonidine. Krabbe et al. [14] found that with higher doses (> 25 mg naltrexone). Although it is a
antagonist-induced withdrawal was more intense but less feasible approach to the management of opioid with-
prolonged than withdrawal managed with reducing doses drawal, it is unclear whether it reduces the duration of
of methadone. McGregor et al. [15] did not directly withdrawal treatment or facilitates transfer to naltrexone
compare withdrawal signs and symptoms in the two study treatment to a greater extent than withdrawal managed
groups. primarily with an adrenergic agonist. Data from direct
comparisons of antagonist-induced withdrawal under
Compared with reducing doses of methadone or cloni- minimal sedation and buprenorphine remain limited.
dine, antagonist-induced withdrawal is associated with
significant reductions in the time between opioid use and Clinical implications: choice of detoxification
the commencement of naltrexone treatment. approach
While choosing detoxification approach, one should take
McGregor et al. [15] and Krabbe et al. [14] reported no into account the evidence of the effectiveness of the
serious adverse events associated with antagonist- different modalities, patient preferences, support and
induced withdrawal or conventional approaches, whereas motivation for abstinence, past history of failed detox-
Collins et al. [8] reported three life-threatening adverse ification attempts and the intended form of postdetox-
events in the anaesthesia group, but none in the bupre- ification treatment.
norphine or clonidine groups. A range of adverse events
has been reported to be associated with antagonist- Inpatient or outpatient detoxification?
induced withdrawal, some life threatening and some fatal Few direct comparisons of inpatient and outpatient
[13]. settings for opioid withdrawal have been made. In a
systematic review, Day et al. [18] identified only two
The diversity of adverse effects that have been reported controlled trials [19,20], with only one of these [19]
indicates that the basis of adverse effects is complex. As meeting the criteria for inclusion in the systematic
has been suggested by others [8,16], it may be inferred review. In both studies, detoxification was managed with
that the rapid precipitation of withdrawal that is possible tapered methadone, and the rate of completion of with-
under anaesthesia imposes a level of physiological stress drawal for inpatient withdrawal was more than double the
that significantly increases the risk of adverse effects, rate for outpatient withdrawal. Of those followed up after
with the nature of the adverse effect dependent on the detoxification in the study by Wilson et al. [19], all in the
physical and mental health status of the individual. inpatient group had returned to heroin use within
3 months of treatment; all but two of the outpatient
Data are limited, but it appears that antagonist-induced group had returned to heroin use within 2 months of
withdrawal under anaesthesia, compared with withdrawal treatment and one of these was in prison.
managed with clonidine, is associated with increased
rates of commencement of naltrexone maintenance treat- In a subsequent cost analysis, Gossop and Strang [21]
ment and increased rates of retention in naltrexone noted that inpatient detoxification is much more expen-
treatment for up to 3 months. No significant differences sive than outpatient treatment (by a ratio of 24 : 1).
in these outcomes for antagonist-induced withdrawal With adjustment for successful outcomes, the costs
under anaesthesia have however been observed com- were almost identical (a ratio of 0.9 : 1). That analysis
pared with withdrawal managed with buprenorphine. was based on abstinence at the end of the methadone
taper and did not consider relapse in the immediate
Antagonist-induced withdrawal with minimal sedation postdetoxification period. Although rates of completion
compared with clonidine in outpatient settings are low, there may be advan-
In a systematic review [17], we identified seven con- tages to withdrawal occurring in the everyday setting
trolled studies comparing antagonist-induced withdrawal where the person will remain once drug-free. In
with treatment regimes based primarily on an adrenergic contrast, those undergoing withdrawal in an inpatient
agonist (clonidine in four studies and lofexidine in three setting have an abrupt transition from a protected setting
studies). to the usual life situation, a transition that is associated
with a high rate of relapse [2].
On the basis of these seven studies, withdrawal induced
by opioid antagonists in combination with an adrenergic Although there may be benefits of undergoing with-
agonist is more intense (higher peak withdrawal severity) drawal on an outpatient basis, the circumstances of the
than withdrawal managed with clonidine or lofexidine patient must support this. The person must be strongly
alone, but the overall severity is less, probably because motivated to become substance free, have a home
symptoms abate more rapidly. Delirium may occur environment that will provide the necessary quiet,
following the first dose of opioid antagonist, particularly safe and comfortable environment, be capable of good

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Detoxification and opioid dependence Gowing and Ali 269

compliance with the treatment protocol and be able to be approach questionable. De Jong et al. [7] estimated the
seen frequently enough to ensure that significant with- cost of antagonist-induced withdrawal under anaesthesia
drawal symptoms or adverse effects can be recognized at s4439 for 1 month, compared to s2517 for the minimal
and addressed promptly. sedation approach (including the period of aftercare).
The higher cost of the anaesthesia-based approach and
Choice of medication the requirement for access to scarce intensive care
For patients wishing to complete detoxification quickly resources further underline the questionable value of
prior to residential or other drug-free treatment, detox- this approach.
ification managed with buprenorphine is likely to provide
the most effective amelioration of withdrawal symptoms. Maintenance or detoxification?
For patients with a strong preference for nonopioid None of the approaches to opioid withdrawal is a magical
treatment, clonidine or lofexidine in combination with cure for dependence. Relapse remains common either
symptomatic medications would also be effective. Due to during or shortly after the completion of detoxification. In
hypotensive side effects, clonidine should be used with all cases, patients will have an increased risk of overdose
caution in outpatient settings. Lofexidine, which has less following detoxification due to reduced tolerance, and
effect on blood pressure [17], or buprenorphine would be depression and other psychiatric conditions may become
preferred for outpatient detoxification. apparent with abstinence, complicating the recovery.
The difficulties in achieving and maintaining abstinence
Those entering residential treatment tend to be signifi- and the significant risks associated with relapse to illicit
cantly affected by dependence. They are likely to be drug use emphasize the importance of follow-up treat-
polydrug users with limited family support, in which case ment and support and the need to have maintenance
an inpatient setting for detoxification is likely to be treatment available for those unable to sustain abstinence
most appropriate. immediately. Maintenance treatment with either bupre-
norphine or methadone has proven effectiveness in terms
For those with marked ambivalence about their ability to of its capacity to retain dependent opioid users in treat-
achieve and sustain abstinence, those choosing out- ment, reduce illicit drug use, prevent transmission of HIV
patient withdrawal and those resistant to postdetoxifi- and provide an opportunity for social stabilization. Trans-
cation treatment, tapered buprenorphine or methadone fer to maintenance treatment should be seen as a positive
would have the advantage of being readily extended outcome of detoxification.
into substitution treatment if patients find themselves
unable to complete detoxification. Substitution treatment Conclusion
is by far preferable to relapse to illicit drug use in Buprenorphine, clonidine, lofexidine, tapered metha-
terms of protection against overdose and transmission done and antagonist-induced withdrawal with minimal
of human immunodeficiency virus (HIV) as well as sedation can all be effective approaches to the manage-
reduction of criminal behaviour and promotion of social ment of opioid withdrawal. While selecting an approach,
stability, but it can take time for opioid users and their one should consider the setting in which withdrawal is to
families to accept substitution treatment. A period of occur, the individual’s motivation, support, drug-use
detoxification treatment with buprenorphine or metha- history and postwithdrawal intentions. In this way,
done can help patients to appreciate the advantages of detoxification can be a gateway to multiple treatment
substitution treatment over illicit drug use. options, and can support the engagement in long-term
treatment that is necessary for recovery from opioid
For those with strong commitment to abstinence and clear dependence.
incentives to remain abstinent (e.g. family, employment,
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