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Comment

Eective drug therapy for cocaine dependence: a milestone


and particularly not in opioid maintenance treatment.
Among the contributing reasons is the restricted access
to psychotherapy because of scarcity of adequately
trained personnel. Furthermore, there are unsolved
issues concerning the use of contingency management,
such as nancial reimbursement of the incurred
costs, the sustainability of eects after treatment
termination,11 or ambiguous study results from
European populations.12 Finally, there remain patients
who refuse or lack the necessary stability to participate
regularly in these interventions. An acceptable and
eective pharmacotherapy that could be widely
prescribed by general practicioners or psychiatrists
would thus be highly desirable.
Despite the positive ndings of this study,1 several
issues remain to be addressed in future research. First,
the study results have to be replicated in heroin-assisted
treatment, in other opioid-maintained populations,
and beyond. Daily supervised medication intake is
a resource-intensive procedure that interfers with
patients autonomy. Although patients in heroinassisted treatment might accept this intervention
because they are used to visiting the provider for
supervised medication dispensing several times daily,
other populations might be less compliant with this
treatment. Hence the authors correctly point out the
need for evaluation of sustained-release dexamfetamine
treatment in combination with compliance-improving
interventions. These might comprise a multitude of

www.thelancet.com Published online March 22, 2016 http://dx.doi.org/10.1016/S0140-6736(16)00563-8

Published Online
March 22, 2016
http://dx.doi.org/10.1016/
S0140-6736(16)00563-8
See Online/Articles
http://dx.doi.org/10.1016/
S0140-6736(16)00205-1

Christoph Hardt/Geisler-Fotopres/dpa/Corbis

In The Lancet, Mascha Nuijten and colleagues1


present the results of a multicentre, randomised,
double-blind, placebo-controlled trial assessing the
acceptance, safety, and ecacy of sustained-release
dexamfetamine in cocaine-dependent patients on
heroin-assisted treatment. The study ndings showed
that 60 mg/day oral sustained-release dexamfetamine
over 12 weeks was well accepted, safe, and superior to
placebo in terms of days of cocaine use (mean 449 days
[SD 294] in the sustained-release dexamfetamine group
vs 606 days [243] in the placebo group [95% CI of
dierence 31284]; p=0031; Cohens standardised eect
size d=058) and all self-reported and urine-based cocaine
use-related outcomes. Cocaine dependence is prevalent
throughout the world and causes major morbidity and
mortality.2 At present, no eective pharmacotherapy
exists. Agonist replacement therapy has been successfully
applied to opioid and tobacco dependence,3,4 but previous
studies examining this approach in cocaine dependence
failed to nd statistically signicant benets in terms
of reduced cocaine use, or showed indecisive results.
This could be due to limitations in the methods, such as
small sample sizes,5 inadequate dosing schemes,6 or large
attrition rates.7 The study by Nuijten and colleagues1
overcomes most of these shortcomings.
First, the trial is adequately powered. Second, it uses
a robust dose of sustained-release dexamfetamine.
Adequate dosing has been shown to be an important
factor aecting the eectiveness of agonist replacement
therapies.3,8 Previous studies often used overly cautious
dosing schemes9 or short-acting formulations,5,7,9 which
might not act long enough to be eective. Third, Nuijten
and colleagues1 were able to restrict attrition because
of the intensive setting of heroin-assisted treatment,
wherein patients visited the treatment centre up to
thrice daily to inhale or inject pharmaceutical heroin
(diacetylmorphine) under medical supervision.
The results of this study1 are promising and have
important implications for the treatment of cocainedependent patients. To date, behaviour-based
interventions such as cognitive-behavioural therapy and
contingency management are the treatment of choice,
showing moderate eect sizes.10 Importantly, however,
these interventions have not been implemented
comprehensively across a variety of treatment settings,

Comment

procedures, such as compliance-enhancement therapy,


contingent reinforcing of correct medication intake, or
electronic interventions such as reminder devices and
machines that dispense medication. Moreover, because
the mean age of the sample was 48 years, with most
being male, the results need to be replicated in younger
age groups and female patients. Second, research needs
to address the optimum target dose and formulation. It is
unlikely that 60 mg/day is a one-size ts all dose. Higher
doses might be more eective in some individuals,
and there might be a threshold for therapeutic eect.
Higher doses, however, would need to be assessed for
their safety and tolerability. Other stimulants, such as
methylphenidate, could also be suitable for use in an
agonist-replacement approach6 and should be tested for
eectiveness and adverse eects in comparable doses
and over longer periods of time.
Although there was a signicant reduction in
cocaine use, and an increase in the proportion of
participants able to abstain from cocaine for longer
than 21 days, participants who received sustainedrelease dexamfetamine continued to use cocaine for
more than half of the days on average.1 This could be
related to participants seeking the rapid-onset eects
of cocaine (much in same way they do with heroin,
which is the reason for them being in heroin-assisted
treatment).13 Future research should therefore assess a
combination of short-acting stimulant-like medication
with long-acting drugs, much like the combination of
diacetylmorphine and methadone that is used in heroinassisted treatment.
In summary, Nuijten and colleagues1 provide evidence
for the eectiveness, acceptability, and tolerability of
sustained-release dexamfetamine to reduce cocaine
use in cocaine-dependent heroin-maintained patients.
Although this might not be the holy grail of cocainedependence treatment, it could be an important step

in the quest for an eective pharmacotherapy of this


severe disorder.
*Kenneth M Drsteler, Marc Vogel
Psychiatric University Clinics Basel, Wilhelm Klein-Strasse 27,
CH 4012 Basel, Switzerland
kenneth.duersteler@upkbs.ch
KMD has received a grant from Mundipharma. MV has received travel supports
from Reckitt Benckiser and Lundbeck, and a grant and personal fees from
Mundipharma.
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www.thelancet.com Published online March 22, 2016 http://dx.doi.org/10.1016/S0140-6736(16)00563-8