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Naltrexone
is a opiate receptor antagonist, that is, a drug that
blocks the analgesic and euphoric effects of heroin
and other opiates (such as methadone) by binding to
opiate receptors, without producing opiate effects.
It is a long-acting drug with relatively few side effects.
Patients need to be opioid free before taking it because
it produces strong withdrawal symptoms in opiate dependent
people (Mattick et al, 1998).
Ultra-Rapid Opioid Detoxification (UROD) combines two
uses of naltrexone: (i) it accelerates withdrawal by
giving opiate dependent people large doses of naltrexone
under general anaesthetic to avoid the unpleasant symptoms
of naltrexone-induced withdrawal; and (ii) then places
the patient on naltrexone maintenance for 6 to 12 months
(Brewer, 1997). While patients continue to take naltrexone,
their usual dose of heroin will not produce any euphoric
effects (Brewer, 1997). Most professionals in the field
believe that UROD should only be used to transfer patients
onto naltrexone maintenance (Mattick et al, 1998).
The
principal rationale for accelerated detoxification is
that use of an anaesthetic ensures that 100% of patients
who initiate UROD complete withdrawal and are immediately
transferred to naltrexone maintenance. This may improve
completion rates among those patients who are unable
to tolerate unpleasant withdrawal symptoms (Brewer,
1997). Neither an anaesthetic nor accelerated withdrawal
are essential for completing opioid withdrawal. Withdrawal
can be moderately accelerated in conscious patients
with small doses of naltrexone (or naloxone) in combination
with clonidine to control withdrawal symptoms. Completion
rates of 90% have been reported (Mattick et al, 1998).
Many patients do not need accelerated detoxification;
they can complete withdrawal while conscious using only
clonidine and sedatives.
Evidence
of Effectiveness
Although some thousands of heroin addicts have reported
undergone UROD, no controlled research on treatment
outcomes at one year or longer have been published in
scientific journals (Gossop and Strang, 1997). The rates
of abstinence after UROD reported in the popular media
have been from uncontrolled and unpublished studies
in highly selected patients. The abstinence rate of
65% at 12 months reported in the media is likely to
be an optimistic estimate of success in routine clinical
practice with unselected patients. The cost of the UROD
(reportedly AUD$12,000) ensures that the patients who
have received it have the personal or family resources
to fund their treatment. Their changes of achieving
abstinence after any treatment are better than that
of the average patient treated for heroin dependence.
Reasons
for Concern
Many professionals in the addictions field have been
concerned about the claims that have been made for naltrexone
as a treatment for heroin dependence.
First,
the history of treating heroin dependence has been marked
similar claims that have not been borne out by later
experience (Kleber and Riordan, 1982). Second, detoxification
is only a first step in recovery from opiate dependence
(Mattick and Hall, 1996). Maintaining abstinence is
generally much harder than completing withdrawal for
most people. Those who complete withdrawal are very
likely to return to heroin use without further support
to prevent relapse (Mattick and Hall, 1996). Relapse
prevention may involve attending self-help groups, living
in a therapeutic community, or taking a drug such as
methadone that prevents withdrawal symptoms and enables
heroin users to rehabilitate themselves.
Third,
naltrexone maintenance has already been evaluated as
an alternative to methadone maintenance in heroin dependent
people. It has been found to be less attractive than
methadone, to retain fewer people than methadone (Osborn
et al, 1986), and it has not been proved to be superior
to placebo treatment in several controlled trials (San
et al, 1991). Naltrexone may have a place in the treatment
of heroin dependence in carefully selected, well motivated
patients who have external pressure to remain opioid
free, such as addicted medical professionals (Thomas
et al, 1976; Washton et al, 1984). It is clearly not
a `cure' for most heroin users (Judson and Goldstein,
1984; Kosten and Kleber, 1984).
Fourth,
authoritative expert opinion overseas based upon reviews
of the research literature have concluded that, at best,
UROD has a limited role in the treatment of opioid dependence
(e.g. Horman et al, 1996; Gossop and Strang, 1997; O'Connor
and Kosten, 1998). A recent Australian literature review
(mattick et al, 1998) concluded that UROD was unlikely
to be a first line of treatment for heroin users. It
was thought to be most appropriate for the small number
of individuals who were so sensitive to withdrawal symptoms
that they are unwilling to withdraw using conventional
treatment approaches. Even in these cases, it is unlikely
to increase rates of long-term abstinence.
Fifth,
UROD is an expensive treatment. Because it involves
a general anaesthetic, it requires intensive care beds,
specialist nursing staff and an anaesthetist. Given
the many competing demands on intensive care and high
dependency beds in Australia, it seems difficult to
justify the use of scarce ICU beds for the palliative
treatment of opioid withdrawal. Opioid dependence does
carry an increased risk of premature death from drug
overdose, suicide and infectious disease (English et
al, 1995) but there is no evidence that those risks
are reduced by detoxification, whether under general
anaesthetic or not (Mattick and Hall, 1996).
Sixth,
concerns have also been raised about the safety of UROD
and naltrexone maintenance. One death has occurred under
general anaesthesia in Britain (Mayor, 1997). Under
good anaesthetic care, the risks of UROD are low but
it seems unnecessary to take this risk when most patients
can withdraw without anaesthesia. There may also be
an increased risk of overdose death during naltrexone
maintenance. Patients who inject heroin shortly after
they stop taking naltrexone will be at high risk of
overdose if they use their usual street dose of heroin
because their opioid tolerance has been reduced to zero.
Patients can also overdose while taking their naltrexone
if they use larger than usual doses of heroin to overcome
the naloxone receptor blockade. One study of naltrexone
maintenance has reported an elevated rate of overdose
and suicide (Miotto et al, 1997).
Why
the Current Demand for Naltrexone?
In the absence of evidence for UROD and the disappointing
results of naltrexone maintenance, why is it in such
demand? A major factor has been the uncritical media
acceptance of the claim that it `cures' heroin addiction
in six hours. The media have not made clear that the
`100%' is the percentage who completes withdrawal, not
the percentage who achieve long-term abstinence. They
have suggested that heroin dependence is not to be feared
because it can be `cured' in six hours.
The
media have not challenged its proponents to present
evidence for their claims to have `successfully treated'
4000 patients in Israel. No information has been presented
on how typical these patients are of heroin addicts,
and none on what has happened to more than a handful
of these patients after UROD. Instead, current affairs
programs have shown patients reporting feeling `cured'
after waking from the anaesthetic. This `evaluation'
makes as much sense as judging the effectiveness of
cancer surgery by whether a handful of patients survive
surgery rather than by how many of a large and representative
sample of patients are alive and well five years later.
Dissatisfaction
with existing treatment
The startling claim that naltrexone `cures' heroin addiction
promises desperate parents and families a swift and
painless way out of heroin- addiction. This is more
than the modest improvements that are slowly achieved
by existing treatments. Dissatisfaction with current
treatment has been amplified by a new wave of heroin
use among young Australians.
It
is over a decade since the last epidemic of heroin use
in Australia so the community has forgotten the unwelcome
fact that heroin dependence can be a chronic and relapsing
condition (Hall, 1996). A proportion of new heroin users
will be able to stop their use, with difficulty. They
will have the shortest periods of heroin use and the
best social resources to escape from heroin use and
its stigma. Nonetheless, a substantial proportion will
fine it difficult to overcome their dependence (Hall,
1996). The subsiding heroin epidemic will leave a sizeable
number of individuals who remain opioid dependent for
substantial parts of their adult lives. We see evidence
of this in the increased rate of overdose deaths among
adults in their late 40s and early 50s, most of whom
initiated heroin use over a quarter of a century ago
(Hall and Darke, 1997).
Commercial
marketing
The most worrying aspect of UROD has been the success
with which its proponents have marketed it in the popular
media in the absence of evidence of its safety and efficacy.
The proponents of UROD have not produced evidence from
controlled clinical trials that it is more effective
and cost-effective than existing forms of treatment.
Because of their commercial interests in patenting and
franchising the procedure (Brewer et al, 1998) secrecy
about their procedure has hindered its evaluation.
Ideally,
the introduction of UROD would be delayed until controlled
clinical trials have evaluated its safety and effectiveness.
Such trials are required for the registration of any
new meditation under the Therapeutic Goods Act (TGA).
Well designed trials will provide evidence on the effectiveness
and safety of UROD and naltrexonic maintenance, and
if they are large enough, they may indicate for whom
it is most appropriate.
Some
politicians have advocated the introduction of UROD
in the absence of controlled trials. This would risk
substantial sums of public money being spent on an expensive
treatment that may benefit very few heroin addicts.
It may even be worse if UROD or naltrexone maintenance
were found to increase overdose deaths and suicides.
Heroin addicts and their families deserve the same protection
from expensive, ineffective and unsafe treatments as
persons with any other chronic disorder. We should not
allow desperation for a `cure' of heroin addiction to
subvert the safeguards which ensure that new treatments
are safe and effective before they are widely used.
The
conduct of controlled trials has become a priority because
UROD and naltrexone maintenance have already been introduced
into the private sector by clinicians who are not trained
or resourced to property evaluate them. Their uncontrolled
introduction will ensure that it takes much longer to
decide how safe and effective they are, and what place
they have in treating opioid dependence.
Trialing
UROD
State governments are now discovering that clinical
trials are expensive and take several years to produce
results. So far, $1.4M has been publicly committed to
trials in three Australian states. It is far from certain
that these trials will provide authoritative assessments
of the safety, efficacy and cost-effectiveness of UROD.
Clinical trials are difficult to do well at the best
of times. And these are not the best of times to be
trialing UROD. Australia is not over- endowed with researchers
who are experienced in conducting such controlled trials.
There are substantial opportunity costs in terms of
the competing use of ICU beds and anaesthetists; and
the media- driven expectations of the UROD will make
it difficult to conduct such trials.
The
outcomes that should be assessed include the rates:
- at which patients complete withdrawal and are symptom-free
at the end of UROD
-at which they are retained on naltrexone for 12 months
-of abstinence after patients have completed 12 months
on naltrexone
-and at which overdose deaths and suicides occur.
Trialing
Naltrexone Maintenance
Carefully controlled trials of naltrexone maintenance
are also required. For safety reasons, these trials
should be restricted to patients who want to become
abstinent and who have good family support to ensure
compliance. The literature suggests that those who will
do best are those who are still employed or have the
education and skills to become employed, those who have
short heroin using careers, and those who have the support
of family or friends who are not drug users. Offering
naltrexone maintenance as a first-line treatment for
all heroin users may increase overdose deaths and suicide
among those who stop taking naltrexone.
Trials
of naltrexone maintenance should be carried out by clinicians
who are experienced in the treatment of opioid dependence.
This will increase safety by ensuring an adequate assessment
of patient suitability for this treatment. The trials
should carefully monitor heroin overdoses and suicides.
Assessment of treatment outcome should include retention
in treatment at 12 months and rates of abstinence at
the end of 12 months on naltrexone.
Improving
Existing Treatment
Existing detoxification services need to provide alternative
to the traditional methadone/clonidine withdrawal. Newer
drugs such as lofexidine and buprenorphine need to be
trialled. Non-anaesthetic accelerated withdrawal may
be appropriate for the minority of patients who fail
using conventional methods. The major challenge will
be to increase choices without reducing patient access
to services for which there is already substantial unmet
needs.
We
need to offer a range of maintenance treatments by trialing
buprenorphine and LAAM. A trial of buprenorphine has
almost been completed in New South Wales and South Australia,
and trials of other agents are planned in several states.
The major issue is whether these trials will be jeopardised
by the use of scarce research funds and technical expertise
in controlled trials of UROD. A nationally co-ordinated
resource is essential if we are to make the most efficient
use of scarce research and clinical resources. The worst
outcome would be a series of small and inconclusive
trials with results that cannot be compared. The use
of common core instruments, clinical protocols and GCRP
standards will provide quicker and more convincing answers
to questions about the efficacy and safety of UROD (Mattick
et al, 1998).
Conclusion
The public demand for UROD and naltrexone maintenance
has been driven by misguided media coverage. In the
face of increasing heroin use among young Australians
this demand is likely to increase. Controlled trials
of UROD and rigorous evaluation of existing naltrexone
treatment programs are essential if we are to advise
on the role this form of treatment may have in responding
to opioid dependence. Efforts need to be made to maximise
the efficient use of scarce research resources by better
co-ordination of effort in the jurisdictions that are
either currently trialing or proposing to trial UROD
or naltrexone maintenance.
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