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Apatient-supported clinical trial.

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EDITORIAL
A Patient-Supported Clinical Trial
N
altrexone is an interesting medication that has been
in clinical trials since 1974 and was approved by
the US Food and Drug Administration for opioid addiction in 1985 and for alcoholism in 1995. Both approvals
were for a dose of 50mg per day. In 2006, a once
monthly depot preparation was approved for the treatment of alcoholism, and approval of the depot for opioid
addiction is pending. The medication is highly effective
in blocking all 3 types of classic opioid receptors (l, d,
j) with highest affinity for l, the receptor most involved
in suppression of pain. The low dose of 4.5mg per day
as used in the Cree et al1 study should have no side
effects, so the therapeutic ratio is very favorable. There is
little to no downside to taking this low-dose medication,
and it appears that at least 1,000 multiple sclerosis
patients are sold on it. Although there is a black box
warning on potential liver toxicity, this relates to a study
at 7 the standard dose, in which reversible liver enzyme
elevation was reported. Recent studies have shown lower
enzymes in alcoholics randomized to naltrexone than in
the placebo control group. Thus, there seems to be questionable justification for the black box.
The fact that patients would voluntarily fund the
Cree et al study implies strong motivation, but also makes
the possibility of placebo effects more likely. However, the
double-blind design should have protected against a bias
in favor of the medication. The difficulty of reliably
detecting the subtle subjective signals of mental well-being
is illustrated by the anecdote of the participant who experienced such a strong positive response to his first treatment episode that he declined to continue in the crossover
design. Yet he later turned out to have been receiving placebo. The authors also checked to see if there were clues
that informed the patient when they were receiving active
medication, but patients were unable to reliably detect the
difference between drug and placebo.
Clearly the findings of Cree and colleagues are worthy of note and deserve replication. Unfortunately, a
large-scale multisite trial would be very expensive, and
the fact that naltrexone has long been generic makes
such a trial even less likely to ever happen. Apparently
low-dose naltrexone can be produced in small quantities
by formulating pharmacists depending on individual state
C 2010 American Neurological Association
124 V
law. The standard 50mg tablet can also be broken into
quarters with relative ease, but this would yield approximately 12mg per morsel, which may give results quite
different from the 4.5mg in the Cree et al study. Thus,
using a careful formulating pharmacist is the better
option.
From a pharmacological perspective, the theoretical
mechanism of the apparent action in this study can only
be speculated. Naltrexone has high affinity for l receptors, and a 50mg dose has activity at receptors far longer
than the plasma half-life.2 Whether a low dose can have
an impact on endorphin release or on resetting of receptors is not known. There is some evidence that naltrexone and naloxone are actually inverse agonists,3 so that
naltrexone could have an effect beyond simply preventing
opioids from binding to receptors. There are no currently
available assay methods to measure endorphin levels in
human subjects. If the significant perceived benefits on
mental health, pain, and cognitive function turn out to
be real, that is, able to be replicated by others, further
studies could search for a mechanism. The benefits could
be useful in other chronic disorders as well.
The question of subjective effects of naltrexone is
complex. Most of the controlled studies have used 50mg
per day, so the 4.5mg dosage has not had adequate study.
At 50mg per day, most placebo-controlled studies in normal volunteers show some negative mood effects in at
least 10% of subjects,4 and some are so severe that the
volunteers are unable to continue in the study. In alcoholics, especially those who have been engaged in heavy
drinking, naltrexone may produce a quasiopioid withdrawal syndrome marked by nausea and occasionally
vomiting.5 Some clinicians prefer to begin treatment
with a half or quarter of a 50mg tablet. The Cree study
is surprising in that the low-dose naltrexone had the opposite effect. No patient reported euphoria, but there was
a significantly positive improvement on subjective scales
compared to placebo treatment.
The bottom line is that clinicians will find this
study interesting and potentially useful. It is always good
to find a treatment that has no apparent downside and
potentially some significant benefits. Because the benefits
are so subjective and difficult to measure, however, a
O’Brien: Patient-Supported Trial
large confirmatory trial is needed before this treatment
could be recommended as standard practice.
References
1.
Cree BAC, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol, published online 19 February, 2010.
2.
Lee MC, Wagner HN, Tanada S, et al. Duration of occupancy of
opiate receptors by naltrexone. J Nucl Med 1988;29:1207–1211.
3.
Cruz SL, Villarreal JE, Volkow ND. Further evidence that naloxone
acts as an inverse opiate agonist: implications for drug dependence and withdrawal. Life Sci 1996;58:L381–L389.
4.
Hollister LE, Johnson K, Boukhabza D, Gillespie HK. Aversive
effects of naltrexone in subjects not dependent on opiates. Drug
Alcohol Depend 1981;8:37–41.
5.
Volpicelli JR, Rhines KC, Rhines JS, et al. Naltrexone and alcohol
dependence. Role of subject compliance. Arch Gen Psychiatry
1997;54:737–742.
Potential Conflict of Interest
Dr. O’Brien has been paid for consultancy from Alkermes,
Embera, and Catalyst. Dr. O’Brien has also been paid for
expert testimony by Robt. Glanville, Esq. and C. Eppolito,
Esq. He’s also been paid an honoraria by University of
Kansas, royalties from a textbook, and had travel/
accomodations expenses covered or reimbursed by the
Manheim Germany Research Institute.
Charles O’Brien, MD, PhD
DOI: 10.1002/ana.22080
University of Pennsylvania
August, 2010
125
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