Opiate Receptors and Antagonists: From Bench to Clinic

767 Pages·2009·6.774 MB·English

by  Lindsay H. Burns, Todd W. Vanderah, Hoau-Yan Wang (auth.), Reginald L. Dean III, Edward J. Bilsky, S. Stevens Negus (eds.)

Opiate Receptors
and Antagonists
From Bench to Clinic
Edited by
Reginald Dean, Edward J. Bilsky,
S. Stevens Negus
N N
OH
O O
HO OH HO O
Opiate Receptors and Antagonists
For other titles published in this series, go to
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Reginald L. Dean III · Edward J. Bilsky
S. Stevens Negus
Editors
Opiate Receptors
and Antagonists
From Bench to Clinic
Editors
Reginald L. Dean, III, M.S. Edward J. Bilsky, Ph.D.
Life Sciences/Toxicology Department of Pharmacology
Alkermes, Inc. University of New England
Cambridge, MA 02139 College of Osteopathic Medicine
USA Biddleford ME 04005
USA
S. Stevens Negus, Ph.D.
Department of Pharmacology
and Toxicology
Virginia Commonwealth University
Richmond, VA 23298
USA
ISBN: 978-1-58829-881-2 e-ISBN: 978-1-59745-197-0
DOI: 10.1007/978-1-59745-197-0
Library of Congress Control Number: 2008941670
© Humana Press, a part of Springer Science+Business Media, LLC 2009
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Preface
The evolution in our understanding of opioid receptors and their subtypes is inti-
mately linked to the development of new pharmacological treatments for diseases/
disorders as diverse as addiction, self-injurious behavior, pain, cancer, inflam-
mation, eating disorders, traumatic injury, pruritis, and movement disorders.
These potential treatments involve both novel chemical entities and classic opioid
antagonists with improved drug delivery systems. The contributions contained in
Opioid Receptors and Antagonists: From Bench to Clinic represent the efforts from
some of the leading international scientists and clinicians making use of the lat-
est information emerging from the study of the opioid receptor system. Given the
number of researchers currently active in this and related fields of study, it would
be inappropriate to suggest that the entire range of activities is fully reflected in this
single volume. Instead, a variety of experimental and clinical approaches involving
the fields of neuroscience, molecular biology, biochemistry, anatomy, pharmacology,
psychology, and psychiatry have been chosen to illustrate rapidly developing
experimental and therapeutic areas.
Opioid Receptors and Antagonists: From Bench to Clinic opens with a for-
ward describing, from first-hand knowledge of the author, the history behind
the clinical development of the classic opioid antagonist naltrexone. The book
is subsequently organized into seven sections. The first section contains four
chapters characterizing the opioid receptor. The second section contains six
chapters describing the chemistry and pharmacology of opioid antagonists of
different subtypes of receptors. The next four sections concentrate on the thera-
peutic areas for opioid antagonists. These sections provide support for the use
of opioid antagonists for substance abuse (seven chapters), alcohol and ingestive
behaviors (four chapters), behavioral disorders (four chapters), and medical indi-
cations, supported by nonclinical and clinical evidence (nine chapters). Finally,
the seventh section provides five chapters which concentrate on the development
of exciting and innovative drug-delivery approaches that are being used with
opioid antagonists.
It is hoped that this volume will serve as a useful reference while also stimulat-
ing continued research on the opioid receptor system and its interactions with hor-
monal and other transmitter systems. The ultimate goal of these efforts is to assist
v
vi Preface
in the development of treatments for “brain reward” disorders and for other medical
indications that may be responsive to opioid receptor antagonists.
Reginald L. Dean III
S. Stevens Negus
Edward J. Bilsky
Foreword
Opiate Receptors and Antagonists
It would have been very difficult to predict the scope of this volume in the early
1970s when the race to learn about the functions of the newly discovered endog-
enous opioid system began. The first clinical studies of naltrexone were published
by Bill Martin and Don Jasinski based on studies done in heroin addicts living in
the USPHS Prison Hospital in Lexington, Kentucky (Martin et al 1973). Founded
in the 1930s, this research unit was the forerunner of the NIH intramural program
which for NIDA is now located in Baltimore. The Lexington unit at that time was
one of the few places in the world doing scientific studies of addiction.
After reading the results of naltrexone studies in Lexington, several groups began
trials of the medication as a new treatment for heroin addiction. My original IND for
naltrexone dates to 1973 when this medication created great excitement as the antag-
onist with better properties than cycloazine and fewer side effects. This was a very
exciting time for both basic and clinical research on the opioid system. Naltrexone
was being hailed as the perfect medication. It was non-addicting with few side
effects but it blocked virtually all of the effects of heroin and other opioids.
Of course, we now know that naltrexone as a treatment for opioid addiction
appeals to few patients. Thus, compliance of the oral form is very low. After several
clinical trials in which naltrexone was tested against placebo, it was found that clas-
sic, double-blind studies did not work with this drug (Hollister 1978). If the patient
tested the blockade, they immediately knew which drug they were on and they often
would simply stop the medication in order to get high. If they failed to test with a
trial dose of heroin-, it made no difference whether they were on placebo or naltrex-
one. In fact, those on placebo would have a tendency to do better because there were
fewer but not zero side effects from placebo. When naltrexone was finally approved
by the FDA in 1984 as a treatment for heroin addiction, approval was based on its
pharmacology and not on clinical trials. Still, the Dupont Company celebrated it as
a major treatment advance. All of the scientists who had been studying naltrexone,
however, had warned the company that naltrexone (Trexan®) was not appealing to
patients and therefore it would likely sell very poorly. In fact that prediction came
true and a disappointed Dupont Merck rapidly lost interest in the product.
vii
viii Foreword
Basic scientists, however, continued to study the opioid system and a major
method for determining its function was to block it utilizing specific antagonists
such as naloxone or naltrexone. One of the earliest workers in this field was Larry
Reid who showed that both opiate agonists and opiate antagonists influenced alco-
hol drinking (Reid and Hunter 1984). Clear evidence of a role for opiate antagonists
in blocking self administration of alcohol was first published by Hal Altshuler of
Houston, Texas who presented a paper at the CPDD Meeting in 1979 showing a
dose-related naltrexone effect on suppression of intravenous alcohol self-admin-
istration in 8 of 22 Rhesus monkeys (Altshuler et al 1980). This work led me to
propose naltrexone as potentially useful in the treatment of alcoholism. I sent a
protocol to the FDA and eventually received an IND in 1983 to study naltrexone in
alcoholics. I tested it in an open trial with alcoholics, some of whom seemed to do
very well. I was encouraged enough to begin a double-blind trial in our Veterans
Administration day treatment center for alcoholism. The subjects were 70 male
alcoholics with an average of 20 years of alcoholic drinking and numerous relapses
after detoxification. The treatment program involved intensive psychotherapy
including 12-step/Alcoholics Anonymous groups plus family therapy and 5 days
per week (25 hours) in the day hospital program.
Recruitment of subjects was very difficult because of outright hostility by coun-
selors who were often recovering alcoholics themselves and were opposed to the
use of medication. The first postdoctoral fellow who was assigned to this study was
able to recruit only a handful of subjects over a year but the next post-doctoral fel-
low, Joe Volpicelli, was convinced that naltrexone was potentially useful because he
had also conducted animal studies with the drug (Volpicelli et al 1986). His enthu-
siasm and determination convinced the counselors to give the study a chance and
we recruited a total of 70 male alcoholics. Half were randomized to 50 mg per day
of naltrexone, a dose selected because this was what we used for the treatment of
heroin addiction. The other half received an identically appearing placebo. Efforts
to obtain funding for this study were completely unsuccessful but because we had
a VA Research Center and a Postdoctoral Research Training Program, we were able
to devote some resources to this effort.
The initial results were positive and we began to report them at various meet-
ings but having the paper published was difficult (Volpicelli et al 1990; 1992).
Fortunately, Stephanie O’Malley at Yale attempted to replicate our work and found
almost identical results in a population that included both males and females and
less intensive psychotherapy (O'Malley et al 1992).
This sequence of testing a laboratory finding in a clinical population points to
the validity of animal models in the study of addiction. The history of new medica-
tions for the treatment other psychiatric disorders is usually the reverse: an effect
is noticed by an astute clinician prescribing the drug for a different reason and
laboratory studies come later.
The diversity among the chapters in this volume is a testimony to the widespread
influences of the endogenous opioid system. The role in alcoholism seems to be
important at least for a subset of alcoholics which could be the first biologically
defined endophenotype for this disorder. Since we initially began trying naltrexone
Foreword ix
as a treatment in patients more than three decades ago, great progress has been
made. The future, in my opinion, lies in pharmacogenetics. All clinical trials hence-
forth should include a request for DNA from the participants. Well-characterized
patients including information on treatment response can be extremely useful in
the future if DNA is preserved. Using such retrospective analysis, we found that a
functional allele of the gene for the µ receptor predicts good response to naltrexone
(Oslin et al 2003). Another group led by Ray Anton recently reported the same
finding in their sample (Anton R 2006). A very recent analysis of the sub-sample of
the VA multisite failed to show a correlation between polymorphism and treatment
outcome (Gelernter et al 2007).Family history plays a major role in alcoholism
and it is likely that other genetic variations will be discovered that have consistent
treatment relevance. A prospective study of the A118G allele certainly should be
accomplished. Future studies will also have the advantage of using the extended
release naltrexone preparation so that the medication compliance variable can be
more effectively managed (Pettinati et al 2000).
We have come a long way since 1973 and I predict that a specific drug such as
naltrexone will become even more important as we become more specific in our
genetic diagnoses. We still do not know the relative contribution of antagonism at
μ, κ and d receptors on the therapeutics effects of naltrexone. Recent research on
the nociception-orphanon receptor will likely yield even more therapeutic potential
as medications targeting those receptors are discovered. The up to date reviews
in this volume will give the reader a chance to catch up on the recent advances
in knowledge of the endogenous opioid system and provide clues to the future as
research continues.
Charles P. O'Brien, M.D., Ph.D.
University of Pennsylvania Health System
Penn Behavioral Health
Charles O’Brien Center of Addiction Treatment
Philadelphia, PA
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x Foreword
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