Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York 10021, USA
In 1963, Professor Vincent P. Dole at the Rockefeller University
formed a small team to develop a pharmacotherapy for the management
of heroin addiction. They hypothesized that heroin addiction
is a disease of the brain with behavioral manifestations, and
not merely a personality disorder or criminal behavior and began
to address the specific question of whether a long-acting opioid
agonist could be used in the long-term maintenance treatment
of heroin addiction. Over the next 35 years, many studies documented
the safety, efficacy and effectiveness of methadone pharmacotherapy
for heroin addiction, but Federal regulations and stigmatization
of heroin addiction prevented implementation of treatment. Finally,
in 1999, NIH published a report unequivocally supporting methadone
maintenance pharmacotherapy for heroin addiction. Two other
effective opioid agonist treatments have been developed: the
even longer acting opioid agonist l-alpha-acetylmethadol (LAAM)
has been approved for pharmacotherapy for heroin addiction,
and still under study is the opioid partial agonist-antagonist
buprenorphine-naloxone combination. A variety of studies, both
laboratory based and clinical, have revealed the mechanisms
of action of long-acting opioid agonists in treatment, including
prevention of disruption of molecular, cellular and physiologic
events and, in fact, allowing normalization of those functions
disrupted by chronic heroin use. Recent molecular biological
studies have revealed single nucleotide polymorphisms of the
human µ opioid receptor gene; the m opioid receptor is
the site of action of heroin, the major opiate drug of abuse,
analgesic agents such as morphine, and the major treatment agents
for heroin addiction. These findings support the early hypotheses
of our laboratory that addiction may be due to a combination
of genetic, drug-induced and environmental (including behavioral)
factors and also, that atypical stress responsivity may contribute
to the acquisition and persistence of, as well as relapse to,
use of addictive drugs.
