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
mu opioid receptor gene; the
mu 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.