Introduction to Addictive Disorders: Implications for Pharmacotherapies

Abstract

In early 1964, a new research team coalesced at The Rockefeller University, including the late Vincent P. Dole, the late Marie Nyswander, and this author, with the goal of developing an effective treatment for heroin addiction. This team conceptualized and formed a working hypothesis which represented a paradigm shift in the concepts then accepted with respect to the nature of addictive diseases, specifically that specific addictions are diseases, diseases of the brain, with behavioral manifestations including drug hunger, drug seeking, and drug taking, and that addictive diseases are not simply due to some personality disorder or criminal behavior. The pioneering work of this team during the first six months of 1964 conducted all of the basic clinical research studies and initiated the prospective studies on safety and efficacy which formed the basis of the first effective chronic pharmacotherapy for any addiction, specifically methadone maintenance treatment for heroin addiction. Subsequent work supported another working hypothesis of that group, that methadone was not only orally effective, but in humans had very long‐acting properties; as hypothesized, such a long‐acting pharmacotherapeutic agent not only reduced and eliminated drug hunger and drug craving, and thus drug seeking and drug taking, but also allowed the normalization of physiological functions disrupted through constant intermittent bombardment of the short‐acting opioid agonist, in this case primarily heroin, on what was to be later definitely defined as the mu opioid receptor and its signal transduction systems. Further, as hypothesized over the ensuing years, it was shown that steady‐dose methadone maintenance treatment (and presumably treatment with other long‐acting opioid agonists or partial agonists such as l‐alpha‐acetylmethadol and buprenorphine) allows normalization of physiological functions disrupted by the constant “on‐off” bombardment of the short‐acting opiate heroin. Further work by our laboratory and many others has been focused on the effects of drugs of abuse on the molecular biology, proteomics and neurochemistry of the brain, as well as resultant integrated neurobiology and behaviors. Other work by our laboratory and others have focused on the contributions of environmental factors, and specifically those of atypical responsivity to stress and stressors, with either stress responsivity altered by chronic exposure to the short‐acting drugs of abuse or, alternatively, present on a genetic basis. Finally, our laboratory and now others are focused on the human molecular genetics of addiction. It has been defined that three domains of factors contribute to increased vulnerability to develop an addiction: genetic factors, which play a substantial role (30–60%) in the potential to develop an addiction; environmental factors, including such diverse contributors as perinatal and neonatal effects of early childhood development, set and setting, along with comorbidity with various psychiatric and medical disorders and stress responsivity; and finally the predictable effects of drugs of abuse on the brain. Reward modulation and countermodulation of reward and their role in specific addictions is also briefly summarized in this introduction to addictive disorders and the implications for pharmacotherapies, both current pharmacotherapies and those which will hopefully be developed in the future.

Search for genetic markers and functional variants involved in the development of opiate and cocaine addiction and treatment

“…Methadone is a synthetic opioid that is administered as a racemic mixture of (R) and (S)‐enantiomers, yet the (R)‐methadone accounts for the opioid effects. Methadone is rapidly absorbed with peak plasma concentrations 2–4 h after oral administration and is metabolized primarily in the liver 1,219 …”

CYP2B6SNPs are associated with methadone dose required for effective treatment of opioid addiction

“…Successful treatment that prevents opiate use, withdrawal and craving relies in part on individual dose optimization and optimal dosage policies. Methadone is a synthetic opioid that is administered as a racemic mixture of ( R )‐ and ( S )‐methadone enantiomers; the ( R )‐methadone is an active enantiomer at the mu‐opioid receptor (Kreek 2007). Methadone is a mu‐opioid receptor full agonist and a modest noncompetitive N‐methyl‐D‐aspartic acid (NMDA) receptor antagonist.…”

ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence

“…Methadone is a synthetic opioid that is generally administered as a racemic mixture of (R)-and (S)-methadone enantiomers, yet the (R)-methadone accounts for the opioid effects (3). Methadone is a mu-opioid receptor agonist and a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist.…”