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Opiate and Cocaine Addictions: Challenge for Pharmacotherapies

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Abstract

Neurobiological and behavioral studies, as well as basic and applied clinical research studies, may all contribute to the development of a pharmacotherapy for a specific addictive disease. This paper reviews recent findings from research work, primarily from one laboratory along with collaborative laboratories, that could have some relevance for the development of pharmacotherapy for cocaine dependency. The much earlier experiences of this laboratory in the development of a pharmacotherapy for opiate addiction will be addressed in the context of providing both some specific suggestions for addictive disease pharmacotherapy development and some warnings about the complexities of the introduction and implementation of a pharmacotherapy once developed. Finally, based on both the earlier perspectives and the more recent research findings, some very specific, though speculative, suggestions will be made about the development of novel pharmacotherapies for early opiate addiction, especially for cocaine abuse or addiction and prevention of relapse to cocaine use. The complex and diverse nature of the challenge for pharmacotherapy for the addictive diseases is presented, including specifically a mandate for broadening educational efforts concerning the basis of addictive diseases and the need for treatment, in parallel with the scientific efforts to develop increasingly sophisticated and targeted pharmacotherapies.

Section snippets

Vulnerability for development of addictions

The intrinsic or acquired vulnerability for the development of addictions must be considered, and we have hypothesized that there are three different types of factors that contribute to vulnerability for the development of addictions, as well as the specific neurobiological or metabolic bases for each addictive disease. First, there may be genetic factors, most likely involving multiple genes. We have hypothesized that specific alleles of a group of specific genes, which could be called

Goals for a pharmacotherapy for an addiction

We have articulated goals for a pharmacotherapy for an addiction. These include prevention of withdrawal symptoms if any pertain. Withdrawal symptoms are profound and consistently observed, although with varying degrees of severity, following cessation of chronic opiate use. Although different and dramatic symptoms have also been described in an outpatient clinic setting following cessation of long-term “binge” pattern cocaine abuse, when studies are carried out in a controlled inpatient

Involvement of the endogenous opioid system in specific addictive diseases

We hypothesized many years ago that disruption of the endogenous opioid system, including the opioid peptides and their specific opioid receptors, may be involved in each of three specific addictive diseases: heroin addiction, cocaine dependency, and alcoholism. In my laboratory, we are continuing to address questions of the role and the precise mechanisms of this disruption 62, 70.

Since the mid-1980s, using techniques of molecular biology, we have been addressing quantitative questions about

Use of the “binge” pattern cocaine administration model for neurobiological studies of cocaine effects

For many years my group, and others, have identified that “binge” pattern cocaine abuse is one of the most common patterns of illicit use of this drug in humans. Consequently, in 1988–1989, I developed an experimental model for use by my laboratory and my NIDA Research Center in which cocaine is administered in a “binge” pattern to rodents maintained in a stress-minimized controlled environment. In this model, cocaine is administered by the intraperitoneal route in three doses, each 1 h apart,

Endogenous opioid system effects of “binge” pattern cocaine administration

These changes in the dopaminergic system that we have observed during chronic cocaine administration are, for the most part, relatively modest. Therefore, we have asked the question of whether or not disruption of the dopaminergic systems alone may be involved following chronic exposure to “binge” pattern cocaine administration and thus potentially in the phenomenon of “drug hunger” or craving, which may lead to self-administration both in animal models and in humans.

Recent basic clinical research studies of the dynorphinergic kappa opioid receptor system

Based on these early findings, we formulated the hypothesis that dynorphin A may act directly or indirectly to lower dopaminergic tone. We went on to specifically hypothesize that because prolactin release in humans is almost exclusively under tonic inhibition by dopamine, administration of dynorphin A to humans would result in a rapid increase in serum prolactin levels by an action in the hypothalamus to reduce dopaminergic tone. Pilot studies have been conducted and reported by our group;

Possible role of dynorphin in modulating dopaminergic tone

These findings have given further support for our hypothesis that dynorphin may serve to modulate dopaminergic tone. Additional studies are ongoing to investigate our hypothesis that such action may also pertain to specific regions of the brain that are central to the reinforcing and locomotor effects of drugs of abuse. These studies combine laser desorption mass spectrometry (for analysis of biotransformation of dynorphin peptides in specific brain regions) and microdialysis techniques with

Patterns of concomitant cocaine and heroin use in humans

Several patterns of cocaine abuse have been noted in humans; two are of particular interest with respect to any consideration of developing a pharmacotherapy for cocaine abuse. First, it has been known for years that some drug abusers use combined self-administration of cocaine plus an opiate, usually heroin, in a so-called “speedball” to achieve an effect that is putatively different qualitatively, as well as quantitatively, from use of either agent alone [58]. However, of potentially more

Historical perspective on development of pharmacotherapies for heroin addiction: possible implications for development of pharmacotherapies for cocaine addiction

It may be helpful in considering the strategy and specific needs in the development of a pharmacotherapy for cocaine addiction to recapitulate some of the very early experiences and scientific findings that were part of our early research in developing the long-term methadone maintenance treatment for heroin addiction. I had the pleasure of joining Professor Vincent P. Dole at the time of inception of his work at the Rockefeller Institute for Medical Research (now the Rockefeller University) in

Early studies related to research on opiate addiction and existence of specific opioid receptors

The action of methadone is to provide a steady plasma level and, thus, a receptor level of medication. It is now known that methadone is highly mu-opioid receptor selective. This long-acting narcotic provides steady levels of opioid at the specific mu-opioid receptor sites. In 1963–1964, when our research was begun, we only could hypothesize the existence of opioid receptors. Subsequent seminal work was performed by many groups, including the early work by Dr. Dole and Dr. A. Goldstein, who

Effectiveness of management of heroin addiction with a long-acting opioid agonist in the prevention of aids: public health impact

Because of the decrease in drug hunger that occurs during long-term methadone maintenance treatment, self-administration of illicit drugs, which often involves use of nonsterile needles, is greatly reduced or eliminated; this effects a highly significant reduction in exposure to infectious diseases. From a public, as well as individual, health standpoint, it is of great importance that initial HIV-1 or AIDS infection is significantly reduced in patients receiving effective methadone maintenance

Problem of comorbidity of cocaine addiction with opiate addiction

One major problem that continues in methadone maintenance treatment, and is very relevant for this discussion, is the concomitant cocaine abuse and cocaine addiction present in a high prevalence of untreated heroin addicts coming into treatment [58]. In a study very recently completed by Dr. L. Borg and colleagues, the progression of the magnitude of the cocaine epidemic among heroin addicts in the greater New York area was demonstrated. In the study patients in a single methadone maintenance

Possible role of atypical responsivity to stressors in the neurobiology of addictions

Since the early 1970s, my laboratory has been addressing various aspects of our hypothesis that opiate, and more recently cocaine, addiction may be due, in part, to an inherent or drug-induced atypical responsivity to stress and stressors, which may include significant alterations of the endogenous opioid system and related aspects of neuroendocrine–neurotransmitter function 46, 50, 59, 63, 70, 148. We have hypothesized that these alterations may persist long after cessation of drug abuse, and

Summary of desirable outcomes of an effective pharmacotherapy for opiate addiction

These studies and others have shown that normalization of physiological functions that have been disrupted by illicit opiate use can be achieved, along with prevention of opiate withdrawal symptoms and highly significant reduction in “drug craving” or drug hunger. Also, a highly significant reduction of illicit use of opiates occurs during successful treatment. Additionally, indirect but certainly desirable outcome measures also include a highly significant reduction of criminal activity, as

Summary of some perspectives and hypotheses: challenge for developing a pharmacotherapy for cocaine addiction and further pharmacotherapies for heroin addicts

In summary, from our extensive (now 32-year) experience with first developing a pharmacotherapy for opiate addiction, one that has turned out to be both safe and highly effective when appropriately used, and also from our continuing studies both on the medical status of heroin addicts entering treatment and on the physiological effects of short-acting opiates (such as heroin and morphine) and, later, of long-acting opiates (such as methadone), we have learned a great deal about what may be the

Challenge for the future

These various research findings from my laboratory, as well as many other findings from numerous other laboratories, point the way to possible sites of action of potential pharmacotherapeutic agents for cocaine dependency. It should be underscored that any pharmacotherapeutic agent, to be effective, will have to be specifically tailored with respect to the targeted site of action, mode of formulation, and route of administration, as well as the intrinsic or fabricated pharmacokinetic profile,

Acknowledgements

I thank Dr. Stefan Schlussman, Dr. James Schluger, Mr. Neil Maniar, Ms. Esperance A. K. Schaefer, and especially Ms. Jennifer Sudul for their help with preparing this paper for publication. This work was conducted with support from NIH-NIDA Research Center grant P50-DAO5130, NIH-NIDA Research Scientific Award grant NIH-NIDA KO5-DA00049, a grant from the New York State Office of Alcoholism and Substance Abuse Services, and a General Clinical Research Center grant (M01-RR00102) from the National

References (152)

  • T.R. Kosten et al.

    A preliminary study of beta-endorphin during chronic naltrexone maintenance treatment in ex-opiate addicts

    Life Sci.

    (1986)
  • T.R. Kosten et al.

    Beta-endorphin levels in CSF during methadone maintenance

    Life Sci.

    (1987)
  • T.R. Kosten et al.

    Beta-endorphin levels during heroin, methadone, buprenorphine and naloxone challengesPreliminary findings

    Biol. Psychiatry

    (1992)
  • M.J. Kreek et al.

    Hepatic extraction of long- and short-acting narcotics in the isolated perfused rabbit liver

    Gastroenterology

    (1978)
  • M.J. Kreek et al.

    Stereoselective disposition of methadone in man

    Life Sci.

    (1979)
  • M.J. Kreek et al.

    Effects of chronic exogenous opioid administration on levels of one endogenous opioid (beta-endorphin) in man

  • M.J. Kreek et al.

    Circadian rhythms and levels of beta-endorphin, ACTH, and cortisol during chronic methadone maintenance treatment in humans

    Life Sci.

    (1983)
  • M.J. Kreek et al.

    Naloxone, a specific opioid antagonist, reverses chronic idiopathic constipation

    Lancet

    (1983)
  • M.J. Kreek et al.

    ACTH, cortisol and beta-endorphin response to metyrapone testing during chronic methadone maintenance treatment in humans

    Neuropeptides

    (1984)
  • C. Mollereau et al.

    ORL1, a novel member of the opioid receptor family

    Cloning, functional expression and localization. FEBS Lett.

    (1994)
  • D.M. Novick et al.

    The medical status of methadone maintained patients in treatment for 11–18 years

    Drug Alcohol Depend.

    (1993)
  • J.A. Barondess et al.

    Contributors to a summary report]Medical education and drug abuse: Report of a Macy Conference

  • L. Borg et al.

    Cocaine abuse is decreased with effective methadone maintenance treatment at an urban Department of Veterans Affairs (DVA) program

  • Y. Burstein et al.

    Thrombocytosis in the offspring of female mice receiving dl-methadone

    Proc. Soc. Exp. Biol. Med.

    (1980)
  • R. Cambor et al.

    Changes in clinical status of newly abstinent hospitalized cocaine users

  • Y. Chen et al.

    Molecular cloning and functional expression of a mu opioid receptor from rat brain

    Mol. Pharmacol.

    (1993)
  • Y. Chen et al.

    Molecular cloning of a rat kappa opioid receptor reveals sequence similarities to the mu and delta opioid receptors

    Biochem. J.

    (1993)
  • J.Z. Chou et al.

    Study of opioid peptides by laser desorption mass spectrometry

  • J.Z. Chou et al.

    Study of dynorphin A[1–17] in vivo processing in rat brain by microdialysis and matrix-assisted laser desorption mass spectrometry

  • J.Z. Chou et al.

    Study of dynorphin A peptides in vitro processing in human blood by matrix-assisted laser desorption mass spectrometry

  • L. Claye et al.

    Both dynorphin A1–17 and [Des-Tyr1] dynorphin A2–17 inhibit adenylyl cyclase activity in rat caudate putamen

    J. Pharmacol. Exp. Ther.

    (1996)
  • L.H. Claye et al.

    Local perfusion of dynorphin A[1–17]reduces extracellular dopamine levels in the nucleus accumbens

  • J.A. Culpepper-Morgan et al.

    Treatment of opioid induced constipation with oral naloxoneA pilot study

    Clin. Pharmacol. Ther.

    (1992)
  • P. Cushman et al.

    Methadone-maintained patients

    Effects of methadone on plasma testosterone, FSH, LH and prolactin. N.Y. State J. Med.

    (1974)
  • P. Cushman et al.

    Some endocrinologic observations in narcotic addicts

  • J.B. Daunais et al.

    Cocaine self-administration increases preprodynorphin, but not c-fos, mRNA in rat striatum

    NeuroReport

    (1993)
  • D.C. Des Jarlais et al.

    Antibodies to a retrovirus etiologically associated with acquired immunodeficiency syndrome (AIDS) in populations with increased incidences of the syndrome

    Morbid. Mortal. Weekly Rep.

    (1984)
  • D.C. Des Jarlais et al.

    HIV I infection among intravenous drug users in Manhattan, New York City 1977 to 1987

    JAMA

    (1989)
  • V.P. Dole

    Biochemistry of addiction

    Annu. Rev. Biochem.

    (1970)
  • V.P. Dole et al.

    Methadone plasma levelSustained by a reservoir of drug in tissue

    Proc. Natl. Acad. Sci. USA

    (1973)
  • V.P. Dole et al.

    Narcotic blockade

    Arch. Intern. Med.

    (1966)
  • C.J. Evans et al.

    Cloning of a delta opioid receptor by functional expression

    Science

    (1992)
  • A. Goldstein et al.

    Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain

    Proc. Natl. Acad. Sci. USA

    (1971)
  • E.F. Hahn et al.

    Naloxone radioimmunoassayAn improved antiserum

    J. Pharm. Pharmacol.

    (1983)
  • E.H. Harte et al.

    Long-term persistence of dl-methadone in tissues

    Clin. Res.

    (1976)
  • A. Ho et al.

    Intensity of craving is independent of depression in newly abstinent chronic cocaine users

  • N.A. Ingoglia et al.

    Localization of d- and l-methadone after intraventricular injection into rat brain

    J. Pharmacol. Exp. Ther.

    (1970)
  • C.E. Inturrisi et al.

    Disposition of methadone in man after a single oral dose

    Clin. Pharmacol. Ther.

    (1972)
  • C.E. Inturrisi et al.

    The levels of methadone in the plasma in methadone maintenance

    Clin. Pharmacol. Ther.

    (1972)
  • S. Izenwasser et al.

    Repeated, daily cocaine administration produces changes in basal and opioid-regulated adenylyl cyclase activity in rat caudate-putamen

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