ArticlesOpiate and Cocaine Addictions: Challenge for 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)
- et al.
Quantitation of preproenkephalin mRNA levels in brain regions from male Fischer rats following chronic cocaine treatment using a recently developed solution hybridization procedure
Mol. Brain Res.
(1992) - et al.
Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a mu, delta or kappa opioid receptor type
FEBS Lett.
(1994) - et al.
Molecular cloning, tissue distribution and chromosomal localization of a novel member of the opioid receptor gene family
FEBS Lett.
(1994) - et al.
Matrix-assisted laser desorption mass spectrometry of biotransformation products of dynorphin A in vitro
J. Am. Soc. Mass. Spectrom.
(1994) - et al.
Cocaine binges differentially alter striatal preprodynorphin mRNA
Mol. Brain Res.
(1995) - et al.
cDNA cloning and regional distribution of a novel member of the opioid receptor family
FEBS Lett.
(1994) - et al.
Quantitative analysis of methadone in biological fluids using deuterium-labeled methadone and GLC-chemical-ionization mass spectrometry
J. Pharm. Sci.
(1977) - et al.
Influence of a single injection of cocaine, amphetamine or GBR 12909 on mRNA expression of striatal neuropeptides
Mol. Brain Res.
(1992) - et al.
Cocaine self-administration differentially alters mRNA expression of striatal peptides
Mol. Brain Res.
(1992) - et al.
Cortisol levels during chronic naltrexone maintenance treatment in ex-opiate addicts
Biol. Psychiatry
(1986)
A preliminary study of beta-endorphin during chronic naltrexone maintenance treatment in ex-opiate addicts
Life Sci.
Beta-endorphin levels in CSF during methadone maintenance
Life Sci.
Beta-endorphin levels during heroin, methadone, buprenorphine and naloxone challengesPreliminary findings
Biol. Psychiatry
Hepatic extraction of long- and short-acting narcotics in the isolated perfused rabbit liver
Gastroenterology
Stereoselective disposition of methadone in man
Life Sci.
Effects of chronic exogenous opioid administration on levels of one endogenous opioid (beta-endorphin) in man
Circadian rhythms and levels of beta-endorphin, ACTH, and cortisol during chronic methadone maintenance treatment in humans
Life Sci.
Naloxone, a specific opioid antagonist, reverses chronic idiopathic constipation
Lancet
ACTH, cortisol and beta-endorphin response to metyrapone testing during chronic methadone maintenance treatment in humans
Neuropeptides
ORL1, a novel member of the opioid receptor family
Cloning, functional expression and localization. FEBS Lett.
The medical status of methadone maintained patients in treatment for 11–18 years
Drug Alcohol Depend.
Contributors to a summary report]Medical education and drug abuse: Report of a Macy Conference
Cocaine abuse is decreased with effective methadone maintenance treatment at an urban Department of Veterans Affairs (DVA) program
Thrombocytosis in the offspring of female mice receiving dl-methadone
Proc. Soc. Exp. Biol. Med.
Changes in clinical status of newly abstinent hospitalized cocaine users
Molecular cloning and functional expression of a mu opioid receptor from rat brain
Mol. Pharmacol.
Molecular cloning of a rat kappa opioid receptor reveals sequence similarities to the mu and delta opioid receptors
Biochem. J.
Study of opioid peptides by laser desorption mass spectrometry
Study of dynorphin A[1–17] in vivo processing in rat brain by microdialysis and matrix-assisted laser desorption mass spectrometry
Study of dynorphin A peptides in vitro processing in human blood by matrix-assisted laser desorption mass spectrometry
Both dynorphin A1–17 and [Des-Tyr1] dynorphin A2–17 inhibit adenylyl cyclase activity in rat caudate putamen
J. Pharmacol. Exp. Ther.
Local perfusion of dynorphin A[1–17]reduces extracellular dopamine levels in the nucleus accumbens
Treatment of opioid induced constipation with oral naloxoneA pilot study
Clin. Pharmacol. Ther.
Methadone-maintained patients
Effects of methadone on plasma testosterone, FSH, LH and prolactin. N.Y. State J. Med.
Some endocrinologic observations in narcotic addicts
Cocaine self-administration increases preprodynorphin, but not c-fos, mRNA in rat striatum
NeuroReport
Antibodies to a retrovirus etiologically associated with acquired immunodeficiency syndrome (AIDS) in populations with increased incidences of the syndrome
Morbid. Mortal. Weekly Rep.
HIV I infection among intravenous drug users in Manhattan, New York City 1977 to 1987
JAMA
Biochemistry of addiction
Annu. Rev. Biochem.
Methadone plasma levelSustained by a reservoir of drug in tissue
Proc. Natl. Acad. Sci. USA
Narcotic blockade
Arch. Intern. Med.
Cloning of a delta opioid receptor by functional expression
Science
Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain
Proc. Natl. Acad. Sci. USA
Naloxone radioimmunoassayAn improved antiserum
J. Pharm. Pharmacol.
Long-term persistence of dl-methadone in tissues
Clin. Res.
Intensity of craving is independent of depression in newly abstinent chronic cocaine users
Localization of d- and l-methadone after intraventricular injection into rat brain
J. Pharmacol. Exp. Ther.
Disposition of methadone in man after a single oral dose
Clin. Pharmacol. Ther.
The levels of methadone in the plasma in methadone maintenance
Clin. Pharmacol. Ther.
Repeated, daily cocaine administration produces changes in basal and opioid-regulated adenylyl cyclase activity in rat caudate-putamen
Cited by (82)
Polydrug use and its association with drug treatment outcomes among primary heroin, methamphetamine, and cocaine users
2017, International Journal of Drug PolicyCitation Excerpt :Moreover, heroin users often report the sequential use of cocaine after heroin to enhance euphoria or to reduce the withdrawal symptoms experienced during their typical day (Leri et al., 2003) or to counteract the physical depressive effects of opioids (Roy et al., 2013). Cocaine users also sequentially use cocaine followed by heroin to self-mediate side effects of chronic cocaine administration (Kreek, 1997). Cocaine and MA are the most prevalent stimulants among those with use disorders (Degenhardt et al., 2014) and are both characterized by intense and short-lived effects (National Institute on Drug Abuse, 2016a; National Institute on Drug Abuse, 2016b).
Sex differences in the neurobiology of drug addiction
2014, Experimental NeurologyUnderstanding and treating opioid addiction in a patient with cancer pain
2011, Journal of PainCitation Excerpt :At the point at which Mr. D. became physically dependent, he most likely had periods of time when he was without heroin and went through acute opioid withdrawal. This could have occurred in as little as 3 to 8 hours of not using heroin.33,39 When Mr. D. was not using for longer periods of time and was not in acute withdrawal (ie, abstinence) he was in a state of protracted abstinence.24,25,32
Methadone maintenance treatment: A protective factor for cocaine injection in a street-recruited cohort of heroin users
2010, Drug and Alcohol DependenceAcupuncture suppresses morphine self-administration through the GABA receptors
2010, Brain Research BulletinCitation Excerpt :This study showed that electroacupuncture-mediated inhibition of morphine-induced CPP was due to increased preprodynorphin mRNA levels in the NAcc. Recent studies indicated that dynorphin has a role in reducing accumbal DA release through the activation of κ-receptors on the presynaptic DAergic nerve terminals in the NAcc [13,18]. Additionally, one study demonstrated that the κ-receptor agonist decreased heroin self-administration [12].
Drug-induced and genetic alterations in stress-responsive systems: Implications for specific addictive diseases
2010, Brain ResearchCitation Excerpt :In turn, those glucocorticoids, in addition to acting at diffuse sites of the body to assure overall response to stress, including sugar and fat mobilization and metabolism, also act in a negative feedback mode by decreasing production and release of CRF in the hypothalamus and also act directly in the anterior pituitary, bringing about reduction of processing and release of POMC and its neuropeptides. Studies of many other groups have shown that the glucocorticoids act in the hippocampus, where the functional relationships to stress responsivity are less clearly delineated, but seem to be closely associated with reduction in hippocampal size when there is chronic exposure to excessive levels of glucocorticoids and thus to a decrement in learning and memory (see reviews of McEwen, 1980; McEwen et al., 1992; Kreek, 1996a,b, 1997; Kreek and Koob, 1998; Kreek, 2000; Kreek et al., 2002, 2004, 2009). In addition to the important negative feedback control of the HPA axis by the glucocorticoids, it has been found that mu-opioid receptor activation by beta-endorphin, or possibly one of the mu-opioid receptor-directed enkephalins, apparently tonically inhibits both production of CRF in the hypothalamus and POMC peptides in the anterior pituitary (Kreek, 1973a; Volavka et al., 1980; Kreek et al., 1983a; Kosten et al., 1986a,b; Culpepper-Morgan et al., 1992; Culpepper-Morgan and Kreek, 1997; Schluger et al., 1998; Farren et al., 1999; Rosen et al., 1999).