The Development of Medications for the Treatment of Opiate and Cocaine Addictions Issues for the Government and Private Sector (1995) / Chapter Skim
Currently Skimming:
2 Overview of the State of Scientific Knowledge Concerning Drug Addiction
2 Overview of the State of Scientific Knowledge Concerning Drug Addiction
Pages 43-73
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From page 43... ...
CONCEPTS OF DRUG ADDICTION The initiating event leading to drug addiction is the administration of an agent, such as heroin or cocaine, to obtain a pleasurable effect. Repeated administration can result in addiction defined by compulsive drug-seeking behavior, loss of control over drug use, return to drug use despite repeated efforts to stop, interference with social functioning, and often, impairments to health.
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From page 44... ...
In support of this hypothesis, basic research has shown that addictive drugs reinforce voluntary drug-taking behavior in humans and laboratory animals (Deneau et al., 1969~. The development of techniques for studying the reinforcing effects of cocaine and opiates has allowed researchers to establish and validate laboratory models of critical features of drug addiction the chronic relapsing behaviors of drug-seeking and drug- taking (Griffiths et al., 1980; Brady and Lukas, 19841.
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From page 45... ...
. As our understanding of the mechanism of drug addiction continues to improve, development of medications to treat drug addiction will be enhanced.
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From page 46... ...
For many addictive drugs, there is a definable acute-abstinence syndrome that is qualitatively and quantitatively different from protracted-abstinence syndrome. Acute abstinence, usually lasting for several days or weeks, is more intense and
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From page 47... ...
Relapse can occur even after medical treatment of acute withdrawal symptoms and psychosocial treatment for psychological and social problems associated with the addictive disorder. Relapse can be triggered by some of the same factors that initially led to drug use, but it often seems unrelated to the original cause of the drug use.
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From page 48... ...
Relapse is also associated with the presence of psychiatric disorders in addition to the drug addiction (McLellan et al., 1979; Rounsavilleet al., 1982; Khantzian, 19851. Another class of variables that has been linked to relapse is conditioning factors, that is, environmental factors and physiological states that become associated with each other over time (Wikler, 1973; O'Brien, 1975~.
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From page 49... ...
The rewarding and subjective effects of opiates are mediated through actions at mu opioid receptors (Holtzman and Locke, 1988; Woods et al., 1988, 1993) , and interference with actions at these receptors presents a rational strategy for developing medications for opiate addiction.
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From page 50... ...
In turn, the availability of such selective chemical probes might provide new mechanistic insights that can be applied to the development of medications to treat the various aspects of opiate addiction. As a result of the identification of the opioid receptors in the early 1970s endogenous Jigands (peptides)
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From page 51... ...
Although mu and delta opioid receptors appear to play important roles in the development of opiate tolerance and dependence, it has been difficult to relate reinforcement, tolerance, or dependence to changes in these receptors themselves (Loin and Smith, 1990; Nestler, 1992~. The acute withdrawal of opiates from humans who are tolerant to and dependent on those drugs produces a reproducible physiological syndrome.
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From page 52... ...
A good methadone program can provide medications for infectious diseases and treatment of psychiatric disorders and other clinical problems that often accompany and aggravate opiate-addicted patients' health status. LAAM, another opiate agonist has recently been approved for use in the treatment of opiate addiction, primarily because of MDD's efforts and those of the Food and Drug Administration (FDA)
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From page 53... ...
Specifically, cocaine blocks the reuptake of dopamine in the synaptic cleft by the dopamine transporter. That increases the amount of dopamine available to dopamine receptors and leads to activation of dopaminergic pathways.
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Similarly, multiple subtypes of dopamine receptors have been identified through molecular cloning (Gingrich and Caron, 1993~. All known dopamine receptors, like opioid receptors, are coupled to a G-protein effecter system (Duman and Nestler, in press)
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, geographical location, specific persons or events, or intoxication with other substances (Gawin and Kleber, 1986~. As in opiate addiction, the major clinical problem in treating cocaine addiction is preventing relapse; in contrast, however, effective medications are lacking.
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MDD AND STRATEGIES FOR THE DISCOVERY OF A COCAINE MEDICATION: DESCRIPTION AND CRITICAL ANALYSIS Introduction A medication developed for the treatment of drug addiction ideally is effective when administered orally or is able to be implanted, is long-acting, clinically safe, causes few side effects, is acceptable to patients, is designed to reduce both reinforcing and toxic effects of the addictive drug, has little abuse liability and is useful for more than one class of abused drugs (because many drug-users use more than one drug)
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From page 57... ...
During clinical trials or during treatment (with approved medications) , clinicians may notice unexpected benefits in their addicted patients from medications not specifically developed to treat addictions.
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From page 58... ...
CTDP has developed a tiered strategy that can use both in vitro biochemical assays and in viva behavioral tests (Figure 2.4~. Screening of chemicals that are known to affect the dopamine system and have CNS activity can begin with in vivo behavioral testing rather than in vitro testing.
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From page 59... ...
MDD's CTDP screening program analyzes compounds from industry, academia, or other sources through a series of assays including in vitro biochemical assays or in vivo behavioral assays. Compounds found serendipitously in clinical trials to be potentially useful for treating cocaine addiction are put through the in vivo screens to test the validity of the screens.
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From page 60... ...
Although the focus on the dopamine system presents problems, no other neurotransmitter system seems a more attractive target. Unlike drug design for opiate addiction, there is no current medication that is effective in treating cocaine addiction.
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From page 61... ...
Discriminative stimulus effects of drugs in laboratory animals are pharmacologically specific and are often predictive of subjective effects in humans (Johanson, 1992; Preston and Bigelow, 1991~. Moreover, the high correlation of discriminative effects with neuropharmacological actions of drugs allows exploration of the neuropharmacological mechanisms that underlie the subjective effects of cocaine.
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From page 62... ...
The lack of successful treatments in humans against which animal models could be validated. The lack of potentially useful chemicals from industry, academe, etc.
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From page 63... ...
Unfortunately, the typical history has been that open clinical trials of potential medications have shown apparent effects but there has been failure to confirm such effects consistently in carefully controlled studies. Even agents that show effectiveness in double blind studies (e.g., desipramine in Gawin et al., 1989)
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From page 64... ...
The clinical evaluation of promising medications, whether derived from screening procedures or from the armamentarium of currently approved drugs, is resource-intensive, and the validity of the findings depends heavily on appropriate experimental design. Human Behavioral Models Two test models that have been developed in human subjects are used to screen potential medications for their efficacy in the treatment of cocaine addiction (Fischman and Foltin, 1992; Robbins et al., 19921.
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From page 65... ...
Of particular focus in the MDD program is development of refined medications to treat opiateaddicted patients and the discovery of compounds that will be effective in treating cocaine-addicted patients. The concept of using medications to help to treat drug-addicted individuals is based on the physiological correlates of drug addiction, and the strategy has been shown to be extremely useful as part of the treatment of opiate addiction.
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From page 66... ...
Animal studies exploring such processes as conditioned-stimulus control of drug taking, incentive and motivational effects, and priming effects have begun to identify potential targets for treatment medications. Identification of such behavioral models must be followed by extensive pharmacological and behavioral characterization to provide benchmarks for evaluation of potential medications.
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From page 67... ...
l, "for the purpose of interdisciplinary research relating to drug abuse and other biomedical, behavioral, and social issues related to drug abuse." These centers would be engaged in and would coordinate all aspects of drug-abuse research, treatment, and education. The committee intends that the designation of such centers would serve as focal points for all aspects of drug-abuse research and would have the added benefit of encouraging new investigators to enter the field; they would also serve as sites for clinical trials and for training clinicians (see Chapter 6 for additional text and recommendations on comprehensive centers)
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From page 68... ...
1993b. Molecular cloning of a rat kappa-opioid receptor reveals sequence similarities to the mu-opioid and delta-opioid receptors.
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From page 69... ...
1993. Recent advances in the molecular biology of dopamine receptors.
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From page 70... ...
1990. Identification of MARPP-58, a morphine- and cyclic AMP-regulated phosphoprotein of 58 kDa, as tyrosine hydroxylase: evidence for regulation of its expression by chronic morphine in the rat locus coeruleus.
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l 990. Molecular characterization of opioid receptors.
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1993. Drug addiction: a model for the molecular basis of neural plasticity.
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From page 73... ...
1990. Effects of chronic cocaine abuse on postsynaptic dopamine receptors.
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