Historical Review: Opiate Addiction and Opioid Receptors.

Substance use disorders (SUDs), defined as a collection of symptoms including tolerance and withdrawal, are chronic illnesses characterized by relapse and remission. In the United States, billions of dollars have been lost due to SUDs. In the past 30 years, effective medications and behavioral interventions have played a major role in preventing relapse and facilitating longer periods of abstinence. From the late 1990s to the present, the opioid epidemic or opioid crisis in the United States has raised public awareness of SUDs. Methadone, buprenorphine, and naloxone have proven their effectiveness in treating addicted individuals, and each of them has different effects on different opioid receptors. Methadone and buprenorphine target mu opioid receptors (MORs) in the brain to treat opioid dependence by reducing withdrawal and craving, whereas naloxone is an opioid antagonist used to treat opioid overdose. Mu, kappa, and delta are opioid receptor subtypes with common analgesic effects, and each also has unique effects and distribution in the brain. MORs in distinct brain regions, such as the nucleus accumbens and basolateral amygdala, trigger the euphoria and incentive properties of rewarding stimuli. Kappa opioid receptors can trigger anti-reward effects and produce dysphoric effects. Delta opioid receptors can induce anxiolytic effects. Though effective medications are available, relapse is still common due to neurobiological changes in brain pathways and tolerance of opioid receptors with repeated abuse of substances. In this article, I summarize the biological mechanisms of opioid dependence and opioid receptors and review previous articles about medications used to treat SUDs and their clinical effects.

The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking.

BACKGROUND: In almost 2 decades of naltrexone research for treating alcoholism, there have been 29 published randomized placebo-controlled trials of opioid antagonists, primarily naltrexone, for the treatment of alcohol dependence. The present review builds on prior systematic reviews while maximizing the number of included studies to date, for the purpose of resolving inconsistencies in naltrexone's reported efficacy across trials. Clinical trial results in this article are evaluated by the type of outcome measure used to determine naltrexone's treatment advantage, that is, measures related to reducing heavy drinking versus those related to increasing abstinence. METHODS: We conducted a Medline search to identify double-blind studies from 1990 to the present (2006) that evaluated the use of anopiate antagonist for the treatment of alcohol dependence. There were 29 studies identified, representing 5997 alcohol-dependent patients, which met our study inclusion criteria for this review. Studies were evaluated in this review on 4 prespecified drinking outcomes-2 related to "any drinking" and 2 related to "heavy or excessive drinking." RESULTS: In the treatment of alcohol dependence, we found that 19 (70%) of 27 clinical trials that measured reductions in "heavy or excessive drinking" demonstrated an advantage for prescribing naltrexone over placebo, whereas only 9 (36%) of 25 clinical trials that measured abstinence or "any drinking" found an advantage for medication over placebo. CONCLUSION: The majority of double-blind clinical trials in the literature favored prescribing naltrexone for alcohol dependence to reduce heavy drinking. This finding is consistent with our understanding of naltrexone's mechanism of action of decreasing excessive drinking by reducing the reward associated with drinking alcohol. Thus, we conclude that outcome measures related to heavy or excessive drinking are most relevant to defining naltrexone's therapeutic effects. Factors influencing naltrexone response (treatment adherence and distinct patient subgroups) are also discussed.

Determinants of the behavioral effects of opioids and their antagonists: contributions of the Laboratory of Psychobiology.

RATIONALE: The behavioral pharmacology of opioids has been influenced significantly by the research and writings of Drs. Peter B. Dews, Roger T. Kelleher, and William H. Morse, their colleagues, and their students. OBJECTIVE: Their conceptual and methodological approach to the topic is reviewed briefly, and three areas of research are described to provide an empirical perspective. RESULTS: The objective of determining the general effects of opioids on behavior is described; the effects of opioids on schedule-controlled behavior and punished behavior are described and compared to non-opioids. The differential effects of opioid antagonists on responding reinforced by different stimuli are also presented. CONCLUSION: The conceptual and methodological approach taken by the group, as well as their discoveries in the behavioral pharmacology of opioids, will continue to exert a positive influence on the field.

Historical introduction and review of chemistry.

A historical introduction and review of the chemistry of the agonist-antagonist analgesics is presented. This development of strong analgesics with a lowered abuse potential from nalorphine to the clinically useful agonist-antagonists pentazocine, butorphanol, nalbuphine and buprenorphine is discussed in detail. The discovery of the pure antagonist naloxone and naltrexone is described. The possible use of cyclazocine and later naltrexone in treatment of post-dependent narcotic addicts is also described. Finally, structure-activity relationships are summarized relating changes in N-alkylation to the production of narcotic antagonist activity over all of the structural types of opioids.

Treatment of heroin-dependent persons with antagonists: current status.

Naltrexone is an important new pharmacologic adjunct to the treatment of heroin dependence. The development of naltrexone has been nurtured in the mature recognition that simple detoxification or simple opiate replacement therapy is not appropriate for every heroin addict. Our current data indicate that naltrexone is safe and effective. Its use may be limited to a minority of addicts, those who are highly motivated and opiate free, because patient compliance has been a major problem with which clinicians using naltrexone have had to contend. Patient compliance is a problem, because there are no immediate consequences to the patient for stopping his naltrexone regimen. Side effects from naltrexone have been minimal and have occurred in a minority of patients. They consist primarily of gastrointestinal symptoms, including nausea and occasionally abdominal pain.

Historical perspective on the chemistry and development of naltrexone.

The first clinically useful narcotic antagonist was nalorphine. This compound was relatively weak, short-acting, and produced a number of side effects, the most prominent of which were psychotomimetic in nature. For these reasons nalorphine did not qualify as a possible modality for the treatment of heroin addiction. Cyclazocine is a totally synthetic narcotic antagonist which is much more potent and longer acting than nalorphine. It was the first compound used by Martin in clinical trials in postaddicts. However, its dysphoric effects necessitated long induction periods and these CNS effects precluded its use in long-acting delivery systems. Naloxone was a "pure" antagonist which did not produce the psychotomimetic effects of either nalorphine or cyclazocine. Although it is a potent antagonist when given parenterally, it is shorter acting than cyclazocine. Replacement of the N-allyl substituent of naloxone with the cyclopropylmethyl radical of cyclazocine led to naltrexone, which is even more potent than either naloxone or cyclazocine and has a longer duration than naloxone. Because of this favorable combination of properties naltrexone proved to be the drug of choice for inclusion in long-acting delivery systems.

History and development of mixed opioid agonists, partial agonists and antagonists.

1 A brief history of the development of narcotic antagonists is outlined. 2 The clinical and pharmacological observations leading to the discovery of dualism of opiate receptors are reviewed. 3 An extension of this theory to a three-receptor model (mu, kappa and sigma) is required to rationalize the pharmacology of the antagonists analgesics cyclazocine, pentazocine and nalorphine. 4 The methodologies available for the study of compounds with dual agonist-antagonist activity are discussed in the light of the above receptor multiplicity, and data appertaining to the kappa-partial agonist, nalorphine and the mu-partial agonist buprenorphine are outlined.

Narcotic antagonists. Treatment tool for addiction.

Narcotic antagonists have recently gained attention through research aimed at evaluating both biochemical effects and treatment potential for opiate addiction. Narcotic antagonists are a classification of drugs which block the euphoric (and all other) effects of opiates. Naltrexone is the most promising narcotic antagonist based on ability to produce blockade, length of duration, and relative absence of side effects. The narcotic antagonists offer an adjunctive or alternative method of treatment for opiate addicts based on Wikler's biobehavioral theory of conditioned abstinence. Narcotic antagonists are presently being investigated at seven research centers throughout the United States and may be available for clinical use in the future.