Drug dependence: stress and dysregulation of brain reward pathways.

Addiction to drugs, such as heroin, cocaine and alcohol, exacts great human and financial costs on society, but the development of pharmacotherapies for addiction has been largely neglected by the pharmaceutical industry. With advances in our understanding of the underlying biology of addictions now opening the door for the development of novel pharmacotherapies, it could be time for a reassessment of involvement in this increasingly important therapeutic area. Here, we summarize the current approved and implemented pharmacotherapeutic approaches to the treatment of addiction, and then highlight the most promising areas for future drug development from the perspective of our laboratory and our National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) Research Center.

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Pharmacotherapy of addictions

In 1963, Professor Vincent P. Dole at the Rockefeller University formed a small team to develop a pharmacotherapy for the management of heroin addiction. They hypothesized that heroin addiction is a disease of the brain with behavioral manifestations, and not merely a personality disorder or criminal behavior and began to address the specific question of whether a long-acting opioid agonist could be used in the long-term maintenance treatment of heroin addiction. Over the next 35 years, many studies documented the safety, efficacy and effectiveness of methadone pharmacotherapy for heroin addiction, but Federal regulations and stigmatization of heroin addiction prevented implementation of treatment. Finally, in 1999, NIH published a report unequivocally supporting methadone maintenance pharmacotherapy for heroin addiction. Two other effective opioid agonist treatments have been developed: the even longer acting opioid agonist l-alpha-acetylmethadol (LAAM) has been approved for pharmacotherapy for heroin addiction, and still under study is the opioid partial agonist-antagonist buprenorphine-naloxone combination. A variety of studies, both laboratory based and clinical, have revealed the mechanisms of action of long-acting opioid agonists in treatment, including prevention of disruption of molecular, cellular and physiologic events and, in fact, allowing normalization of those functions disrupted by chronic heroin use. Recent molecular biological studies have revealed single nucleotide polymorphisms of the human mu opioid receptor gene; the mu opioid receptor is the site of action of heroin, the major opiate drug of abuse, analgesic agents such as morphine, and the major treatment agents for heroin addiction. These findings support the early hypotheses of our laboratory that addiction may be due to a combination of genetic, drug-induced and environmental (including behavioral) factors and also, that atypical stress responsivity may contribute to the acquisition and persistence of, as well as relapse to, use of addictive drugs.

Methadone‐Related Opioid Agonist Pharmacotherapy for Heroin Addiction: History, Recent Molecular and Neurochemical Research and Future in Mainstream Medicine

Rationale: Preclinical observations suggest that NMDA receptor-mediated glutamatergic neurotransmission is involved in the expression and maintenance of opioid dependence. Objective: The present study evaluated whether memantine, the clinically available non-competitive NMDA receptor antagonist, decreases naloxone-precipitated withdrawal in morphine-dependent humans. Methods: Eight heroin-dependent, non-treatment seeking, inpatient participants were stabilized on a fixed dose of morphine (30 mg PO qid). Subsequently, they received a series of challenges with naloxone (0.4 mg, IM) and the severity of opioid withdrawal was monitored. Either placebo or memantine (60 mg PO) was given 6 h before each naloxone challenge. A modified multiple baseline, across-participants design was used to evaluate the effects of memantine on the severity of naloxone-precipitated opioid withdrawal. Results: Naloxone increased ratings and produced physical changes consistent with opioid withdrawal. Memantine attenuated the severity of opioid withdrawal as assessed with the Clinical Institute for Narcotic Withdrawal Scale scale. Withdrawal was significantly reduced when naloxone was administered at 6 and 52 h after memantine, but not when administered 126 h (5 days) after memantine. Medication effects, assessed 5 h after memantine administration and before naloxone administration, included significant increases in ratings of "strong" and "good" drug effect, and "I feel sedated", "mellow", and "high". Conclusions: Memantine attenuated the expression of opioid physical dependence in humans, indicating that glutamatergic neurotransmission at the NMDA receptor site contributes to the maintenance of opioid dependence. This finding suggests that memantine may be a useful adjunct in the treatment of opioid dependence.

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The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans.

Background This study used an opioid antagonist challenge procedure to evaluate the responsivity of the endogenous opioid system in nicotine-dependent individuals, as evidenced by naloxone-induced alterations in both behavioral (withdrawal, craving) and neuroendocrine (cortisol levels) parameters. Methods Twenty subjects (9 smokers and 11 nonsmokers) participated in 4 laboratory sessions during which they were challenged with 0, 0.8, 1.6, or 3.2 mg/70 kg of naloxone and then monitored for 1 hour for subjective signs and symptoms of opiate-like withdrawal, nicotine craving, and alterations in cortisol levels. Results Nicotine-dependent subjects evidenced naloxone dose-dependent increases in withdrawal signs and symptoms. Lower doses of naloxone also produced increases in urges to smoke (craving) and tiredness in smokers. Smokers, when compared with nonsmokers, had lower prenaloxone baseline levels of cortisol and attenuated cortisol release in response to challenge with naloxone. Conclusion These results provide preliminary evidence to suggest that long-term exposure to cigarette smoke is associated with alterations in the responsivity of the endogenous opioid system and the hypothalamic-pituitary-adrenal axis that may contribute to the development of nicotine dependence.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/205120/yoa8421.pdf

Naloxone challenge in smokers. Preliminary evidence of an opioid component in nicotine dependence.

To determine the reliability of serial naloxone challenges, five heroin addicts stabilized on methadone were given 0.2 mg naloxone intravenously on three consecutive days. Two-factor ANOVA revealed that the between-subjects effect accounted for at least 63% of the variance in each of the dependent measures, and the effect of challenge number for at most 22%. Withdrawal tended to be slightly more severe for the first challenge. Intraclass correlation coefficients were calculated for the area-under-the-curve of the change from baseline: subject-rated (.74) and observer-rated (.71) withdrawal, pulse (.88), systolic blood pressure (.58), diastolic blood pressure (.85), and skin temperature (.63).

Gill Ts

Papers

Reliability of sequential naloxone challenge tests.