Pharmacological Interventions And Treatment Implications

In summary, the various biological models of drug addiction are complementary and broadly applicable to chemical addictions. We next illustrate how long-term pharmacotherapies for opioid dependence, such as methadone, nal-trexone, and buprenorphine, can counteract or reverse the abnormalities underlying dependence and addiction. These agents are particularly informative, because they are an agonist, antagonist, and partial agonist, respectively. We do not review short-term treatments for relieving withdrawal symptoms and increasing abstinence but refer readers elsewhere for detailed neurobiologi-cal explanations for various abstinence initiation approaches (see Kosten & O'Connor, 2003).

Methadone, a long-acting opioid medication with effects that last for days, causes dependence, but because of its sustained stimulation of the mu receptors, it alleviates craving and compulsive drug use. In addition, methadone therapy tends to normalize many aspects of the hormonal disruptions found in addicted individuals (Kling et al., 2000; Kreek, 2000; Schluger, Borg, Ho, & Kreek, 2001). For example, it moderates the exaggerated cortisol stress response (discussed earlier) that increases the danger of relapse in stressful situations.

Naltrexone is used to help patients avoid relapse after they have been detoxified from opioid dependence. Its main therapeutic action is to occupy mu opioid receptors in the brain with a 100-fold higher affinity than agonists such as methadone or heroin, so that addictive opioids cannot link up with them and stimulate the brain's reward system. Naltrexone does not activate the G-protein-coupled cyclic AMP system and does not increase or decrease levels of cyclic AMP inside the neuron, and it does not promote these brain processes that produce feelings of pleasure (Kosten & Kleber, 1984). An individual who is adequately dosed with naltrexone does not obtain any pleasure from addictive opioids and is less motivated to use them. An interesting neurobiological effect of naltrexone is that it appears to increase the number of available mu opiate receptors, which may help to renormalize the imbalance between the receptors and G-protein coupling to cyclic AMP (Kosten, 1990). Naltrexone is also sometimes used to detoxify patients rapidly from opioid dependence. In this situation, while naltrexone keeps the addictive opioid molecules away from the mu receptors, clonidine may help to suppress the opioid-induced excessive NA output that is a primary cause of withdrawal (Kosten, 1990). Clonidine is capable of this withdrawal relief because alpha-adrenergic autoreceptors are co-localized with mu opiate receptors on the neurons of the LC, and both receptor types inhibit cyclic AMP synthesis through similar inhibitory G proteins.

Buprenorphine's action on the mu opioid receptors elicits two different therapeutic responses within the brain cells, depending on the dose. At low doses, buprenorphine has effects like methadone, but at high doses, it behaves like naltrexone, blocking the receptors so strongly that it can precipitate withdrawal in highly dependent patients (i.e., those maintained on more than 40 mg methadone daily). Several clinical trials have shown that buprenorphine is as effective as methadone, when used in sufficient doses (Kosten, Schottenfeld, Ziedonis, & Falcioni, 1993; Oliveto, Feingold, Schottenfeld, Jatlow, & Kosten, 1999; Schottenfeld, Pakes, Oliveto, Ziedonis, & Kosten, 1997). Buprenorphine has a safety advantage over methadone, since high doses precipitate withdrawal rather than the suppression of consciousness and respiration seen in overdoses of methadone and heroin. Thus, buprenorphine has less overdose potential than methadone, since it blocks other opioids and even itself as the dosage increases. Finally, buprenorphine can be given three times per week, simplifying observed ingestion during the early weeks of treatment.

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