New Insights Into Relapse

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NIDA Acting Director, Glen R. Hanson

Drug addiction is a chronic relapsing disorder. As when patients in treatment for hypertension or asthma temporarily lose control, relapse to drug abuse does not mean treatment does not work, or the patient is not making an effort, or he or she will never have a productive life with long-term freedom from disease. Nevertheless, relapse is perhaps the most frustrating and demoralizing feature of drug addiction, for those who have it and those who would help them.

Clinical observation and research tell us that three types of stimulus can trigger intense drug craving, leading to renewed abuse:

  • Priming: "Just one" exposure to the formerly abused substance -- be it a cigarette, a drink, or an illegal drug -- can precipitate rapid resumption of abuse at previously established levels or greater.
  • Environmental cues (people, places, or things associated with past drug use): One vivid illustration of the power of such cues is a negative one: A small percentage of American service personnel became addicted to heroin while overseas during the Vietnam War. When they were removed from that environment, the great majority, after detoxification, reported no further problems with opiates.
  • Stress: Both acute and chronic stress can contribute to the establishment, maintenance, and resumption of drug abuse. Patients and treatment providers alike point to stress as the most common cause of relapse. The impact of stress recently was highlighted when researchers documented increased rates of smoking and alcohol consumption by New Yorkers after the September 11, 2001, attacks.

Our knowledge of relapse is incorporated in science-based drug treatments. In cognitive-behavioral therapy, for example, patients learn to confront the consequences of their drug use, recognize the environmental cues and potentially stressful situations that trigger strong drug cravings, and develop strategies to steer clear or respond without relapsing. Recent research has shown that patients who benefit from cognitive-behavioral therapy may even show further improvement after treatment has ended and with passing time.

New research findings appear to shed light on one of the deepest mysteries involving drug relapse: What accounts for the extraordinary persistence of drug cravings?

Science-based medical treatments buffer patients against the craving that leads to relapse. Methadone and other opioid agonist agents block the euphoric effects of opioids and stabilize brain processes whose disruption is linked to craving. Naltrexone, an opioid antagonist, blocks opioid-induced euphoria and counters opioid craving with an aversive effect. Disulfiram (Antabuse) is used to treat alcohol abuse, and it is currently being tested to determine whether it also can offset cocaine craving. Anti-anxiety agents are prescribed to moderate stress.

New research findings appear to shed light on one of the deepest mysteries involving drug relapse: We know that former abusers of addictive drugs remain vulnerable to powerful drug cravings for months or years after establishing abstinence. What accounts for the extraordinary persistence of drug cravings?

Scientists have known for some time that addictive drugs hyperactivate key brain circuits that provide pleasure and are closely linked to motivation and memory. Research also has shown that drugs change brain cells in these circuits in numerous ways, some of which might be linked to craving. However, these changes generally last only as long as a drug is actually present, or a little longer. To explain how craving can recur after long abstinence, researchers need to show that the drugs change the cells in ways that change back slowly or not at all.

The natural place to look for long-lasting drug-induced alterations is in the same circuits that produce short-term effects. Key cells in these circuits are located in an area called the midbrain; they manufacture a chemical called dopamine and release it in a nearby area called the nucleus accumbens, where it produces powerful mood effects.

During the past 3 years, research teams at Yale and Texas Southwestern Universities demonstrated that repeated exposure to cocaine produces alterations in gene activity in the nucleus accumbens that can persist for weeks. Last year, researchers at the University of Michigan showed that cocaine self-administration changes the actual shape of these neurons -- a change that is long-lasting or even permanent. Moreover, its specific nature -- a proliferation of signal receptors -- might be expected to contribute to craving by heightening the cells' general reactivity.

Further research will tell whether these changes are critically important to long-term vulnerability to drug craving, or whether they play a relatively minor role. The studies were conducted with laboratory animals and cocaine, and we need to find out whether they also apply in humans and with other drugs. Although uncertainties remain, these new results provide powerful confirmation of the neurobiological and chronic nature of drug addiction, evidenced at still more fundamental levels of brain cell operation. The studies also demonstrate the power of new neuroscience tools to elucidate the underlying causes of drug abuse. Ultimately, we need approaches this powerful to gain the understanding necessary to solve the mysteries of craving and generate treatments that help all patients move beyond the reach of relapse.