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In medicine, relapse or recidivism is a recurrence of a past (typically medical) condition. For example, multiple sclerosis and malaria often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or recrudescence.

In the context of drug use, relapse or reinstatement of drug-seeking behavior, is a form of spontaneous recovery that involves the recurrence of pathological drug use after a period of abstinence. Relapse is often observed in individuals who have developed a drug addiction or either form of drug dependence.

Dopamine D2 receptor availability
The availability of the dopamine receptor D2 plays a role in self-administration and the reinforcing effects of cocaine and other stimulants. The D2 receptor availability has an inverse relationship to vulnerability to the reinforcing effects of the drug. That is, as D2 receptors become limited the user becomes more susceptible to the reinforcing effects of cocaine. It is currently unknown if a predisposition to low D2 receptor availability is possible; however, most studies support the idea that changes in D2 receptor availability are a result, rather than a precursor, of cocaine use. It has also been noted that D2 receptors may return to the level existing prior to drug exposure during long periods of abstinence, a fact which may have implications in relapse treatment.

Social hierarchy
Social interactions, such as the formation of linear dominance hierarchies, also play a role in vulnerability to drug abuse. Animal studies suggest that there exists a difference in D2 receptor availability between dominant and subordinate animals within a social hierarchy as well as a difference in the function of cocaine to reinforce self-administration in these animal groups. Socially dominant animals exhibit higher availability of D2 receptors and fail to maintain self-administration.

Triggers
Drug taking and relapse are heavily influenced by a number of factors including the pharmacokinetics, dose, and neurochemistry of the drug itself as well as the drug taker’s environment and drug-related history. Reinstatement of drug use after a period of non-use or abstinence is typically initiated by one or a combination of the three main triggers: stress, re-exposure to the drug or drug-priming, and environmental cues. These factors may induce a neurochemical response in the drug taker that mimics the drug and thus triggers reinstatement. These cues may lead to a strong desire or intention to use the drug, a feeling termed craving by Abraham Wikler in 1948. The propensity for craving is heavily influenced by all three triggers to relapse and is now an accepted hallmark of substance dependence. Stress is one of the most powerful stimuli for reinstating drug use because stress cues stimulate craving and drug-seeking behavior during abstinence. Stress-induced craving is also predictive of time to relapse. Comparably, addicted individuals show an increased susceptibility to stressors than do non-addicted controls. Examples of stressors that may induce reinstatement include emotions of fear, sadness, or anger, a physical stressor such as a footshock or elevated sound level, or a social event. Drug-priming is exposing the abstinent user to the drug of abuse, which will induce reinstatement of the drug-seeking behavior and drug self-administration. Stimuli that have a pre-existing association with a given drug or with use of that drug can trigger both craving and reinstatement. These cues include any items, places, or people associated with the drug.

Treatment
Relapse treatment is somewhat of a misnomer because relapse itself is a treatment failure; however there exist three main approaches that are currently used to reduce the likelihood of drug relapse. These include pharmacotherapy, cognitive behavioral techniques, and contingency management. The main goals of treating substance dependence and preventing relapse are to identify the needs that were previously met by use of the drug and to develop the skills needed to meet those needs in an alternative way.

Pharmacotherapy

 * Related article: Drug rehabilitation

Various medications are used to stabilize an addicted user, reduce the initial drug use, and prevent reinstatement of the drug. Medications can normalize the long-term changes that occur in the brain and nervous system as a result of prolonged drug use. This method of therapy is complex and multi-faceted because the brain target for the desire to use the drug may be different from the target induced by the drug itself. The availability of various neurotransmitter receptors, such as the dopamine receptor D2, and changes in the medial prefrontal cortex are prominent targets for pharmacotherapy to prevent relapse because they are heavily linked to drug-induced, stress-induced, and cue-induced relapse. Receptor recovery can be upregulated by administration of receptor antagonists, while pharmacotherapeutic treatments for neruoadaptations in the medial prefrontal cortex are still relatively ineffective due to lacking knowledge of these adaptations on the molecular and cellular level.

Cognitive behavioral techniques
The various behavioral approaches to treating relapse focus on the precursors and consequences of drug taking and reinstatement. Cognitive behavioral techniques (CBT) incorporate Pavlovian conditioning and operant conditioning, characterized by positive reinforcement and negative reinforcement, in order to alter the cognitions, thoughts, and emotions associated with drug taking behavior. A main approach of CBT is cue exposure, during which the abstinent user is repeatedly exposed to the most salient triggers without exposure to the substance in hopes that the substance will gradually lose the ability to induce drug-seeking behavior. This approach is likely to reduce the severity of a relapse than to prevent one from occurring altogether. Another method teaches addicts basic coping mechanisms to avoid using the illicit drug. It is important to address any deficits in coping skills, to identify the needs that likely induce drug-seeking, and to develop another way to meet them.

Relapse prevention
Relapse prevention attempts to group the factors that contribute to relapse into two broad categories: immediate determinants and covert antecedents. Immediate determinants are the environmental and emotional situations that are associated with relapse, including high-risk situations that threaten an individual’s sense of control, coping strategies, and outcome expectancies. Covert antecedents, which are less obvious factors influencing relapse, include lifestyle factors such as stress level and balance, and urges and cravings. The relapse prevention model teaches addicts to anticipate relapse by recognizing and coping with various immediate determinants and covert antecedents. The RP model shows the greatest success with treatment of alcoholism but it has not been proven superior to other treatment options.

Contingency management
In contrast to the behavioral approaches above, contingency management concentrates on the consequences of drug use as opposed to its precursors. Addict behavior is reinforced, by reward or punishment, based on ability to remain abstinent. A common example of contingency management is a token or voucher system, in which abstinence is rewarded with tokens or vouchers that individuals can redeem for various retail items.

Animal models
Animal Models

To understand the processes behind relapse and addiction, several animal models have been developed. Rodents, usually rats, have been extensively used in animal testing, not only due to the similarities of behavioral and neural mechanisms involved in drug addiction on humans and rodents, but also because of the ethical challenges of studying relapse in humans. Much our knowledge in the genetic, behavioral, and neurobiological mechanisms of addiction has been enhanced by animal models. Although self-administration of addictive drugs has initially studied using non-human primates, rats have extensively been used after Week’s pioneering work in 1962, who developed an operant procedure that delivered intravenous infusions to rats. In this context, some of the most common preclinical models for studying drug addiction are extinction reinstatement, forced abstinence, and voluntary (self-imposed) abstinence, the latter being the most recent animal model. All these models are designed to make animals go through the three phases of drug addiction: self-administration, abstinence and relapse. These phases mimic the natural cycle of drug addiction on humans. However, they are different in how the second phase is simulated.

Protocols

Self-administration

In this classical and most popular protocol, intravenous self-administration requires the implementation of a catheter into the rat’s jugular vein allowing direct intravenous infusions. After recovery, rats perform an operant response such as nose poking or lever pressing. The latter response requires a chamber equipped with two levers:  one active and one inactive lever. Pressing on the active lever lead to an infusion of the drug, the reinforcement, which may also be paired with discrete cues (e.g., light and/or tone), while responding on the inactive has not further consequences. Different types of schedule of reinforcements are used in self-administration (fixed ratio, variable ratio, fixed interval, variable interval) to assess different processes of drug taking and seeking behavior. Once subjects have learned to self-administer and perform has reached a stable value, then animals undergo a period of abstinence, which can be achieved through extinction, forced or voluntary methods.

Abstinence

Extinction-based abstinence model. In the extinction training, pressing the lever, or any other conditioned operant response (e.g., nose poking), no longer results in drug infusions nor drug cues (light and/or tone). Training stop when responding eventually drop to zero (or close). Following this, a relapse test for drug seeking is performed. Although, the extinction-based abstinence procedure is widely used, it has been realized that there are clear limitations.

Forced-based abstinence model. In the forced abstinence procedure, animals do not undergo extinction training following self-administration training. Instead, subjects are removed from the operant chamber and housed in an alternative context, where they are not exposed to the drug for a specific period of time. On the test day, subjects are put back in the first self-administration chamber for a drug-paired context-induced relapse. This form of abstinence simulates a specific aspect of human conditions in which abstinence is forced for a period of time by hospitalization or incarceration.

Voluntary abstinence based on alternative nondrug reward. In the voluntary-based approach, rats are first trained to self-administer a nondrug reward, like palatable food. Then rats are trained to self-administer drugs, in the presence of discrete drug-related cues. Following each self-administration training, rats are given mutually exclusive choice sessions between the nondrug reward and the drug in question. Voluntary abstinence can be induced by other nondrug rewards like social relationships, novelty seeking and physical exercise. This abstinence-based alternative nondrug reward mimics, to some degree, human choice-based abstinence: having a steady job, a social stable relationship, and a good health.

Punishment-imposed abstinence model. Several clinical studies have shown that abstinence in humans is most often voluntary due to the negative consequences of taking the drug or the availability of competing alternative nondrug reward. To simulate this form of abstinence in rats, a mild electric shock is introduced through the grid floor of the chamber while the drug remains available. The foot shock (punishment) is then eventually associated with drug taking. Like humans, rats have the choice between taking the drug or taking the risk of being punished.

Relapse to drug-seeking

Following abstinence-based procedure, drug-seeking behavior is triggered. Indeed, there are three different main factors that trigger relapse: re-exposure to the drug itself, re-exposure to drug-associated cues, and stress. For example, if the animal if re-exposed to the drug, it will likely begin working on the operant task (e.g. lever pressing) for which it was previously reinforced. The stimulus may be the drug itself, the visual stimulus that was initially paired with the drug intake (e.g., light and tone), or a stressor such as acoustic startle, foot shock, social isolation, physical restriction, forced swimming, food deprivation, etc. In humans, these relapse triggers cause drug addicts in abstinence to crave drugs and eventually relapse.

Limitations

Although the extinction-reinstatement model is in the surface, a good model for drug addiction in laboratory settings, there are some limitations to the validity of the procedures as a model of craving and relapse in humans. The primary limiting factor is that in humans, relapse rarely follows the strict extinction of drug-seeking behavior. That is, extinction involves animals responding for the drug when actually there is not drug delivery upon the drug-taking response. Regarding to the forced abstinence model, although it simulates features like hospitalization or incarceration and allows for potential treatments, it cannot be generalized. Further, neither this model nor the extinction gives the animal the option to make its choices (drug taking vs no drug taking) as it is the case in humans. Several studies have shown that abstinence in humans is more voluntary due to the negative consequences of taking the drug. Although the punishment-based abstinence procedure attempts to simulate this essential feature, it has its limitations. For example, in the procedure, punishment (foot shock) is delivered during the taking session. In humans, the negative consequences are more complex and occur (most often) sometime later. Despite this limitation, the punishment-based abstinence model has higher ecological validity than any other model.

Differences between sexes
There exists a higher rate of relapse, shorter periods of abstinence, and higher responsiveness to drug-related cues in women as compared to men. One study suggests that the ovarian hormones, estradiol and progesterone, that exist in females at fluctuating levels throughout the menstrual cycle (or estrous cycle in rodents), play a significant role in drug-primed relapse. There is a marked increase in progesterone levels and a decrease in estradiol levels during the luteal phase. Anxiety, irritability, and depression, three symptoms of both withdrawal and the human menstrual cycle, are most severe in the luteal phase. Symptoms of withdrawal not associated with the cycle, such as hunger, are also enhanced during the luteal phase, which suggests the role of estradiol and progesterone in enhancing symptoms above the naturally occurring level of the menstrual cycle. The symptoms of craving also increase during the luteal phase in humans (it is important to note that the opposite result occurs in female subjects with cocaine addiction suggesting that cyclic changes may be specific for different drugs of abuse). Further, the drug-primed response is reduced during the luteal phase suggesting a time in the cycle during which the urge to continue use may be reduced. These findings implicate a cyclic, hormone-based timing for quitting a drug of abuse and preparing for magnified symptoms of withdrawal or susceptibility to relapse.