Relapse

"Reinstatement" redirects here. For general concept in classical conditioning, seeClassical conditioning § Recovery from extinction.For other uses, seeRelapse (disambiguation).

Ininternal medicine,relapseorrecidivismis a recurrence of a past (typically medical) condition. For example,multiple sclerosisandmalariaoften exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse orrecrudescence.

Inpsychiatry,relapseorreinstatement of drug-seeking behavior,is the recurrence of pathological drug use, self harm or other symptoms after a period of recovery. Relapse is often observed in individuals who have developed adrug addictionor a form ofdrug dependence,as well as those who have amental disorder.

Risk factors

Dopamine D2 receptor availability

The availability of thedopamine receptor D2plays a role inself-administrationand thereinforcing effectsofcocaineand otherstimulants.The D2 receptor availability has aninverse relationshipto the vulnerability of reinforcing effects of thedrug.With the D2 receptors becoming limited, the user becomes more susceptible to the reinforcing effects of cocaine. It is currently unknown if apredispositionto low D2 receptor availability is possible; however, most studies support the idea that changes in D2 receptor availability are aresult,rather than aprecursor,of cocaine use. It has also been noted that D2 receptors may return to the level existing prior to drug exposure during long periods ofabstinence,a fact which may have implications in relapsetreatment.

Social hierarchy

Social interactions,such as the formation oflinear dominance hierarchies,also play a role in vulnerability to substance use.Animal studiessuggest that there exists a difference in D2 receptor availability betweendominantand subordinate animals within asocial hierarchyas well as a difference in the function of cocaine toreinforceself-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 thepharmacokinetics,dose,andneurochemistryof the drug itself as well as the drug taker’senvironmentand 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 environmentalcues.These factors may induce aneurochemicalresponse 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 termedcravingbyAbraham Wiklerin 1948. The propensity for craving is heavily influenced by all three triggers to relapse and is now an accepted hallmark ofsubstance dependence.Stress is one of the most powerful stimuli for reinstating drug use because stress cues stimulate craving and drug-seeking behavior duringabstinence.Stress-induced craving is also predictive of time to relapse. Comparably, addicted individuals show an increased susceptibility tostressorsthan do non-addicted controls. Examples of stressors that may induce reinstatement include emotions offear,sadness,oranger,a physical stressor such as a footshock or elevated sound level, or a social event.Drug-priming is exposing the abstinent user to the addictive substances, 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 amisnomerbecause relapse itself is a treatment failure; however there exist three main approaches that are currently used to reduce the likelihood of drug relapse. These includepharmacotherapy,cognitive behavioral techniques,andcontingency management.The main goals of treating substance dependence and preventing relapse are to identify theneedsthat 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

Variousmedicationsare 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 thebrainandnervous systemas 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 variousneurotransmitter receptors,such as thedopamine receptor D2,and changes in themedial prefrontal cortexare prominent targets for pharmacotherapy to prevent relapse because they are heavily linked to drug-induced, stress-induced, and cue-induced relapse. Receptor recovery can beupregulatedby administration ofreceptor antagonists,while pharmacotherapeutic treatments forneruoadaptationsin the medial prefrontal cortex are still relatively ineffective due to lacking knowledge of theseadaptationson themolecularandcellularlevel.

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) incorporatePavlovian conditioningandoperant conditioning,characterized bypositive reinforcementandnegative reinforcement,in order to alter thecognitions,thoughts,andemotionsassociated 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 basiccoping mechanismsto avoid using theillicit drug.It is important to address any deficits in coping skills, to identify the needs that likely inducedrug-seeking,and to develop another way to meet them.

Relapse prevention

Main article:Relapse prevention

Relapse preventionattempts 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,andoutcome expectancies.Covert antecedents, which are less obvious factors influencing relapse, include lifestyle factors such as stress level and balance, and urges andcravings.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 ofalcoholismbut it has not been proven superior to other treatment options.Relapse may also be more likely to occur during certain times, such as the holiday season when stress levels are typically higher.So, emphasizing relapse prevention strategies during these times is ideal.

Contingency management

Main article:Contingency management

In contrast to the behavioral approaches above,contingency managementconcentrates on the consequences of drug use as opposed to its precursors. Addict behavior isreinforced,by reward orpunishment,based on ability to remainabstinent.A common example of contingency management is atokenorvoucher system,in which abstinence is rewarded with tokens or vouchers that individuals can redeem for various retail items.

Animal models

There are vastethical limitationsindrug addictionresearch because humans cannot be allowed to self-administer drugs for the purpose of being studied.However, much can be learned about drugs and the neurobiology of drug taking by the examination of laboratory animals.Most studies are performed on rodents ornon-human primateswith the latter being most comparable to humans inpharmacokinetics,anatomyof theprefrontal cortex,social behavior,andlife span.Other advantages to studying relapse in non-human primates include the ability of the animal to reinstateself-administration,and to learn complex behaviors in order to obtain the drug.Animal studies have shown that a reduction in negative withdrawal symptoms is not necessary to maintain drug taking in laboratory animals; the key to these studies is operant conditioning and reinforcement.

Protocols

Self-administration

To self-administer the drug of interest the animal is implanted with an intravenouscatheterand seated in a primate chair equipped with a response lever. The animal is seated in a ventilated chamber and trained on a schedule of drug self-administration. In many studies the self-administration task begins with presentation of a stimulus light (located near the response panel) that may change colors or turn off upon completion of the operant task. The change in visual stimulus is accompanied by an injection of the given drug through the implanted catheter. This schedule is maintained until the animals learn the task.

Extinction

Extinctionin non-human primates is analogous, with some limitations, to abstinence in humans. In order to extinguish drug-seeking behavior the drug is substituted with asalinesolution. When the animal performs the task it has been trained to perform it is no longer reinforced with an injection of the drug. The visual stimulus associated with the drug and completion of the task is also removed. The extinction sessions are continued until the animal ceases the drug-seeking behavior by pressing the lever.

Reinstatement

After the animal’s drug-seeking behavior is extinguished, a stimulus is presented to promote the reinstatement of that same drug-seeking behavior (i.e., relapse). For example, if the animal receives an injection of the drug in question it will likely begin working on the operant task for which it was previously reinforced.The stimulus may be the drug itself, the visual stimulus that was initially paired with the drug intake, or a stressor such as anacoustic startleor foot shock.However, the stimulus used to trigger reinstatement can influence the psychological processes involved.

Neuroimaging

A transverse segment fMRI scan showing activated regions in orange.

Neuroimaginghas contributed to the identification of theneuralcomponents involved in drug reinstatement as well as drug-taking determinants such as thepharmokinetics,neurochemistry,anddoseof the drug. The neuroimaging techniques used in non-human primates includepositron emission tomography(PET), which usesradiolabeledligandtracers to measure neurochemistryin vivoandsingle-photon emission computed tomography(SPECT).Functional magnetic resonance imaging(fMRI) is widely used in human subjects because it has much higher resolution and eliminates exposure toradiation.

Limitations

Although the reinstatementprotocolsare used frequently inlaboratorysettings there are some limitations to thevalidityof the procedures as a model ofcravingand relapse in humans. The primary limiting factor is that in humans, relapse rarely follows the strictextinctionof drug-seeking behavior. Additionally, human self-reports show that drug-associatedstimuliplay a lesser role in craving in humans than in the laboratory models. Thevalidityof the model can be examined in three ways:formal equivalence,correlational models, and functional equivalence. There is moderate formal equivalence, orface validity,meaning that the model somewhat resembles relapse as it occurs outside of the laboratory setting; however, there is little face validity for the procedures as a model of craving. Thepredictive validity,which is assessed by correlational models, has yet to be determined for the procedures. There is sound functional equivalence for the model, which suggests that relapse in the laboratory is reasonably similar to that in nature. Further research into other manipulations or reinforcements that could limit drug-taking in non-human primates would be extremely beneficial to the field.

Differences between sexes

There exists a higher rate of relapse, shorter periods ofabstinence,and higher responsiveness to drug-related cues in women as compared to men. One study suggests that theovarian hormones,estradiolandprogesterone,that exist in females at fluctuating levels throughout themenstrual cycle(orestrous cyclein rodents), play a significant role in drug-primed relapse. There is a marked increase in progesterone levels and a decrease in estradiol levels during theluteal phase.Anxiety,irritability, anddepression,three symptoms of bothwithdrawaland 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 addictive substances). Further, the drug-primed response is decreased 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 an addictive substance and preparing for magnified symptoms of withdrawal or susceptibility to relapse.

See also

• Substance use disorder
• National Institute on Drug Abuse