A relapse or recidivism is a recurrence of a past (typically medical) condition. For example, MS or malaria often exhibit peaks of activity and sometimes long periods of dormancy.
Relapse, in relation to drug misuse, is resuming the use of a drug or a chemical substance after one or more periods of abstinence. The term is a landmark feature of both substance dependence and substance abuse, which are learned behaviors, and is maintained by neuronal adaptations that mediate learning and processing of various motivational stimuli. An important aspect of drug use is the propensity for repeated use and dependence, tendencies that are influenced by the nature of the drug itself and thus vary from substance to substance. Those substances that are cleared from the body most quickly, those with the highest pharmacological efficacy, and those that induce the highest tolerance elicit the most severe tendencies in users. Drug dependence can lead to increased tolerance to the substance in question, cravings, and withdrawal if the drug use ceases.
- Stimulants increase activity in the cerebral cortex leading to increased motor activity.
- Depressants slow down neuronal activity.
- Benzodiazepines (i.e.: Xanax)
- Opioids activate or block opiod receptors in the brain typically to reduce the effect of pain. Some common opioids are:
- Alcohol produces disinhibition in the nervous system when introduced, and it depresses the frontal cortex while speeding up the rest of the brain. This can lead to decreased ability to perceive and evaluate risks and make good decisions, and other characteristics of what is commonly known as intoxication.
- Nicotine is neither a stimulant nor a depressant but rather a chemical that is absorbed by the skin and mucous membranes and activates the nicotinic acetylcholine receptors.
DEA schedules of controlled substances 
The Drug Enforcement Administration (DEA) has categorized controlled substances into 5 major categories based on the drug’s addictive potential and intended use. Drugs with the highest addictive potential are listed in DEA Schedules I and II. Schedule I drugs are those with no accepted medical or therapeutic use whereas Schedule II drugs are those that can be used therapeutically but may lead to severe physical or psychological dependence.
Addictive potential 
- Related article: Substance dependence
The addictive potential, also sometimes called abuse potential, varies greatly between substances and is based on both the pleasurable effects associated with the drug and the likelihood that the drug will induce dependent behavior. The system for quantifying addictive potential based on scientific knowledge was first established by Professor David Nutt in 2007. The addictive potential for the 14 substances examined in this study was derived by scoring the drugs on a four-point scale in 9 different parameters. The parameters were established by dividing the three categories of harm into 3 further subgroups.
Categories of harm 
The three main categories to determine addictive potential are the physical harm of the drug to the user, the drug’s tendency to cause dependence, and effects of the drug on society.
Physical harm 
The first category can be further divided into three parameters of harm: acute physical harm, chronic physical harm, and intravenous harm. Acute harm is defined as the immediate effects associated with use of the given drug such as respiratory depression or myocardial infarction. Chronic harm is the consequence of continued and repeated use such as psychosis or lung disease. Lastly, intravenous harm refers to problems associated with the route of administration such as the spread of blood-borne pathogens like HIV.
The second parameter of harm is subdivided into three smaller categories: the pleasurable effects of the drug, the induced physical dependence, and the induced psychological dependence. The intensity of pleasure experienced is influenced by the initial rapid effect, called the rush, and the subsequent lasting euphoria, called the high.
Social harm 
This category is subdivided into the last three parameters: intoxication, other social harms, and healthcare costs. These parameters attempt to rate a drug’s impact on families, communities, and societies.
The nine parameters used to evaluate addictive potential of various substances:
|Category of harm||Parameter||Subgroup|
|Dependence||4||Intensity of pleasure|
|8||Other social harms|
Risk Factors 
Dopamine D2 receptor availability 
|Dopamine receptor D2|
Homology model of the dopamine D2 receptor
|Alt. symbols||D2DR; D2R|
|Locus||Chr. 11 q22-q23|
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.
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.
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.
- 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 
There are vast ethical limitations in drug addiction research 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 or non-human primates with the latter being most comparable to humans in pharmacokinetics, anatomy of the prefrontal cortex, social behavior, and life span. Other advantages to studying relapse in non-human primates include the ability of the animal to reinstate self-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.
Self administration 
To self-administer the drug of interest the animal is implanted with an i.v. catheter and 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 in non-human primates is analogous, with some limitations, to abstinence in humans. In order to extinguish drug-seeking behavior the drug is substituted with a saline solution. 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 is the animal equivalent to relapse in humans. After the animal’s drug-seeking behavior is extinguished a stimulus is presented to promote the reinstatement of that same drug-seeking behavior. For example, if the animal receives an injection of the drug in question it will likely begin working on the operant task for which is 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 an acoustic startle or foot shock.
Neuroimaging has contributed to the identification of the neural components involved in drug reinstatement as well as drug-taking determinants such as the pharmokinetics, neurochemistry, and dose of the drug. The neuroimaging techniques used in non-human primates include positron emission tomography (PET), which uses radiolabeled ligand tracers to measure neurochemistry in vivo and single-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 to radiation.
Although the reinstatement protocols are used frequently 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. Additionally, human self-reports show that drug-associated stimuli play a lesser role in craving in humans than in the laboratory models. The validity of the model can be examined in three ways: formal equivalence, correlational models, and functional equivalence. There is moderate formal equivalence, or face 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. The predictive 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 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.
See also 
- Substance abuse
- Substance dependence
- Drug and Alcohol Dependence (journal)
- Controlled Substances Act
- Cognitive behavioral therapy
- Drug rehabilitation
- National Institute on Drug Abuse
- Kadden RM (2002-09-10). "Cognitive-Behavior Therapy for Substance Dependence: Coping Skills Training" (pdf). Behavioral Health Recovery Management, University of Chicago. Retrieved 2011-12-03.
- Van den Oever MC, Spijker S, Smit AB, De Vries TJ (November 2010). "Prefrontal cortex plasticity mechanisms in drug seeking and relapse". Neurosci Biobehav Rev 35 (2): 276–84. doi:10.1016/j.neubiorev.2009.11.016. PMID 19932711.
- Nutt D, King LA, Saulsbury W, Blakemore C (March 2007). "Development of a rational scale to assess the harm of drugs of potential misuse". Lancet 369 (9566): 1047–53. doi:10.1016/S0140-6736(07)60464-4. PMID 17382831.
- Erickson CK (2007). The science of addiction: from neurobiology to treatment. New York: W. W. Norton & Co. ISBN 0-393-70463-7.
- Section 812. Schedules of Controlled Substances. (2007). Retrieved November 21, 2011from http://www.deadiversion.usdoj.gov/21cfr/21usc/812.htm
- Czoty PW, Gage HD, Nader MA (December 2005). "PET imaging of striatal dopamine D2 receptors in nonhuman primates: increases in availability produced by chronic raclopride treatment". Synapse 58 (4): 215–9. doi:10.1002/syn.20200. PMID 16206180.
- Czoty PW, Morgan D, Shannon EE, Gage HD, Nader MA (July 2004). "Characterization of dopamine D1 and D2 receptor function in socially housed cynomolgus monkeys self-administering cocaine". Psychopharmacology (Berl.) 174 (3): 381–8. doi:10.1007/s00213-003-1752-z. PMID 14767632.
- Murnane KS, Howell LL (July 2011). "Neuroimaging and drug taking in primates". Psychopharmacology (Berl.) 216 (2): 153–71. doi:10.1007/s00213-011-2222-7. PMID 21360099.
- Wikler A (November 1948). "Recent progress in research on the neurophysiologic basis of morphine addiction". Am J Psychiatry 105 (5): 329–38. PMID 18890902.
- Breese GR, Sinha R, Heilig M (February 2011). "Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse". Pharmacol. Ther. 129 (2): 149–71. doi:10.1016/j.pharmthera.2010.09.007. PMC 3026093. PMID 20951730.
- McClung J, Fantegrossi W, Howell LL (May 2010). "Reinstatement of extinguished amphetamine self-administration by 3,4-methylenedioxymethamphetamine (MDMA) and its enantiomers in rhesus monkeys". Psychopharmacology (Berl.) 210 (1): 75–83. doi:10.1007/s00213-010-1818-7. PMC 2862592. PMID 20309529.
- Larimer ME, Palmer RS, Marlatt GA (1999). "Relapse prevention. An overview of Marlatt's cognitive-behavioral model". Alcohol Res Health 23 (2): 151–60. PMID 10890810.
- Nader MA, Czoty PW (August 2005). "PET imaging of dopamine D2 receptors in monkey models of cocaine abuse: genetic predisposition versus environmental modulation". Am J Psychiatry 162 (8): 1473–82. doi:10.1176/appi.ajp.162.8.1473. PMID 16055768.
- Lussier JP, Heil SH, Mongeon JA, Badger GJ, Higgins ST (February 2006). "A meta-analysis of voucher-based reinforcement therapy for substance use disorders". Addiction 101 (2): 192–203. doi:10.1111/j.1360-0443.2006.01311.x. PMID 16445548.
- Howell LL, Votaw JR, Goodman MM, Lindsey KP (February 2010). "Cortical activation during cocaine use and extinction in rhesus monkeys". Psychopharmacology (Berl.) 208 (2): 191–9. doi:10.1007/s00213-009-1720-3. PMC 2819208. PMID 19924404.
- Howell LL, Murnane KS (May 2011). "Nonhuman primate positron emission tomography neuroimaging in drug abuse research". J. Pharmacol. Exp. Ther. 337 (2): 324–34. doi:10.1124/jpet.108.136689. PMID 21317354.
- Kirkland Henry P, Davis M, Howell LL (August 2009). "Effects of cocaine self-administration history under limited and extended access conditions on in vivo striatal dopamine neurochemistry and acoustic startle in rhesus monkeys". Psychopharmacology (Berl.) 205 (2): 237–47. doi:10.1007/s00213-009-1534-3. PMC 2796974. PMID 19365621.
- Andersen ML, Kessler E, Murnane KS, McClung JC, Tufik S, Howell LL (June 2010). "Dopamine transporter-related effects of modafinil in rhesus monkeys". Psychopharmacology (Berl.) 210 (3): 439–48. doi:10.1007/s00213-010-1839-2. PMC 2874656. PMID 20386883.
- Katz JL, Higgins ST (July 2003). "The validity of the reinstatement model of craving and relapse to drug use". Psychopharmacology (Berl.) 168 (1-2): 21–30. doi:10.1007/s00213-003-1441-y. PMID 12695875.
- Hudson A, Stamp JA (January 2011). "Ovarian hormones and propensity to drug relapse: a review". Neurosci Biobehav Rev 35 (3): 427–36. doi:10.1016/j.neubiorev.2010.05.001. PMID 20488201.
- Czoty PW, Riddick NV, Gage HD, Sandridge M, Nader SH, Garg S, Bounds M, Garg PK, Nader MA (February 2009). "Effect of menstrual cycle phase on dopamine D2 receptor availability in female cynomolgus monkeys". Neuropsychopharmacology 34 (3): 548–54. doi:10.1038/npp.2008.3. PMID 18256593.