Cue reactivity


Cue reactivity is a type of learned response which is observed in individuals with an addiction, and involves significant physiological and psychological reactions to presentations of drug-related stimuli. The central tenet of cue reactivity is that cues previously predicting receipt of drug reward under certain conditions can evoke stimulus associated responses such as urges to use drugs. In other words, learned cues can signal drug reward, in that cues previously associated with drug use can elicit cue-reactivity such as arousal, anticipation, and changes in behavioral motivation.
Responses to a drug cue can be physiological, behavioral, or symbolic expressive. The clinical utility of cue reactivity is based on the conceptualization that drug cues elicit craving, which is a critical factor in the maintenance and relapse to drug use. Additionally, cue reactivity allows for the development of testable hypotheses grounded in established theories of human behavior. Therefore, researchers have leveraged the cue reactivity paradigm to study addiction, antecedents of relapse, and craving, translate pre-clinical findings to clinical samples, and contribute to the development of new treatment methods. Testing cue reactivity in human samples involves exposing individuals with a substance use disorder to drug-related cues and drug neutral cues, and then measuring their reactions by assessing changes in self-reported drug craving and physiological responses, such as blood pressure, salivation, and brain activity.

Cue types

Drummond identified a preliminary classification of cue types including four main categories: Exteroceptive; Interceptive; Temporal; and Cue relationship.
  • Cues that are exteroceptive are characterized as external drug-related stimuli, such as sight, smell, and taste. Visual cues include sight of a preferred drug, or advertisement, or environment where drug use occurs. Olfactory cues include smell of preferred drug or smells associated with drug use. Gustation cues include having a sip of alcohol or initial inhale of smoke. Cues that are exteroceptive are the most commonly studied in the laboratory.
  • Interoceptive cues are characterized as internal cues, such as stress response, negative or positive mood, and withdrawal related states.
  • Temporal cues relate to the proximity or distance to substance use and time of day.
  • Complex relationships between cues.
For instance, cues occurring more proximally to the ingestion of a substance may be more salient and produce greater reactivity compared to distal cues. Additionally, the time of day at which cues are encountered may impact the salience of the cue, such that the time of day when a substance is habitually consumed may become a temporal cue. For example, the end of a workday or a weekend day may become in and of itself a cue eliciting craving. Lastly, the theory behind cue relationships is that it is likely there is a complex relationship between cues. Drug cues rarely occur in isolation in the real-world, thus an inter-relationship between cues in eliciting cue reactivity is possible. Such inter-relationship can be described as a “cue cluster,” “cue chain,” and “cue cascade.” A “cue cluster” describes co-occurring cues, such that each co-occurring cue is necessary for reactivity but not a sufficient condition for substance use. A “cue chain” describes the sequential relationship between cues leading up to use. For example, the sight of a preferred substance like an alcoholic drink may be more salient for an individual in a certain context like at a bar. Similarly, a “cue cascade” describes the process of each cue increasing the likelihood of encountering and the salience of the next cue.

Theoretical background

Cue reactivity is most often conceptualized through models of classical conditioning, such that it is theorized that cues that are nearly exclusively encountered at the time of drug administration will develop the ability to predict the administration and effect of the substance. In other words, after systematic association of exteroceptive or interoceptive cues with drug administration, the cues will reliably signal administration and drug effects. When cues predict administration, they acquire the ability to elicit physiological and psychological responses which increase the likelihood of substance use. Although there is a substantial amount of research on cue reactivity, the exact theoretical explanation of cue reactivity remains unclear.

Prominent models of cue reactivity

There are three prominent models of cue reactivity: Conditioned withdrawal model; Conditioned appetitive motivational model; and Conditioned compensatory response model. In common across all three models is that they are all described in terms of classical conditioning and that cues repeatedly associated with substance administration will eventually elicit a conditioned reaction. The three models differ in the nature of the reaction that is elicited.
The conditioned withdrawal model, developed by Wikler, characterizes the conditioned response as an unconditioned substance withdrawal state. For instance, during a drinking episode and individual with an alcohol use disorder is exposed to cues at a point when their blood alcohol level is falling, such as the morning after a heavy drinking episode. During this time the individual is likely in a state of unconditioned alcohol withdrawal. The exteroceptive cue becomes associated with alcohol withdrawal. Therefore, during a period of abstinence and the individual is exposed to the exteroceptive cues a conditioned withdrawal-like reaction is elicited. The conditioned appetitive motivational model states that drug cues become associated with the pleasurable unconditioned effects of substances and leads to drug-like conditioned responses. In other words, the conditioned response resembles the unconditioned effect of the substance. The conditioned compensatory response model, formed by Siegel, postulates that the conditioned response is opposite to the unconditioned drug effect, such that the conditioned response is part of a homeostatic response resulting in the development of drug tolerance. Each conditioning model is empirically supported.

Cognitive theories of cue reactivity

Although most theories of substance dependence acknowledge the role of conditioning and view this research as invaluable, not all theories assume that conditioning is sufficient in explaining this phenomenon as cue reactivity appears to be complex and highly individual. Therefore, cognitive theories have been proposed. The cognitive urge and automaticity model is a prominent cognitive theory of addiction and purposes that behaviors associated with substance administration become automatic and cues can trigger such automatized behaviors. This model is consistent with addiction models that emphasize habit-like processes. Additionally, cognitive labeling theory argues that the contextual and cue state an individual is in contributes to the interpretation of an arousal, such that a cue may trigger an arousal and the individual may perceive the cue as predicting substance administration which then triggers craving and substance intake. Other cognitive behavioral theories hypothesize that cues can elicit craving by highlighting the positive effects of the substance resulting in substance use. Lastly, attentional bias has been used to conceptualize cue reactivity in that substance-related cues can “grab” the attention of the individual engaging in substance use behaviors.

Factors affecting cue reactivity

Cue, individual, contextual, and substance factors affect the salience of cue reactivity. Regarding cue characteristics, in vivo cues, cues that are directly experienced, have greater salience than imaginal cues. Moreover, interoceptive cues have been found to have greater salience than imaginal and visual cues. Overall, cues with greater association with substance consumption are likely to be more salient than cues with limited association. Research has found individual variability in cue reactivity. For instance, craving is highly variable among individuals and reactions to laboratory cues vary with some participants not showing much cue reactivity. Specific sources of individual variability include gender, genetic factors, personality, and treatment status of the individual. Degree of alcohol dependence is an additional individual factor affecting cue reactivity, in that individuals who are more alcohol dependent are more cue-reactive. Additionally, context-specific expectancies such as perceived availability of a substance and efficacy expectations have been found to be important. Pertaining to substance factors, latency since last use is an important factor to consider. A critical component of this factor is the impact of withdrawal, such that withdrawal may increase the salience of cues. Similarly, an additional potential effect is the deprivation of one substance on another in that the deprivation of one substance will increase urge or reactivity of another substance.

Cue reactivity in different substances

Research has shown that cue reactivity is experienced among individuals dependent on a variety of substances including alcohol, nicotine, opiates, and cocaine. However, research focused on these substances have been primarily done in isolation of each other and there are nuances regarding cue reactivity within each substance. The cues that elicit the greatest reactivity among those with an alcohol use disorder are the ingestion of a small amount of alcohol or expectancy of alcohol availability. The responses most commonly elicited from alcohol cue exposure among those with an alcohol use disorder includes increased salvation, increased sweating, and greater self-reported alcohol craving. The smoking cue-reactivity responses commonly reported are psychophysiological arousal including skin conductance, vasoconstriction, heart rate, and craving as the strongest response. Regarding opiates, auditory, visual, or role play of drug sales appear to be the most influential cues. Mood states may also significantly elicit cue-reactivity. Psychophysiological responses commonly elicited by opiate cues include decreases peripheral temperature and skin resistance. Cocaine cue reactivity is much less researched. Of the limited research, audiovisual stimuli of drug sales and consumption commonly elicit significant reactivity. Psychophysiological responses associated with cocaine use cues are decreased peripheral temperature, skin resistance, decreased heart rate, and greater self-reported craving.