A conceptual framework for the intersection of hyperalgesia and hyperkatifeia in alcohol addiction.

Alcohol use disorder is a chronically relapsing disorder that is characterized by compulsive drug seeking and is hypothesized to result from multiple sources of motivational dysregulation in a three-stage cycle of addiction (incentive salience/pathological habits, withdrawal/negative affect, and preoccupation/anticipation). One major source of motivation in the withdrawal/negative affect stage is the physical pain and emotional pain of withdrawal and protracted withdrawal that drive pronounced drug-seeking behavior via the process of negative reinforcement. The construct of negative reinforcement is defined as alcohol taking to alleviate both physical pain and emotional pain (hyperkatifeia) that are created by alcohol abstinence following excessive alcohol consumption. Hyperkatifeia (derived from the Greek "katifeia" for dejection or negative emotional state) is defined as an increase in intensity of the constellation of negative emotional or motivational signs and symptoms of withdrawal from drugs of addiction. In humans and animal models, the repeated misuse of alcohol results in hyperalgesia and hyperkatifeia and is reflected by elevations of reward thresholds, lower pain thresholds, and anxiety- and dysphoric-like responses during alcohol withdrawal. Such symptoms are hypothesized to derive from molecular and neurocircuitry neuroadaptations within the reward system and brain stress systems (e.g., corticotropin-releasing factor, dynorphin, norepinephrine, hypocretin, vasopressin, glucocorticoids, and neuroimmune factors) and brain anti-stress systems (e.g., neuropeptide Y, endocannabinoids, and oxytocin) in the extended amygdala. Thus, our hypothesis is that alcohol withdrawal-induced hyperalgesia and hyperkatifeia persist into protracted withdrawal and contribute to the development and persistence of compulsive alcohol seeking. A conceptual framework for the intersection of physical and emotional pain in addiction is elaborated in the Catastrophizing, Anxiety, Negative Urgency, and Expectancy (CANUE) model, and a significant overlap of brain circuits that mediate emotional pain and physical pain involves the extended amygdala. The intersection of emotional and physical pain reinforces even more dramatically the role of negative reinforcement in alcohol addiction and fits a framework of allostasis (defined as stability with change) where other allostatic loads (defined as the cost of breaks with homeostasis on the body), such as genetics/epigenetics, childhood trauma, and other stressors, exacerbate hyperalgesia/hyperkatifeia in driving alcohol use disorder. The focus on treating hyperalgesia/hyperkatifeia that is associated with acute and protracted withdrawal opens new and exciting avenues for understanding the etiology of alcohol use disorder.