A Conceptual Framework for the Intersection of Hyperalgesia and Hyperkatifeia in Alcohol Addiction

Opponent process

Counteradaptation as an explanation for drug withdrawal has long been invoked to explain physiological effects of opioid tolerance and withdrawal (Himmelsbach, 1943; Martin, 1968) and alcohol tolerance and withdrawal (Elvig et al., 2021). Later, opponent process theory was formulated to explain how the initial acute hedonic effects of a drug are opposed or counteracted by homeostatic changes in these same hedonic systems that mediate primary hedonic effects of the drug (Solomon and Corbit, 1973; Solomon and Corbit, 1974; Solomon, 1980; Siegel, 1975; Poulos and Cappell, 1991). Indeed, opponent process theory was argued to be a general phenomenon that is associated with motivational breaks from homeostasis (Solomon and Corbit, 1973; Solomon and Corbit, 1974; Hoffman and Solomon, 1974; Solomon, 1980).

In its original formulation, euphoria that is produced by a drug was termed the a-process that was followed by dysphoria, which was termed the b-process (Solomon, 1980). The b-process was hypothesized to grow with repeated administration, and it can be equated with the development of withdrawal. Under this framework, development of the b-process reflects the development of hyperkatifeia in opposition to hedonic effects (a-process) of alcohol, including malaise, irritability, alexithymia, anxiety, dysphoria, and subjective feelings of unease and simply not feeling “hedonically normal,” all of which are also withdrawal symptoms. Here, negative reinforcement becomes the source of motivation for drug seeking, in which the individual will work to reduce, terminate, or prevent this sensitized negative emotional state. As a result, a greater amount and more frequent use of alcohol is needed to maintain or approach hedonic euthymia (tolerance). Alcohol use is hypothesized to be compulsively escalated or renewed (in relapse) via negative reinforcement mechanisms because it transiently prevents or relieves hyperkatifeia and hyperalgesia, and this compulsive drug seeking defends a hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state (Koob et al., 2020; Koob and Le Moal, 2001).

Negative reinforcement

Negative reinforcement can be defined as an increase in the probability of a response that is produced by the removal of an aversive event. Classically, individuals with alcohol use disorder (AUD) may start with recreational use of the drug during the binge/intoxication stage and progress to the withdrawal/negative affect stage as negative reinforcement evolves (Koob, 2021). However, much of the misuse of alcohol also develops because negative reinforcement may be the initial starting point either via self-medication or chronic pain, both of which can exacerbate hyperkatifeia (Edwards et al., 2012; Koob et al., 2020).

Negative reinforcement that motivates drug misuse has long been associated with self-medication, in which individuals consume alcohol and other drugs to alleviate aversive physical or emotional states (Cappell and Herman, 1972; Sher and Levenson, 1982; Khantzian, 1985; Baker et al., 2004; McGinn et al., 2021a). Individuals often report consuming alcohol to self-medicate physical pain (hyperalgesia) and emotional pain (hyperkatifeia; Holahan et al., 2001; Brennan et al., 2005; Aira et al., 2008; Riley and King, 2009; Zale et al., 2015). From this perspective of pain, both physical and emotional pain serve as situational motivators of alcohol consumption, partly as a function of pain-induced negative affect (Zale et al., 2015).

Overview of the neurocircuitry of addiction

Alcohol use disorder can be defined as a chronically relapsing disorder that is associated with compulsive alcohol drinking, the loss of control over intake, and the emergence of a negative emotional state when alcohol is no longer available (Koob et al., 2020; Koob, 2021). The diagnosis of AUD is based on individuals who meet at least two of 11 criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5^th edition (DSM-5; American Psychiatric Association, 2013), and its severity is classified as mild (2-3 criteria), moderate (4-5 criteria), or severe (≥ 6 criteria), based on the number of diagnostic criteria that are met within a 12-month period. This nosological framework captures a wide spectrum of alcohol misuse in AUD that can range from a pattern of intermittent episodes of binge alcohol intake to prolonged heavy drinking that escalates to continual drinking via the fear of withdrawal.

A neurobiological framework for AUD, and addiction in general, with strong heuristic validity outlines a dynamic cycle with three stages—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—that provides a starting point for the interaction of pain and AUD (Koob and Le Moal, 1997; Koob, 2021; Koob and Vendruscolo, 2023). Under this framework, three functional domains of dysregulation are conceptualized for each of the three stages. Incentive salience and pathological habits frame the binge/intoxication stage. Negative emotional states frame the withdrawal/negative affect stage. Executive function deficits frame the preoccupation/anticipation stage (Koob and Volkow, 2010). Each stage is mediated by three major neurocircuitry systems where the binge/intoxication stage involves the basal ganglia, the withdrawal/negative affect stage involves the extended amygdala, and the preoccupation/anticipation stage involves largely prefrontal cortex (Koob and Le Moal, 1997; Koob and Volkow, 2010; Koob and Volkow, 2016).

Classically, a feed-forward system is hypothesized, such that the excessive engagement of reward system activation by alcohol during the binge/intoxication stage ultimately causes a break from hedonic homeostasis and subsequent compensatory responses in brain reward and stress systems to generate the negative emotional state of withdrawal (termed hyperkatifeia; see below; Koob and Le Moal, 1997). Therefore—and often in parallel—executive function is compromised, thus contributing to deficits that are associated with the preoccupation/anticipation stage and leading to craving for alcohol and perpetuating the addiction cycle (Koob and Volkow, 2010; Koob and Volkow, 2016; Figure 1).

However, using such a neurobiological framework, an individual can enter the three-stage cycle at any stage by engaging neuroadaptations that lead to compulsive-like alcohol consumption. Although a typical trajectory is for individuals with AUD to start with alcohol misuse in the binge/intoxication stage and progress to the withdrawal/negative affect stage as negative reinforcement evolves (Koob et al., 2019; Figure 1), much alcohol misuse also develops because negative reinforcement may be the initial starting point via the self-medication of hyperalgesia/hyperkatifeia (Ballantyne et al., 2019; Koob, 2021; Vendruscolo et al., 2023; Koob et al., 2020).

Alcohol withdrawal-induced hyperalgesia

Drug withdrawal-induced hyperalgesia can be defined as a state of diffuse greater pain sensitivity to stimuli of a stable intensity that is observed during withdrawal from drugs of addiction (Arout et al., 2015). In humans, alcohol can have significant analgesic effects, particularly on the ascending limb of the blood alcohol-over-time function and at doses that approach binge drinking levels (Thompson et al., 2017). In a meta-analysis of 18 controlled studies that compared pain in people who were given alcohol versus no alcohol provided support for the pain-reducing effects of alcohol (Thompson et al., 2017). The threshold for producing a small elevation of pain thresholds appeared to be a mean blood alcohol level of 0.08% (i.e., the legal driving limit), and there was a significant reduction of pain intensity with higher blood alcohol levels (Thompson et al., 2017).

Similarly, alcohol produces dose-dependent analgesia in rodent models using various measures of analgesia (Gatch and Lal, 1999: Neddenriep et al., 2019; Jorgensen and Hole, 1981; Pohorecky and Shah, 1987; Friedman et al., 1980). For example, cumulative alcohol administration caused a dose-dependent analgesic effect, reaching significance at 2 g/kg, using the radiant heat tail flick procedure in rats (Gatch and Lal, 1999). In mice, alcohol administration (0-1.25 g/kg) produced a dose-dependent reversal of mechanical hypersensitivity in models of chronic inflammatory and neuropathic pain (Neddenriep et al., 2019).

However, withdrawal from chronic alcohol consumption, like opioids, produces hyperalgesia in rodents (Edwards et al., 2020; Gilpin et al., 2021; Gatch and Lal, 1999; Gatch, 2009; Shumilla et al., 2005; Dina et al., 2006; Dina et al., 2008; Egli et al., 2012) and humans (Jochum et al., 2010; Figure 2). For example, individuals who underwent alcohol withdrawal exhibited greater heat pain sensitivity on both the left hand and sternum (Jochum et al., 2010). Pain thresholds and tolerance to electric stimuli did not differ between groups (Jochum et al., 2010). Alcohol-dependent mice developed hyperalgesia that was completely reversed after voluntary drinking (Borgonetti et al., 2023).

Alcohol withdrawal-induced hyperkatifeia

The construct of hyperkatifeia derived from an attempt to concisely define the motivational drive for alcohol seeking during the withdrawal/negative affect stage of the addiction cycle and was argued to be a conceptual parallel to hyperalgesia in the context of emotional pain (Shurman et al., 2010; Koob, 2021). The word “hyperkatifeia” derives from the Greek “katifeia,” for dejection or a negative emotional state, and is defined as an increase in intensity of the constellation of negative emotional or motivational signs and symptoms of drug withdrawal (Shurman et al., 2010; Koob et al., 2020; Koob, 2021). Although originally conceptualized in the context of opioid addiction, this construct applies equally well to alcohol addiction and all addictions (Shurman et al., 2010; Koob et al., 2020; Koob, 2021). All drugs with addiction potential have positive reinforcing properties, which inevitably produce hyperkatifeia in acute and protracted withdrawal in the withdrawal/negative affect stage that in turn generate a second motivational drive to drug use via negative reinforcement.

Hyperkatifeia in the context of alcohol withdrawal is hypothesized to represent elements outside the physical/somatic pain dimension. These include such symptoms as dysphoria, malaise, anxiety, irritability, alexithymia, emotional pain, sleep disturbances, or simply symptoms that are often self-described as “ill at ease,” uncomfortable within “one’s own skin,” or not hedonically normal (Koob, 2021). The construct of hyperkatifeia has been argued to incorporate all motivational signs of withdrawal that characterize the withdrawal/negative affect stage of the addiction cycle in humans, and hyperkatifeia can be considered the emotional parallel to hyperalgesia (i.e., greater sensitivity to physical pain) that is observed during withdrawal from the repeated administration of chronic alcohol (Shurman et al., 2010; Koob, 2021).

In humans, measures of symptoms that are associated by hyperkatifeia include elements of self-report scales, such as the Beck Depression Inventory, Beck Anxiety Inventory, and Fawcett-Clark Pleasure Scale, and neuropsychological tests, such as the facial emotional matching task and approach avoidance task (Kwako et al., 2016; Kwako et al., 2019; Kwako and Koob, 2017). Indeed, hyperkatifeia in humans, as operationalized by scores on the Hamilton Depression Rating Scale (Brown and Schuckit, 1988) or Beck Depression Inventory (Humeniuk, 1999), was manifested in spontaneous alcohol withdrawal for up to 4 weeks after the last drink (Brown and Schuckit, 1988; Humeniuk, 1999; see Figure 2).

In rodents, elements of hyperkatifeia can be modeled with such measures as anxiety-like behavior (e.g., elevated plus maze, defensive burying paradigm, and social interaction test) and by animal models of dysphoria-like symptoms (e.g., sucrose preference test, brain reward thresholds, and conditioned place aversion; Schulteis et al., 1997). Figure 2 illustrates elements of hyperkatifeia in humans and rats.

Like opioid withdrawal-induced hyperalgesia, alcohol withdrawal-induced hyperkatifeia is hypothesized to sensitize over the course of repeated compulsive alcohol ingestion and precede the onset of severe somatic signs of withdrawal (Gottlieb et al., 2024). In humans, the sudden decrease in blood alcohol levels can result in alcohol withdrawal syndrome symptoms, with elements of hyperkatifeia, such as heightened anxiety and insomnia, that emerge within 6-8 h. Concomitantly, somatic signs, such as tremors, headache, nausea/vomiting, diaphoresis, palpitations, tachycardia, hypertension, hyperthermia, and delirium tremens, emerge, peaking at 48-72 h. These somatic symptoms typically diminish by 5-7 days (Gottlieb et al., 2024), whereas hyperkatifeia can persist long into protracted abstinence (Koob, 2021).

Alcohol-dependent rats exhibited an increase in anxiety-like behavior 8 h into withdrawal, which normalized after 2 weeks of abstinence but markedly resurged at 6 and 12 weeks of alcohol abstinence. Hypoactivity was observed throughout all stages of withdrawal (Zhao et al., 2007). In another study in alcohol-dependent rats, increases in anxiety- and aggressive-like behavior and hypolocomotion were observed 8 h into alcohol withdrawal (Somkuwar et al., 2017). Aggressive-like behavior and peak plasma corticosterone levels remained altered for several weeks following alcohol exposure (Somkuwar et al., 2017). In parallel, escalated alcohol drinking and the robust reinstatement of alcohol seeking were reported during acute and protracted alcohol abstinence, effects that may involve glucocorticoid receptor activity and the central nucleus of the amygdala (CeA) and may represent a neuroadaptation that is shared with opioid addiction (Vendruscolo et al., 2012; Repunte-Canonigo et al., 2015; Somkuwar et al., 2017; Khom et al., 2022; Carmack et al., 2022).

Within-system neuroadaptations

Alcohol dependence is defined here in the context of animal models of alcohol addiction as chronic alcohol administration that is sufficient to produce withdrawal signs. For hyperkatifeia, a major focus for within-system neuroadaptations in alcohol dependence has been on the mesolimbic dopamine system that projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAc; Figure 3). Significant evidence has also emerged of a role for the lateral habenula–VTA circuit in driving aversive responses to the loss of reward and mediating and encoding aversive states by modulating dopamine neurotransmission via actions on dopamine neurons in the VTA (Hikosaka, 2010; Velasquez et al., 2014; Boulos et al., 2017; Borsook et al., 2016). Dynorphin circuits that interact with the mesolimbic dopamine system have been hypothesized to be activated and ultimately contribute to the hypodopaminergic state of alcohol withdrawal (Carlezon et al., 2000).

For hyperalgesia, alcohol dependence is associated with the dysregulation of multiple forebrain and midbrain circuits that largely overlap with those that are involved in ascending and descending pain processing (Edward et al., 2020; Egli et al., 2012; Apkarian et al., 2013), including the dysregulation of opioid and dopamine system circuits (Gilpin et al., 2021). Dopamine has analgesic effects in the dorsal striatum and NAc. Like alcohol dependence, chronic pain is associated with dopamine hypofunction, which maintains and exacerbates pain (Ziolkowska, 2021; Borsook et al., 2016).

Between-systems neuroadaptations

For hyperkatifeia, a major focus for between-systems neuroadaptations has been on neurocircuitry within the extended amygdala (Figure 4; Koob and Le Moal, 2008; Koob, 2021). The extended amygdala is defined by several major basal forebrain structures, including the bed nucleus of the stria terminalis (BNST) and CeA, and the sublenticular substantia innominata and a transition zone in the shell of the NAc (Heimer and Alheid, 1991). The extended amygdala has been considered a key link that interfaces structures that are involved in emotion with structures that are involved in motor action and motivation, such as the extrapyramidal motor system (Alheid et al., 1995).

Corticotropin-releasing factor (CRF) not only controls the hypothalamic-pituitary-adrenal axis to activate the hormonal response to stress but also plays an extrahypothalamic role in mediating behavioral responses to stress in rodents (Bale and Vale, 2004; Vendruscolo et al., 2023). Acute withdrawal from alcohol increases the release of CRF in the CeA (Merlo-Pich et al., 1995) and BNST (Olive et al., 2002), and CRF receptor antagonist administration in the amygdala in rats blocks anxiety-like effects of acute withdrawal from alcohol (Rassnick et al., 1993) and the increase in alcohol intake that is associated with dependence (Funk et al., 2006). The inactivation of the CeA neuronal ensemble with Daun02 produced a long-term decrease in alcohol drinking in dependent rats (de Guglielmo et al., 2016). The optogenetic inhibition of CeA CRF projections to the BNST reduced alcohol addiction-like behaviors in rats, an effect that was mediated by the inhibition of CRF₁ receptors and inhibition of BNST cell firing (de Guglielmo et al., 2019).

The role of the CRF system in alcohol dependence is further amplified via the hypothalamic-pituitary-adrenal axis. Chronic exposure to high amounts of alcohol blunted the hypothalamic-pituitary-adrenal axis but sensitized the extrahypothalamic CRF system (Edwards et al., 2015; Vendruscolo et al., 2023), and glucocorticoid receptor antagonists also decreased dependence-induced drinking in rodents, monkeys, and humans with AUD (Vendruscolo et al., 2012; McGinn et al., 2021b; Vendruscolo et al., 2015; Jimenez et al., 2020; Savarese et al., 2020), an effect that may involve the CeA (Khom et al., 2022).

Reversal of the increase in drinking that associated with alcohol dependence was also observed with the blockade of activity of the dynorphin/κ-opioid receptor system but with a focus on the NAc shell (Nealey et al., 2011; Rose et al., 2016). Antagonists of other brain stress systems, such as dynorphin, norepinephrine, vasopressin, hypocretin, substance P, and neuroimmune systems, have similar effects on hyperkatifeia-like responses that are associated with alcohol withdrawal (for review, see Koob, 2021). Additionally, there are anti-stress or stress-buffering systems in the extended amygdala, such as neuropeptide Y, nociceptin, endocannabinoids, and oxytocin, that block hyperkatifeia-like responses and dependence-induced drinking (for review, see Koob, 2021). Such alcohol-induced dysregulation of emotional processing may be a significant contributor to between-system opponent processes that help maintain alcohol addiction and trigger relapse to excessive drinking in situations of high stress.

For hyperalgesia, the neurobiological substrates for alcohol withdrawal-induced hyperalgesia have some overlap with neurocircuitry that is associated with hyperkatifeia. For example, CRF in the amygdala, particularly in the CeA, plays an important role in affect-like responses that are associated with pain and pain modulation (Ji et al., 2007). Hyperalgesia that is associated with alcohol withdrawal can be blunted by the blockade of CRF₁ receptors (Edwards et al., 2012; Park et al., 2015), and CRF receptor antagonists can blunt nociceptive hypersensitivity in a wide variety of pain assays in animals (Hummel et al., 2010).

Similarly, and in parallel with the key role of glucocorticoids in driving compulsive-like drinking, the glucocorticoid receptor antagonist mifepristone, administered systemically, blocked alcohol withdrawal-induced hyperalgesia in rats (Dina et al., 2008). An antisense oligonucleotide against glucocorticoid receptors and a β₂-adrenergic receptor antagonist, administered intrathecally, both prevented and reversed hyperalgesia that resulted from withdrawal from an alcohol liquid diet (Dina et al., 2008). Apremilast, an FDA-approved phosphodiesterase type 4 (PDE4) inhibitor with pronounced antiinflammatory neuroimmune actions, reduced alcohol drinking and mechanical sensitivity and increased γ-aminobutyric acid-ergic transmission in CeA slices from alcohol-exposed rats (Vozella et al., 2025). Other molecular targets that contribute to hyperalgesia in alcohol withdrawal include several neurotransmitter and molecular targets, again suggesting multiple interactions with the same systems that mediate hyperkatifeia (Table 1).

Neuroanatomical and neurochemical overlap

The extended amygdala has been shown to play a key role in fear, anxiety, and stress and also in the emotional component of pain processing (Neugebauer et al., 2004). The neural substrates of hyperkatifeia that are associated with AUD may overlap with substrates of emotional aspects of pain processing in such areas as the amygdala (Neugebauer, 2007; Neugebauer et al., 2020). In addition to the classic spinothalamic pain pathway that ultimately connects with the amygdala, the spino(trigemino)-ponto-amygdaloid pathway projects from the dorsal horn of the spinal cord to the mesencephalic parabrachial area and then directly to the CeA. This pathway has been implicated in processing emotional components of pain (Price, 2000; Bester et al.,1995; Figure 5).

Indeed, the lateral part of the CeA contains a significant number of pain-responsive neurons (Neugebauer and Li, 2002), an area that may also be responsible for negative emotional responses to alcohol (Rassnick et al., 1993). Both anxiety-like responses and hyperalgesia that are produced by withdrawal from chronic alcohol exposure are blocked by CRF receptor antagonists (Edwards et al., 2012).

Another circuit that may be involved in both hyperalgesia and hyperkatifeia involves a focal point within the lateral habenula. Alcohol withdrawal-induced hyperalgesia and relapse-like alcohol consumption were reversed by the chemogenetic inhibition of lateral habenula neurons, the pharmacological activation of M-channels, and overexpression of the M-channel subunit KCNQ3 (Kang et al., 2019). An intra-lateral habenula infusion of serotonin 5-hydroxytryptamine-2 receptor antagonists or a serotonin reuptake blocker decreased nociceptive sensitivity and alcohol intake in alcohol-withdrawn rats (Zuo et al., 2019).

Conceptual overlap: CANUE and the three-stage cycle

In a theoretical integrative review of current evidence regarding pain, substance use, and associated risk factors, including negative affect, pain-related attitudes, negative urgency, and substance use outcome expectancies, the CANUE model was formulated to highlight modifiable risk factors for self-medicating pain with substance use, including alcohol use (Ferguson et al., 2021; Figure 6).

The CANUE model is predicated on the well-established self-medication hypothesis of addiction that is based on negative reinforcement as a major motivation for addiction (Khantzian, 1997) and on the hypothesis that there is a reciprocal relationship between substance misuse and pain, where each condition exacerbates the other (Ditre et al., 2019). Others have hypothesized a similar parallel reciprocal relationship between emotional pain and addiction (Koob and Le Moal, 2005; Koob, 2015; Koob and Vendruscolo, 2023; Vendruscolo et al., 2023). Indeed, much evidence supports the hypothesis that individuals self-medicate pain with alcohol (Alford et al., 2016; Riley and King, 2009; Holahan et al., 2001; Brennan et al., 2005; Aira et al., 2008; Zale et al., 2015; Edwards et al., 2020). Using alcohol to manage pain-related symptoms and stress has been well established across various painful conditions, and individuals use alcohol to cope with pain. The CANUE model was elaborated to better understand the interaction between pain and substance misuse, with the aim of elucidating the processes and mechanisms for such an interaction.

The authors argued that negative affect, or in our terminology hyperkatifeia, is a well-documented contributor to, and consequence of, both repeated or heavy substance use and chronic pain. They further argued that as one moves through the addiction cycle, chronic substance and alcohol use can both be risk factors for hyperkatifeia and exacerbate existing negative emotional states (Ferguson et al., 2021). The CANUE model identifies modifiable risk factors for self-medicating pain with substance use, including greater negative affect (hyperkatifeia) and maladaptive pain-related attitudes (i.e., pain catastrophizing, pain anxiety, and fear of pain), negative urgency, and substance-related outcome expectancies for pain relief and enhanced pain coping (Ferguson et al., 2021).

The focus of the CANUE model is on specific parts of the three-stage cycle of addiction, notably the withdrawal/negative affect stage and preoccupation/anticipation stage. The authors identified multiple factors that contribute to negative reinforcement that drives the reciprocal pain and alcohol misuse relationship, including negative affect, negative urgency, pain attitudes, and pain expectancies (Figure 6). Here, negative affect is both a consequence of, and contributor to, chronic pain (Ferguson et al., 2021), and negative affect has a reciprocal relationship, in which individuals with chronic pain report higher levels of depression and anxiety, and individuals with depression show more pain symptoms (Bair et al., 2003; McWilliams et al., 2003). Clearly, hyperkatifeia is both a consequence of, and contributor to, alcohol misuse (Koob, 2021; Koob et al., 2020). Major components of pain attitudes are pain catastrophizing, pain anxiety, and pain fear expectancies, which contribute to driving pain and negative affect that is associated with pain (Ferguson et al., 2021). Pain catastrophizing, pain-related anxiety, and the fear of pain are all maladaptive cognitive responses that interact with negative affect to exacerbate negative consequences of chronic pain (Ferguson et al., 2021). Pain catastrophizing represents a high perceived threat from pain (Quartana et al., 2009). Pain-related anxiety promotes anxious or fearful responses to pain (McCracken and Dhingra, 2002), and the fear of pain represents a compelling avoidance of activities that may result in the experience of pain (Zale and Ditre, 2015). Negative urgency (i.e., the tendency to act impulsively to escape negative emotions when distressed) has been associated with a range of negative behaviors, including alcohol misuse (Zorrilla and Koob, 2019; Vendruscolo et al., 2023), and likely contributes to the pain/alcohol misuse interaction. How negative urgency that is associated with pain contributes to pain as an antecedent for alcohol misuse remains to be explored (Ferguson et al., 2021).

Thus, the CANUE model is a scholarly attempt to integrate previous theorizing on the role of negative reinforcement in the intersection of pain and addiction and to utilize this model to understand elements of key factors that drive such a powerful form of motivation (Ferguson et al., 2021). The CANUE framework fits well with the three-stage addiction cycle, applies well to hyperkatifeia as well as hyperalgesia, and provides a framework for understanding the neurobiological mechanisms that are involved in mediating how the domains that drive the withdrawal/negative affect and preoccupation/anticipation stages interact (Figure 6). The CANUE model may also explain how reward deficits/stress surfeit manifestations and executive function deficits, respectively, interact and feed on each other to allostatically drive pain and emotional pain, key components of the motivation to compulsively misuse alcohol.

Much evidence suggests a major intersection of hyperalgesia and hyperkatifeia during the withdrawal/negative affect stage of the addiction cycle as elaborated in human studies. As noted above, theorists have long hypothesized that a negative reinforcement model of drug use assumes that individuals frequently consume alcohol to alleviate aversive physical or emotional states (Baker et al., 2004; Cappell and Herman, 1972; Khantzian, 1985; Sher and Levenson, 1982). This misregulation leads to the vulnerability to addiction in general and AUD in particular. For example, there is a positive association between pain severity and a higher risk for AUD (Edlund et al., 2013; Demyttenaere et al., 2007; Lawton and Simpson, 2009). Perhaps more compelling, physical pain appears to be a significant predictor of alcohol use and heavy alcohol use and relapse to drinking after periods of abstinence (Caldeiro et al., 2008; Larson et al., 2007; Witkiewitz et al., 2015; Ferguson et al., 2021).

One prominent hypothesis is that pain serves as a situational motivator of alcohol consumption, partly as a function of pain-induced negative affect, or hyperkatifeia (Zale et al., 2015). Under this framework, excessive drinking and AUD were associated with deleterious pain-related outcomes, more specifically greater pain severity (Zale et al., 2015). As noted above, individuals often report consuming alcohol to self-medicate physical and emotional pain (Aira et al., 2008; Zale et al., 2015; Holahan et al., 2001; Brennan et al., 2005; Riley and King, 2009).

From the perspective of the intersection of physical pain and emotional pain, negative affect can potentiate effects of physical pain for both opioids (Carcoba et al., 2011) and alcohol (Jochum et al., 2010). As mentioned above, in a study of human male patients who were undergoing withdrawal from alcohol, the perception of innocuous and noxious thermal or electric stimuli that were applied to the left hand or sternum showed that subjects who were undergoing alcohol withdrawal presented greater heat pain sensitivity, but pain thresholds and tolerance to electric stimuli did not differ between groups (Jochum et al., 2010). In a subgroup analysis, a higher sensitivity to electrical pain thresholds and tolerance were observed in patients with severe withdrawal, suggesting an effect in patients who were more dependent on alcohol. Additionally, the perceived painful thermal and electrical sensations were substantially influenced by the patients’ affective state (Jochum et al., 2010). In two large clinical trials of AUD, based on a secondary analysis, negative affect significantly mediated the association between pain and drinking outcomes (Witkiewitz et al., 2015). In another study with participants who were randomized to either experimental pain induction versus no pain, participants in the pain condition subsequently endorsed a greater urge and intention to drink, and these effects were mediated by pain-induced negative affect (Moskal et al., 2018).

Allostasis framework for the intersection of pain and addiction

In summary, individuals with comorbid pain and AUD may drink to alleviate pain-related negative affect, and behavioral treatments that focus on pain-coping skills may augment pain management abilities, subsequently reducing drinking to cope with pain (Moskal et al., 2018). Together, these pain hyperkatifeia interactions may explain why alcohol misuse is so prominent in chronic pain patients and point to a focus on treatments that alleviate both physical and emotional pain that may be useful for treating AUD.

The physiological construct of allostasis, defined as “stability through change,” was introduced by the neurobiologist Peter Sterling and epidemiologist James Eyer to explain the basis of vulnerability in human mortality and pathophysiology (Sterling and Eyer, 1988). Allostasis is the process by which a state of internal, physiological equilibrium is maintained by an organism in response to actual or perceived environmental and psychological stressors. Originally, allostasis was described in the context of a change in physiological parameters, such as higher blood pressure that is associated with chronic stress, where one attempts to return to homeostasis. Allostasis refers to the continuous readjustment of such parameters toward new set points (Sterling and Eyer, 1988). However, when an organism is repeatedly challenged, the ability to return to homeostasis may not be achieved, and the organism settles on a state of chronic deviation of the regulatory system from its normal (homeostatic) operating level (Koob and Le Moal, 2001). Allostatic load is the cost to the brain and body of the deviation from homeostasis that accumulates over time, reflecting in many cases pathological states and the accumulation of damage (McEwen et al., 1998). In this framework, the allostatic state reflects allostatic load and can be considered an intermediate stage in the allostatic process (Koob and Le Moal, 2001), which may reflect ways a disease state can progressively lead to a psychiatric disorder (Koob and Le Moal, 2001; Koob and Shulkin, 2019).

In the context of addiction, an allostatic change in emotional state has been associated with the transition to addiction, reflecting a shift in underlying motivational mechanisms and the progression of addiction over time. From initial, positive-reinforcing, pleasurable effects of the drug, the addictive process progresses to a point at which drug (alcohol) seeking is ultimately maintained by negative-reinforcing relief from a negative emotional state. Our argument is that the intersection of hyperalgesia and hyperkatifeia manifests, and they together contribute significantly to the pathophysiology of addiction, invoking many of the parameters of the CANUE model that is illustrated above. Understanding the neurobiological basis of this interaction remains a challenge for the treatment of chronic pain and alcohol addiction.

Limitations and challenges

The limitations of this review center around issues about the heterogeneity and standardization of pain assessment tools and a general lack of assessments for measuring hyperkatifeia in humans. Although beyond the scope of this review, a few salient points in the domains of measurement can be gleaned from the literature. First, animal models of hyperalgesia for alcohol and opioids have largely settled on thermal and mechanical hypersensitivity with significant replication across different laboratories (Edwards et al., 2020: Hastings et al., 2023). Second, many of the mechanistic and conceptual interpretations at the preclinical level that are discussed in the present review are consistent with results from opioid withdrawal-induced hyperalgesia (Park et al., 2013; Marchette et al., 2021). Similarly, in the limited human studies to date on the interaction of hyperalgesia and negative mood, conclusions of negative emotional states that exacerbate hyperalgesia are also true and even more dramatic for opioid addiction (Carcoba et al., 2011). Admittedly, measures of hyperkatifeia in both animals and humans are limited. The hyperkatifeia construct was introduced in 2011 and only became more widely used beginning in 2020 (Koob et al., 2020).

Challenges remain to advance the field in understanding the key role of pain, both physical and emotional, in addiction. For example, as elegantly outlined by De Aquino and colleagues, one area that needs attention includes the development of better human laboratory models to systematically investigate alcohol–pain (both physical and emotional) interactions (De Aquino et al., 2024). Another challenge that is outlined by De Aquino et al. is the need for standardized pain assessment tools and data collection methods for both preclinical and clinical studies that include brief measures and measures of affective components of pain (De Aquino et al, 2024). Notably, recent studies have begun to address this challenge (Hall et al., 2024; Hall et al., 2025). For example, in preclinical work, there are models that incorporate a non-reflex-based method to measure pain avoidance-like behavior in rats in the context of hyperalgesia (Pahng and Edwards, 2018), and recent work has begun to address the paucity of measures of hyperkatifeia with the publication of the Withdrawal Interference Scale, which measures the impact of withdrawal on daily life (Hall et al., 2025). The Withdrawal Interference Scale presents structural validity, convergent validity, construct validity, internal consistency, and composite reliability (Hall et al., 2025).

Finally, strategies are needed to translate laboratory findings to real-world clinical outcomes, to have these phenotypes to inform clinical trial designs, and to use such phenotypes to inform precision medicine approaches. In this latter domain, a whole series of studies have demonstrated, using the Addiction Neuroclinical Assessment framework, that negative emotional states that are associated with the withdrawal/negative affect stage predict more relapse, heavier drinking, and poorer recovery (Kwako et al., 2016; Witkiewitz et al., 2023).

However, more importantly, a major goal remains, namely to convince the field that negative reinforcement is a critical part of the motivation for compulsive alcohol use. This review has taken a major step to show that hyperalgesia and hyperkatifeia are major driving forces in alcohol research that set up the self-medication of alcohol that has its roots in both physical and emotional pain, the neurobiological basis of which involves crosstalk between neurobiological circuits that mediate hyperalgesia and hyperkatifeia.