Alcohol dependence as a chronic pain disorder

Abstract

Dysregulation of pain neurocircuitry and neurochemistry has been increasingly recognized as playing a critical role in a diverse spectrum of diseases including migraine, fibromyalgia, depression, and PTSD. Evidence presented here supports the hypothesis that alcohol dependence is among the pathologies arising from aberrant neurobiological substrates of pain. In this review, we explore the possible influence of alcohol analgesia and hyperalgesia in promoting alcohol misuse and dependence. We examine evidence that neuroanatomical sites involved in the negative emotional states of alcohol dependence also play an important role in pain transmission and may be functionally altered under chronic pain conditions. We also consider possible genetic links between pain transmission and alcohol dependence. We propose an allostatic load model in which episodes of alcohol intoxication and withdrawal, traumatic stressors, and injury are each capable of dysregulating an overlapping set of neural substrates to engender sensory and affective pain states that are integral to alcohol dependence and comorbid conditions such as anxiety, depression, and chronic pain.

Fig. 1

Intersection of neural substrates mediating nociception and alcohol dependence. (A) Ascending pathways mediating the supraspinal processing of pain. Blue structures are involved in the “fast” processing of pain via the spinothalamic tract and arrive indirectly at the amygdala. Pink structures are involved in the “fast” processing of pain via the spinoparabrachial-amygdala pathway that arrives directly at the amygdala. Yellow structures are involved in the “slower” cognitive/affective processing of pain. (B) Pathways for the supraspinal processing of pain superimposed on key elements of addiction circuitry implicated in negative emotional states. Addiction circuitry is composed of structures involved in the three stages of the addiction cycle: binge/intoxication (ventral striatum, dorsal striatum, and thalamus), withdrawal/negative affect (ventral striatum, bed nucleus of the stria terminalis, central nucleus of the amygdala; red structures), preoccupation/anticipation (prefrontal cortex, orbitofrontal cortex, and hippocampus). Note the significant neuroanatomical intersection of the supraspinal regulation of pain and addiction in the amygdala. (C) Regions involved in the preoccupation/anticipation stage of addiction (green) are accessed by ascending pain circuitry, and this interaction may promote compulsive alcohol seeking under conditions of acute or chronic pain. ACC, anterior cingulate cortex; AMG, amygdala; BNST, bed nucleus of the stria terminalis; DRG, dorsal root ganglion; DS, dorsal striatum; GP, globus pallidus; Hippo, hippocampus; Hyp, hypothalamus; Insula, insular cortex; OFC, orbitofrontal cortex; PAG, periaqueductal grey; PB, parabrachial nucleus; PFC, prefrontal cortex; PPC, posterior parietal cortex; S1, S2, somatosensory cortex; SMA, supplementary motor area; Thal, thalamus; VS, ventral striatum. Modified with permission from Blackburn-Munro and Blackburn-Munro (2003),Koob et al. (2008), and Shurman et al. (2010).

Fig. 2

Schematic diagram describing the hypothesized role of chronic pain in facilitating alcohol dependence. Although alcohol consumption produces analgesia, excessive use promotes hyperalgesia that may represent a negative and pathological emotional state associated with dependence. In turn, we propose that negative emotional states associated with drug withdrawal and protracted abstinence can also exacerbate dysregulated nociception. Hyperalgesia (increased sensitivity to pain) caused by protracted and excessive alcohol intake could therefore be closely associated with the parallel development of hyperkatifeia (increased sensitivity to negative emotions; Shurman et al., 2010).

Fig. 3

A model of how alcohol intoxication and withdrawal, trauma (stress) and injury transition to the corresponding disease states of alcohol dependence, anxiety disorders/depression, and chronic pain through actions upon an overlapping set of neural circuits (symbolized by the outer oval). Under normal, homeostatic conditions (symbolized by the upper inner oval), alcohol intoxication produces emotional and sensory pain though a compensatory opponent response (i.e., withdrawal) to an initial rewarding and analgesic action. Emotional and sensory pain comprise the initial response to trauma and injury that may be followed by a compensatory analgesic/euphoric response when terminated. When the initiating condition is not resolved (i.e., chronic alcohol intoxication and withdrawal, untreated injury) homeostasis can no longer be sustained. Neural circuits become dysregulated (indicated by the dashed arrow) resulting in an allostatic state (symbolized by the lower inner oval) characterized by persistent hyperkatifeia and hyperalgesia. According to the model, chronic alcohol intoxication and withdrawal increases allostatic load and results in hyperkatifeia and hyperalgesia. Vulnerability to develop chronic pain disorders following intense and/or untreated injury is increased because the ability to restore physiologic stability is compromised by dysregulated neural circuits. Similarly, the model predicts that intense and/or untreated injury increases allostatic load through similar neural mechanisms enhancing vulnerability to alcohol dependence by affecting relevant alcohol actions upon dysregulated neural circuits. As illustrated in the model, intense and unresolved trauma is also predicted to contribute to allostatic load in this system to influence vulnerability to chronic pain disorders and alcohol dependence. The model also acknowledges the role of genetic influences, such as those discussed previously, on the initial homeostatic responses, as well as the parameters involved in the development of allostatic load.