Review
Alcohol dependence as a chronic pain disorder

https://doi.org/10.1016/j.neubiorev.2012.07.010Get rights and content

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.

Highlights

► We discuss role of pain in promoting alcohol misuse and dependence. ► Sites involved in alcohol dependence and in pain transmission are discussed. ► We propose a model to explain pain states related to alcoholism and other conditions.

Introduction

Chronic pain affects an estimated 116 million American adults and costs the nation up to $635 billion each year (Committee on Advancing Pain Research, Care, and Education; Institute of Medicine, 2011). Approximately 18 million Americans suffer from alcohol abuse or dependence, contributing to 100,000 deaths and $185 billion in costs annually (Grant et al., 2004a). Although the relationship between pain and opiate misuse has been extensively studied, considerably less attention has been devoted to the study of pain and alcohol use despite evidence that alcohol ingestion can acutely reduce pain. In addition, associations between chronic pain conditions and alcohol problems have been reported with episodes of alcohol abuse antedating chronic pain in some people and alcohol dependence emerging after the onset of chronic pain in others (Katon et al., 1985). In light of the great public health impact of both alcohol dependence and chronic pain, a mechanistic understanding of this relationship is important for preventing and treating both problems.

In addition to the well-established acute alcohol actions (reward, stimulation, and impairment) and withdrawal effects (CNS/ANS hyperexcitability, anxiety, sleep disturbances, and dysphoria) that contribute to excessive drinking and relapse, alcohol produces analgesia followed by hyperalgesia after withdrawal (Gatch, 2009). We hypothesize here that pain sensitivity, analgesic actions of alcohol and withdrawal-induced hyperalgesia also contribute to alcohol misuse and alcohol addiction. This hypothesis is supported by observations that problem drinkers are more likely to report pain conditions and heightened sensitivity to painful stimulation than the general population. Alcohol dependence also was found to be a major predictor of pain severity following serious injury (Castillo et al., 2006, Holmes et al., 2010). Other studies suggest that people who do not have drinking problems, but have a positive family history of alcoholism (FHP), are more sensitive to painful stimulation than those having no family history of alcoholism (FHN; Stewart et al., 1995). Likewise, people with chronic pain conditions are more likely to have family members with drinking problems (Goldberg et al., 1999, Katon et al., 1985). Another facet of this relationship is revealed in studies showing that people experiencing chronic pain turn to alcohol presumably for relief (e.g., Brennan et al., 2005, Riley and King, 2009).

An important aspect of the pain–alcohol link rests on neural substrates of alcohol reinforcement and dependence which are also observed to influence critical pain transmission and perception functions. In this review, we discuss neuroreceptor systems that may play a dual role in alcohol reinforcement and pain transmission and the implications this has for imparting genetic vulnerability to develop pain-related problems in addition to compulsive alcohol seeking. We also extend previous thinking in which alcohol dependence and addiction are thought to arise when brain reward and extrahypothalamic stress systems, including the central nucleus of the amygdala (CeA), are dysregulated by chronic alcohol intoxication and withdrawal cycles such that there is a progressive and enduring shift away from a homeostatic reward set point seemingly maintained in recreational drinkers (Edwards and Koob, 2010, Koob and Le Moal, 2001). The dysregulated reward and stress systems result in the emergence of allostasis-like negative emotional states during abstinence periods. According to this view, alcohol is consumed in ever increasing amounts to alleviate negative motivational symptoms arising in the absence of alcohol. Below we suggest affective as well as sensory dimensions of pain should be considered as part of the abstinence syndrome contributing to alcohol use. In addition, we propose a model in which pain-related affective and sensory dysregulation associated with functional changes in an overlapping set of neurocircuitry occurs in response to repeated episodes of alcohol intoxication and withdrawal, unresolved chronic pain, stress and other insults. The hypothesized model helps explain the relationship between pain symptoms and alcohol use, as well as comorbidity between alcohol dependence, anxiety disorders, and chronic pain. A mechanistic understanding of how these core circuits are dysregulated by diverse insults will promote strategies for preventing and treating a spectrum of debilitating pain-associated disorders.

Section snippets

Alcohol analgesia

Alcohol dose-dependently produces analgesia in humans and animals and the possibility that analgesia may contribute to alcohol use is supported by reports that as many as 25% of people experiencing pain self-medicate with alcohol (e.g., Riley and King, 2009). Pseudoaddiction describes an addictive-like seeking of analgesic drugs by people experiencing chronic pain in an effort to alleviate undertreated pain (Weissman and Haddox, 1989). Although pseudoaddiction is primarily associated with

Chronic pain and neural substrates of alcohol addiction

The many brain regions contributing to pain reflect the pain's adaptive function in transmitting actual or potentially harmful stimulation and the recruitment of cognitive, affective and motivated behavior necessary to respond to such stimuli. By implication, functional changes in pain pathways could also influence other functions supported by non-primary pain systems as indicated by higher incidences of depression and anxiety in people with chronic pain disorders (Fröhlich et al., 2006,

Neural dysregulation, alcohol dependence and chronic pain

The transition from recreational alcohol use to alcohol dependence has been hypothesized to arise when brain reward and stress systems are dysregulated by chronic alcohol intoxication and withdrawal episodes (Koob and Le Moal, 2001, Edwards and Koob, 2010). This dysregulation engenders persistent negative emotional states and hypersensitivity to emotional distress when alcohol use is discontinued (Edwards and Koob, 2010). The transition to alcohol dependence involves a recruitment and/or

Genetic influences on pain, alcohol analgesia and alcohol dependence

Pain sensitivity and alcohol analgesia are enhanced in alcohol dependent patients and FHP individuals and may also be altered in animal models of genetic vulnerability for alcohol dependence. In one study, alcohol administration enhanced tolerance for a painful electric shock only in FHN subjects (Perrino et al., 2008) whereas a more comprehensive study (Ralevski et al., 2010) found that FHP subjects scoring high for neuroticism displayed greater alcohol analgesia than FHN subjects and FHP

Allostatic load, chronic emotional pain, and alcohol dependence

The brain and body respond to events such as alcohol intoxication, stress, and injury by activating neuronal and hormonal responses to promote physiological stability in the face of a changed set point (allostasis). When these events are frequent or severe, as with chronic excessive alcohol intoxication and withdrawal episodes, the stabilizing responses become dysregulated (allostatic load) as result of structural and functional changes in the brain to engender an enduring pathophysiological

Further considerations

The proposed allostatic emotional state model is supported by observations that pain transmission and emotional aspects of alcohol dependence involve overlapping neurocircuitry and that alcohol dependent and FHP individuals are more sensitive to painful stimulation. It is also consistent with observed affective disorders associated with alcohol dependence and pain disorders, use of alcohol to cope with pain (Brennan et al., 2005, Sheu et al., 2008), affective pain experience as a significant

Remaining questions

Our model raises additional questions centered on three fundamental issues: (1) What is the spectrum of sensory and affective pain responses associated with alcohol dependence, stress-related affective disorders, and chronic pain disorders? (2) What functional neuroanatomical and neurochemical changes of circuitry are mutually affected by alcohol intoxication and withdrawal, trauma and other stressors, and injury and other insults leading to hyperalgesia and hyperkatifeia; (3) What are the

Acknowledgements

Preparation of this review was partially supported by funds from the National Institute on Alcohol Abuse and Alcoholism (AA008459, AA012602, AA006420, AA007456, and AA020608, GFK), a National Research Service Award (AA018250, SE), and by the Pearson Center for Alcoholism and Addiction Research at The Scripps Research Institute. We also thank Janet Hightower and Mike Arends for graphic and editorial assistance. This is article number 21689 from The Scripps Research Institute. The authors declare

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