Alcohol Use Disorder and Chronic Pain: An Overlooked Epidemic

Although the analgesic utility of alcohol has been well known for millennia, studies of the relationship between chronic pain and AUD in laboratory animals and humans remains in an incipient stage, and few satisfactory approaches are available for managing either of these devastating conditions. Despite the limitations of preclinical models, they have provided important new information about the biological basis of pain, AUD, as well as their interactions. Continued refinement of rodent models and improved insights into how chronic pain interacts with multiple physiological and psychiatric disease processes in humans will be necessary to propel future research discoveries (Figure 1). Motivational/affective components of pain need to be considered in both preclinical and clinical studies to further our understanding of pain, AUD, and their common comorbidity for the development of future treatment strategies.

According to the National Institute on Alcohol Abuse and Alcoholism, as many as 28 percent of people with chronic pain turn to alcohol to alleviate their suffering. The problem is that alcohol is not a long-term pain management solution and comes with many risks when used this way. Acceptance and Commitment Therapy (ACT) and Dialectical Behavior Therapy (DBT) are evidence-based approaches that incorporate mindfulness practices. ACT emphasizes building psychological flexibility and emphasizes values-congruent practices, while DBT emphasizes the development of emotional regulation and distress tolerance skills. These approaches transform our relationship with our thoughts, emotions, and physical sensations, including pain. This can change the quality of our experience in ways that change the subjective experience of pain as well as the suffering precipitated by it.

• Longer exposure strategies, such as 12 weeks of intermittent access to a two-bottle choice (water vs. 20% alcohol) resulted in very robust hyperalgesia, as assessed through thermal or mechanical hyperalgesia/allodynia, as well as other withdrawal symptoms including tail stiffness, decreased ambulation and lower-limb flexion.
• 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).
• Mixing opioids and alcohol can be particularly dangerous since both substances suppress respiration and can cause a person to stop breathing.
• CD1 mice subjected to a peripheral nerve injury consumed more ethanol in a drinking-in-the-dark procedure compared with sham-operated mice, yet cold hyperalgesia and depressive behaviors were not altered by ethanol consumption (Gonzalez-Sepulveda et al., 2016).

OVERLAPPING DYSFUNCTION IN AUD AND PAIN

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.

Prescription opioid misuse has been defined as inappropriate use of opioid medication, including aberrant drug behaviors (e.g., dose escalation, use other than as prescribed; Pergolizzi et al., 2012). Multiple reviews have concluded that a history of substance use disorder, including alcohol, is the strongest predictor of opioid misuse (Turk, Swanson, & Gatchel, 2008), and that excessive alcohol consumption appears to precede the onset of opioid misuse (Pergolizzi et al., 2012). Neuro-immune interaction in defensive action, homeostatic recovery, and maintenance is incompletely understood. For example, a recent study calls attention to our gaps in understanding of neuroimmune processes in the treatment of acute pain and the transition of acute pain to chronic pain. Treatment with steroidal and non-steroidal anti-inflammatory drugs for early musculoskeletal pain conditions have hypoalgesic efficacy, however early anti-inflammatory treatment interfered with a protective effect of acute inflammatory responses against the development of chronic pain in the long-term 26.

Neuronal activation and circuitry implicated in AUD

Female rodents voluntarily consume more alcohol than males in both social and isolated housing (Li and Lumeng, 1984; Middaugh and Kelley, 1999; Yoneyama et al., 2008). Notably, no how alcohol consumption contributes to chronic pain effect of estrous cycle has been observed regardless of strain or drinking paradigm (Priddy et al., 2017). Further investigations are necessary to see if the sex-related differences in withdrawal, negative affect and social support/pressure noted in humans are maintained across species. Evolution of pain’s influence on alcohol use during progression from binge drinking to AUD to alcoholic neuropathy. Following cessation of acute binge drinking, hangover causes pain during the acute withdrawal phase, which can increase time between drinking events.

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 subjects with low neuroticism scores. Studies in rodents selectively bred for differences in alcohol preference also provide partial evidence alcohol preference and pain response covary (Chester et al., 2002; Kampov-Polevoy et al., 1996; but see Kimpel et al., 2003). Given the possibility of a genetic link between pain processing and alcohol dependence, we suggest possible candidates having the potential to influence neurotransmitter systems involved in alcohol dependence and pain. While MOR and DOR have roles in both pain relief and reward, KORs in the mesolimbic reward system contribute to the aversive affective components of drug withdrawal and chronic pain (Walker et al., 2012; Karkhanis et al., 2017). Increases in the endogenous KOR agonist dynorphin lead to decreased dopamine release in regions such as the NAC, resulting in dysphoria and stress (Goldstein et al., 1979; Anderson and Becker, 2017).

MOLECULAR RATIONALE FOR INTERSECTION BETWEEN AUD AND CHRONIC PAIN

Use of this test in animals experiencing drug and alcohol withdrawal might be challenging because withdrawal produces both anxiety- and pain-like behaviors, which are opposite motivational components of this model. However, Pahng and colleagues (2017) revealed increases in pain avoidance-like behavior in opioid-dependent animals under conditions that did not produce differences in anxiety-like behavior in this test. This study also revealed significant, yet modest, correlations in hyperalgesia-like behaviors measured via von Frey versus pain avoidance tests, suggesting that these two measures detect overlapping yet potentially distinct aspects of pain-related behaviors in animals.

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As these factors may confound the study of relations between pain and alcohol, future research would benefit from accounting for these relevant third variables. Future research may also examine other relevant third variables (e.g., comorbid medical conditions, emotional distress) that could further inform our evolving conceptualization of reciprocal relations between pain and alcohol use. Alcohol interacts with various neurotransmitters such as gamma-aminobutyric acid (GABA), glutamate, dopamine, acetylcholine, and serotonin, or their receptors in the central nervous system, particularly within the descending pain modulatory system interfering with the balance between excitatory and inhibitory neurotransmitters (Valenzuela, 1997). For instance, while alcohol consumption initially potentiates GABA, a major inhibitory neurotransmitter, the number of GABA receptors declines with excessive drinking over a long period of time (Davies, 2003; Oscar-Berman & Marinkovic, 2003; Valenzuela, 1997). This also may interfere with efficiency in descending pain inhibition at the midbrain level and precipitate development of chronic pain conditions in which deficiency in descending pain modulatory system is thought to be a central cause (Ossipov et al., 2014). 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).

For decades, studies suggested that moderate alcohol intake could protect the heart, reduce diabetes risk or even help you live longer. Researchers have suggested that motivation to consume alcohol for pain-coping may increase when alternative coping strategies have failed (Lawton & Simpson, 2009). Thus, the availability and effectiveness of strategies for coping with pain may relate to drinking motivation in at least two ways. First, the employment of more adaptive approaches to pain-coping may depend on the degree to which an individual believes that consuming alcohol will sufficiently diminish pain reactivity. That is, drinkers who believe or come to learn that alcohol can provide adequate pain relief may not engage or develop more adaptive coping strategies (e.g., Cooper et al., 1988).

The CeA receives functionally distinct inputs from the pontine parabrachial area (PB, nociceptive information) and basolateral amygdala (BLA, sensory-affective information) that are magnified in chronic pain states (Ikeda et al., 2007; Neugebauer et al., 2003). This plasticity is driven in part by an enhancement of glutamatergic systems, most notably activation of group I metabotropic glutamate receptors (mGluR1/mGluR5; Kolber et al., 2010; Li and Neugebauer, 2004; Neugebauer et al., 2003; Ren and Neugebauer, 2010). Such altered processing may orient the organism’s motivational capacity to act toward alleviating this condition via heightened arousal (Koob et al., 1976) or negative reinforcement mechanisms (Koob and Le Moal, 2008).

• In a study on the relationship between fibromyalgia and familial history of depression and AUD in first-degree relatives (Katz & Kravitz, 1996), patients who had both fibromyalgia and depression also had higher odds of AUD in their first-degree relatives.
• This polysynaptic reflex is activated involuntarily by noxious stimuli applied to a limb causing a protective withdrawal response.
• We outlined studies on interactions between alcohol use and pain using both self-reports and objective experimental measures and discussed potential underlying mechanisms of these interactions.
• This delayed appearance suggests that any motivation to consume alcohol following pain induction to alleviate pain-related changes in affect may not be apparent until at least 2–3 months following pain inducement.
• This will likely sound very familiar to anyone who has experienced chronic pain firsthand or has seen its effects on friends or family members.

Although effects of chronic pain on the pharmacology and neurochemistry of alcohol self-administration have not been reported, several studies have shown that neuropathic pain alters the rewarding and reinforcing effects of opiates in rodent models. For example, spontaneous pain induced by nerve injury reduced morphine’s ability to induce conditioned place preferences (Ozaki et al., 2002, 2004) and suppressed the ability of morphine to lower brain stimulation reward (BSR) thresholds (Ewan and Martin, 2011). Because baseline BSR thresholds were unchanged by nerve injury, changes in heroin effects could not be attributed to general disruption of reward function. In light of alcohol’s effects on opioid systems, examining alcohol self-administration, particularly dose–response functions (see Carnicella et al., 2011) in chronic pain models such as these is warranted.