For example, Gatch and Lal 46 showed that alcohol administered to rats acutely (i.p.) induces hypoalgesia (dose-dependently) and when given chronically in a liquid diet. Although the hypoalgesic effect of chronic alcohol shows tolerance, withdrawal of alcohol induces hyperalgesia that is reversed by re-administration of alcohol. Withdrawal-induced hyperalgesia and mechanical allodynia is also seen when alcohol is given as a chronic intermittent ethanol vapor although the effects are moderated by several factors including amount of alcohol exposure and sex 47–49. Protocols using intermittent chronic alcohol exposure in rodents have been used successfully as reliable and valid animal models of drug and alcohol dependence. Preclinical studies on chronic pain and AUD provide new insight into the reciprocal influences between the common morbidity of pain and alcohol dependence and potential treatment strategies 45. Gatch and Lal (1999) performed a seminal set of studies describing the anti-hyperalgesic effects of alcohol in the context of alcohol withdrawal-induced hyperalgesia.
Health risks of alcohol use
The analgesic effects of alcohol on pain perception have been measured in a variety of ways, including examining pain threshold, tolerance, and pain ratings (e.g., intensity). Regarding ratings of discomfort versus intensity of pain, alcohol alleviates discomfort at lower doses and to a greater extent than intensity, suggesting the effect of alcohol may vary across components of pain. In addition, pain is influenced by alcohol dose and blood alcohol concentration (BAC), with the magnitude of the analgesic effects increasing at higher BACs (Cutter et al., 1976; Gustafson & Kallmen, 1988; Horn-Hofmann et al., 2015; Stewart, Finn, & Pihl, 1995; Thompson, Oram, Correll, Tsermentseli, & Stubbs, 2017). Studies also have shown that alcohol has less of an impact on pain as the BAC drops, due to metabolism, excretion, or evaporation (Duarte, McNeill, Drummond, & Tiplady, 2008; Horn-Hofmann et al., 2015; Zacny, Camarillo, Sadeghi, & Black, 1998). As a multifaceted experience that is not exclusively driven by the noxious input, pain involves much more than sensory activities.
Notably, recent studies have highlighted a primary link to activity in prefrontal cortex (Seminowicz & Moayedi, 2017) and to prefrontal volumetric differences in response to cognitive behavioral therapy in patients with chronic pain (Seminowicz et al., 2013). Finally, as mentioned above the motivational and affective components of pain have started to be more thoroughly investigated in rodent models. To escape from this environment, the rodent needs to run across probes of varying heights to reach a dark, less aversive compartment. The latency to exit onto the nociceptive probes is used as index of pain avoidance-like behavior, which is expected to be longer in animals in a pain-like state. 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.
Alcohol May Speed Alzheimer’s Progress in the Brain
It should be noted that this model does not rule out or ignore the role of biological factors in the development of chronic pain, but instead emphasizes the significance of reinforcement and learning in the development and maintenance of chronic pain (Gatzounis, Schrooten, Crombez, & Vlaeyen, 2012). For instance, it is likely that dopamine release in the mesocorticolimbic dopamine system (precipitated by consuming alcohol) is responsible for relief from acute pain. In turn, relief from acute pain can be a positive reinforcing factor for maintenance of the pain state as it will lead to reward (alcohol intake and resulting dopamine release), with the alcohol itself acting then as a negative reinforcing factor. The onset of chronic pain may precede memory problems, and chronic pain has been shown to increase the risk of dementia in older adults (Whitlock et al., 2017). Unfortunately, the assessment of pain in patients who already have been diagnosed with varying types or combinations of types of dementia and amnesia, is especially challenging, and therefore, research and clinical treatment with these populations has been limited and inadequate (Buffum, Hutt, Chang, Craine, & Snow, 2007). Compared to healthy controls, individuals suffering from chronic back pain or complex regional pain syndrome have a smaller hippocampus, a brain structure that is involved in memory formation and consolidation (Mutso et al., 2012).
Alcohol affects immune responses
Behavioral intervention approaches developed specifically for comorbid AUD and chronic pain are also lacking. However, there is promising preliminary data to support the efficacy of cognitive-behavioral treatment (CBT) for comorbid pain and substance use disorders (Barry et al., 2019, Morasco et al., 2016), although CBT has been shown to be modestly effective for AUD (Magill and Ray, 2009). Mindfulness- and acceptance-based interventions are effective for pain (McCracken and Vowles, 2014) and AUD (Bowen et al., 2014), and may be effective for the treatment of comorbid pain and AUD, particularly given recent evidence of effectiveness in the treatment of comorbid pain and OUD (Garland et al., 2014). Given the chronic and enduring nature of chronic pain, an acceptance-based approach that improves functioning and is less concerned with pain relief may be particularly important for individuals who have a history of using alcohol for pain relief.
- Decades ago, large surveys of adults began showing an association between how much alcohol someone drank and their risk of death.
- Yet, to our knowledge, no studies have examined the neural circuitry of chronic pain and AUD in human clinical samples and we could only identify two studies that examined neural correlates of substance use among chronic pain patients (Boissoneault et al., 2017, Petre et al., 2015).
- Approximately one in ten U.S. children grow up in a home with at least one parent who is addicted to alcohol, a fact that dramatically affects the child’s home life and general well-being.
- Research suggests that alcohol has a pain-dampening effect and can relieve hyperalgesia — increased sensitivity to pain — even at nonintoxicating doses.
Emerging Studies on Neuroadaptations and Neural Circuitry in Humans
Characterization of the interrelatedness of alcoholism and pain allows for early detection and treatment of patients at risk for developing chronic pain conditions, and for preemptive interventional approaches to reduce the risk of consequent alcohol abuse. As noted above, there have been few clinical studies examining chronic pain and AUD populations, and more work is needed to explore this comorbidity in human samples. Given the available preclinical and clinical models of pain and alcohol use, there is great potential to bridge bench to bedside in informing future treatment strategies and new research directions for understanding the comorbidity of chronic pain and AUD. In this section we review approaches to studying pain and alcohol use in humans and have attempted to align, when possible, with the preclinical approaches, described above.
Future Directions for Research and Treatment of Comorbid Chronic Pain and AUD
- Twin studies and studies of the offspring of individuals with AUD have shown that family history of AUD mediates the risk of AUD.
- Interestingly, chemogenetic inactivation of the ACC reduced hyperalgesia symptoms in both alcohol-exposed mice and their bystander partners (Smith et al., 2017).
- The neurotransmitters involved in excitatory interactions include glutamate and substance P, while inhibitory neurotransmitters include GABA.
- Twin studies indicate that up to half of the variability in both AUD and chronic pain may be explained by genetic factors, indicating a large genetic component for both conditions.
Evidence of opioid-induced hyperalgesia after chronic exposure to opioids is well established in preclinical studies how alcohol consumption contributes to chronic pain and is observed in clinical populations particularly individuals with opioid use disorder 124, 142. Chronic alcohol consumption results in neural alterations that are also seen in chronic pain—a decrease in inhibitory GABA activity along with hyperglutamatergic activity 109, 143, 144. Stimulation of endogenous cannabinoid systems represents another emerging area of analgesic development, along with some very promising preliminary studies. As one example, systemic CB2 receptor stimulation alleviates hyperalgesia symptoms in an animal model of chronic pancreatitis pain induced by an alcohol/high fat diet (Zhang et al., 2014). Because CB2 receptors are predominantly distributed outside of the central nervous system, targeting these receptors may produce fewer undesireable psychotropic side effects.
To adapt to these new persistent environmental demands allostatic processes are engaged that predict the optimal physiological parameters needed to achieve stability 105. Thus, unlike homeostasis which maintains optimal parameters within steady state “normal” levels, allostasis is a dynamic whole-body process involving the prediction of optimal levels of functioning based on anticipated demand from changing environmental variables. Although allostasis reflects efficient physiological regulation, current allostatic models of disease conceptualize the gradual life-time buildup of “wear and tear” of the body (or allostatic load) as causing the overactivation or dysregulation of allostatic systems that mediate the effects of chronic stress on disease and mental health 105, 106. This concept of maladaptive allostasis in brain stress systems have also been advocated to explain addiction and possibly chronic pain. Finally, management of chronic pain in AUD patients cannot be optimized without considering the reciprocal risks and benefits of the treatment choices on exacerbating drinking patterns or increasing the risk of relapse. Opioids in particular may not be appropriate for managing pain in individuals with AUD, as they probably engage the same brain reward pathways as in AUD.
But acetaldehyde and alcohol’s other metabolic effects also impact the liver, where it contributes to inflammation and fatty liver disease, and the brain, where it disrupts signaling related to mood, memory and decision making. “In the past 10 years or so, in my practice, I’ve added alcohol to the list of substances I recommend my patients either reduce or eliminate from their diet,” said Randall Stafford, MD, PhD, a professor of medicine and director of the Program on Prevention Outcomes and Practices. More than 13,000 Americans are killed in alcohol-related automobile accidents yearly, many of whom are not drinking but are hit by drunk drivers. Even when not fatal, alcohol use severely affects the health and vitality of those who consume it excessively.
In another study, Dina et al. (2008) reported that adrenal medullectomy or the blockade of β2-adrenergic receptors on nociceptors in male Sprague-Dawley rats that were subjected to an intermittent alcohol liquid diet procedure (4 days on the diet and 3 days off the diet) prevented/reversed alcohol withdrawal-induced hyperalgesia. Β-adrenergic receptor antagonism was shown to decrease alcohol self-administration in alcohol vapor-exposed dependent rats (Gilpin et al., 2010). In addition to participation of the sympatho-adrenal axis, daily systemic administration of the glucocorticoid receptor antagonist mifepristone (30 mg/kg) blocked the development of alcohol withdrawal-induced mechanical hyperalgesia. Once hyperalgesia had already been established, repeated, systemic injections of mifepristone and an acute intradermal injection of mifepristone reversed alcohol withdrawal-induced hyperalgesia (Dina et al., 2008). Chronic mifepristone administration was also shown to block the escalation of alcohol drinking in rats that were exposed to alcohol vapor (Vendruscolo et al., 2012). Moreover, acute mifepristone administration reversed the escalation of alcohol drinking in dependent rats (alcohol vapor), without affecting alcohol drinking in nondependent rats (Vendruscolo et al., 2015).
Endocannabinoid signaling might reduce pain-like symptoms due to their stress-buffering capacities (Morena et al., 2016) or via anti-inflammatory actions (Katz et al., 2015). Targeting systemic inflammatory processes via endocannabinoid signaling or other processes would appear to be a highly valuable strategy, although sex differences may need to be more closely investigated. For example, the tetracycline derivative tigecycline was found efficacious in reducing mechanical and thermal hyperalgesia in binge-drinking male mice, although this treatment actually increased pain-like sensitivity in females (Bergeson et al., 2016). Although the precise mechanism of tigecycline is still debatable (Oliveros and Choi, 2017), these findings highlight vital importance of investigating sex as a factor in all pain studies, especially given the fact that females are disproportionately affected across most pain syndromes.
Despite this challenge, there are a number of validated for assessments of pain intensity and for evaluating multiple dimensions of the pain experience, as well as overall functioning, that rely on subjective perceptions of pain apart from physiologic or neurologic measurements (Younger et al., 2009). Alcohol Use Disorder and pain are complex conditions having multiple additional etiological impacts reviewed elsewhere (Oscar-Berman et al., 2014; Zale et al., 2015). While ALDH2 is the most common inherited variation to affect how well someone can handle alcohol — and its’ long-term risks — it is not the only factor. Some people are already at higher risk of chronic diseases like diabetes and heart disease because of their genetics or other risky behaviors like tobacco use. Even in people who are not struggling with alcohol use disorder, drinking alcohol can affect other psychiatric conditions. Alcohol consumption also changes how the brain processes pain signals and how immune system activation occurs, both of which can lead to more sensations of physical pain.
This phenomenon was further strengthened by alcohol (1.5 g/kg), although the non-contingent nature of alcohol administration may limit the applicability of findings. These data complement a series of investigations in drinking animals suggesting that alcohol withdrawal-induced hyperalgesia may also be transmitted to conspecifics (Smith et al., 2016; Walcott et al., 2018). Indeed, the social transfer of hyperalgesia may represent an adaptive biobehavioral process to facilitate the communication of dangers within a group of animals.