The chronic intermittent ethanol vapor-two bottle choice (CIE-2BC) mouse model used in this study paves the way for more research in this area. Yet, to our knowledge, it is unclear if alcohol continues to provide analgesic effects among those with chronic pain and AUD, or whether alcohol could increase pain hypersensitivity among those with more severe AUD, as seen in the preclinical models, discussed in the next section. Importantly, few studies in humans have directly studied patients with chronic pain and AUD who did not have other comorbidities (e.g., depression, opioid use disorder). Thus, looking to the refinement and utilization of preclinical models is important for gaining a better understanding of the mechanisms that may underlie the interaction of pain and AUD. However, this practice is frequently counterproductive, as increased consumption to counteract tolerance can lead to serious complications, including hyperalgesia, psychiatric disorders, and significant difficulties in managing both pain and alcohol use disorder (AUD).

Alcohol and Pain: A Translational Review of Preclinical and Clinical Findings to Inform Future Treatment Strategies

A narrative literature review was conducted using PubMed with the terms “alcohol use disorder” and “chronic pain.” English and Portuguese articles from the last 10 years were included, yielding 85 results. Interest in the role of EW in stress, pain, and alcohol consumption increased with the discovery of Un1 neurons 97. Un1 belongs to the CRF neuropeptide superfamily, the principal hypothalamic stress-related neuropeptide, and binds with CRF-1 and CRF-2 receptors to induce G-protein-coupled signaling. The EWcp projects to many sympathetic-innervated targets in the brainstem and spinal cord and has been proposed to function as a central orchestrator of the sympathetic nervous system’s response to stress 97.

Emerging Circuitry & Molecular Signatures of Alcohol Withdrawal Hyperalgesia

For decades, studies suggested that moderate alcohol intake could protect the heart, reduce diabetes risk or even help you live longer. The researchers showed that alcohol consumption itself may be a leading cause of users’ physical pain, even as users turn to alcohol as a means of coping with pain symptoms. For decades, many have thought that alcohol consumption reduces or dulls pain due to the depressant nature of alcohol. However, new findings show that when one drinks regularly and over time, even if they are consuming alcohol “in moderation,” it is more likely that they will become more sensitive to pain, a physiological phenomena that is then exacerbated when they attempt to withdraw from alcohol. In the meantime, while chronic pain should always be evaluated by a medical professional, there are many options for medication/opioid-based treatment, drawing on complementary and alternative approaches. Even some of the non-dependent mice — 40% of non-dependent male mice and 50% of non-dependent female mice — showed allodynia compared to the alcohol-naïve control group.

Rodent Models of Thermal and Mechanical Sensitivity

Furthermore, nociception needs to be viewed more broadly, not simply as the direct initiator of nociceptive-pain and the perception of pain but in a broader context of neuro-immune regulation and possible alcohol-induced dysfunction of homeostasis and allostasis. Older laboratory-based studies have examined analgesic effects of alcohol in humans (Stewart et al., 1995, Brown and Cutter, 1977, Cutter et al., 1979, Cutter et al., 1986) and have generally found that alcohol reduces acute pain (Thompson et al., 2017). Expectancies for pain reduction partially explained the effects in these prior studies (Egli et al., 2012). More recent studies, using placebo-controlled designs have found additional evidence that alcohol produces analgesic effects, which may be moderated by family history of AUD and neuroticism (Ralevski et al., 2010). Yet, these prior studies have focused on acute pain reducing effects and not effects of alcohol on pain sensitization and hyperalgesia, which is more important for understanding the role of alcohol in chronic pain. When how alcohol consumption contributes to chronic pain levels of inflammatory proteins were measured, the researchers discovered that while inflammation pathways were elevated in both dependent and non-dependent mice, specific molecules were only increased in dependent mice.

Molecular aspects of nociception

• Because the NFR is moderately positively correlated with verbal reports of pain this measure is also used as an indicator of nociceptive-pain 14.
• There are no standardized procedures for the alcohol liquid diet across laboratories, and the concentration of alcohol in the diet varies considerably (e.g., 5–35%).
• Family history of AUD also could be a mediating risk factor for comorbid affective disorders in pain patients.
• “There is an urgent need to better understand the two-way street between chronic pain and alcohol dependence,” says senior author Marisa Roberto, PhD, the Schimmel Family Chair of Molecular Medicine, and a professor of neuroscience at Scripps Research.

Interestingly, chemogenetic inactivation of the ACC reduced hyperalgesia symptoms in both alcohol-exposed mice and their bystander partners (Smith et al., 2017). These recent insights demonstrate the preclinical potential to investigate important social components of affective pain that may directly relate to the fundamental reinforcing properties of alcohol in human populations. To study alcohol dependence, a liquid diet protocol was proposed (Lieber and DeCarli, 1982) where animals are given access to a nutritionally balanced diet that contains alcohol as their sole source of calories. There are no standardized procedures for the alcohol liquid diet across laboratories, and the concentration of alcohol in the diet varies considerably (e.g., 5–35%). However, this unique approach results in BALs that are sufficient to induce liver damage, intoxication, tolerance, dependence, and withdrawal (Lee et al., in press; Gilpin et al., 2009). Equally effective in producing alcohol dependence is the chronic, intermittent alcohol vapor exposure model, where animals are typically exposed to alcohol vapor for 14 hours/day (intoxication), followed by 10 hour with vapor off (withdrawal).

• For decades, many have thought that alcohol consumption reduces or dulls pain due to the depressant nature of alcohol.
• Furthermore, chronic mifepristone treatment decreased alcohol drinking in humans with alcohol use disorder (Vendruscolo et al., 2015).
• Un1 belongs to the CRF neuropeptide superfamily, the principal hypothalamic stress-related neuropeptide, and binds with CRF-1 and CRF-2 receptors to induce G-protein-coupled signaling.
• As mainly central rather than peripheral mechanisms are thought to be involved in the chronification of pain, identifying structural and functional differences in the brain in relation to AUD is key to recognizing links between the two conditions.

Levine and colleagues exended these original investigations to investigate mechanism, using male Sprague-Dawley rats given a Lieber-DeCarli alcohol (6.5%) liquid diet for 12 weeks (Dina et al., 2000, 2006, 2008). Alcohol-exposed rats exhibited hyperalgesia for 4–12 weeks in the Randall-Sellito test compared with controls. Alcohol-exposed rats also exhibited mechanical hypersensitivity in the von Frey test and thermal hyperalgesia in the Hargreaves test after 8 weeks of alcohol exposure compared with control rats. Mechanical hypersensitivity in alcohol-exposed rats increased at 5 weeks after the cessation of alcohol, indicating the long-lasting allodynic effects of alcohol withdrawal.

Yet, women with AUD tend to have more severe consequences, particularly medical and psychiatric comorbidities as compared to men (Agabio et al., 2017). There are also racial and ethnic differences in pain perception, assessment, and treatment (Campbell and Edwards, 2012), and racial and ethnic differences in alcohol use, AUD, and treatment (Vaeth et al., 2017, Williams et al., 2016). Intersectionality of sex and racial/ethnic differences have also been examined in chronic pain (Forsythe et al., 2011, Meints et al., 2018) and AUD (Glass et al., 2017, Witbrodt et al., 2014). Yet, to our knowledge, only a few studies have explored sex, race, or the intersection of sex and race in the association between pain and AUD. 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.

In the alcohol-dependent mice, allodynia (in which a harmless stimulus is perceived as painful) developed during alcohol withdrawal, and subsequent alcohol intake significantly decreased pain sensitivity. Separately, about half of the mice that were not dependent on alcohol also showed signs of increased pain sensitivity during withdrawal, but unlike the dependent mice, this pain was not reversed by re-exposure to alcohol. The researchers found increased levels of IBA-1 and CSF-1 in the spinal cord tissue of mice with alcohol withdrawal-related allodynia and mice with alcohol-induced neuropathic pain. Not only does early and protracted abstinence induce a type of pain characteristic of early recovery, but it also has the tendency to exacerbate dysregulated nociception (Egli et al., 2012). In cases where pain among AUD individuals results from a comorbid condition (e.g., cancer, neuralgia, fibromyalgia), abstinence of any duration can reveal the presence and intensity of pain that was previously being masked by the analgesic effects of alcohol. This dynamic can present unique challenges for recovering individuals suffering from acute and/or chronic pain, as well as for the physicians responsible for treating both conditions.

Noninvasive brain stimulation approaches, including transcranial magnetic stimulation and transcranial direct current stimulation, may also be promising tools given evidence of effectiveness for the treatment of pain (Ong et al., 2019) and AUD (Stein et al., 2018). Finally, physical exercise may be beneficial for improving health outcomes and quality of life among both chronic pain patients (Geneen et al., 2017) and individuals with AUD (Hallgren et al., 2017). Unlike preclinical models of pain, it is not ethical to randomly assign individuals to have a chronic pain condition, thus most studies of pain induction in humans are based on acute pain manipulations or provoked sensitization models that are designed to mimic aspects of neuropathic pain. Importantly, human experimental pain models provide a bridge to preclinical pain models and provide the opportunity to evaluate mechanisms of pain severity, pain sensitization, and analgesia. Further, the lack of a chronic pain experimental model is a limitation of clinical research and necessitates that associational studies conducted with chronic pain patients are still critical for gaining insights into chronic pain and comorbid conditions. Models of thermal hyperalgesia are mostly utilized to evaluate inflammatory pain, but animals with neuropathic pain have been shown to exhibit greater sensitivity to thermal stimuli.

The corticotropin-releasing factor type-1 receptor (CRFR1) may be similarly leveraged to modulate specific circuits for reducing pain in individuals with AUD. It remains to be determined whether CRFR1 effects in CeA on hyperalgesia can be attributed to their expression on specific subsets of CeA projection cells. Future work will undoubtedly build on these initial circuit-level findings and also identify roles for new as yet unidentified circuits in alcohol withdrawal hyperalgesia. Maladaptive allostasis in addiction emphasizes the role of emotional states in guiding motivated behavior. It may be positive reinforcement (or reward) due to the pleasant experience of the alcohol consumption (“a buzz”) or the social approval of drinking in the presence of others. Or it may be negative reinforcement as a result of the temporary reduction of an unpleasant experience such as transient relief of physical or psychological pain.

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. Ultimately, clinicians like Stafford and Humphreys said they hope people who decide to drink alcohol do it consciously, armed with knowledge about its risks. Recent research has also shown that adults over the age of 50 or 60 show signs of impairment at lower blood alcohol concentrations than younger people.

A moveable infrared generator is placed below the glass pane, and heat is directed toward the hind paw until the animal retracts the paw. In animals, nociception and nociceptive-pain are assessed and inferred, respectively, using several accepted stimulus-dependent tests (see 8). For humans, the nociceptive flexion reflex (NFR) is a popular objective neurophysiological tool for the assessment of nociception and nociceptive-pain. This polysynaptic reflex is activated involuntarily by noxious stimuli applied to a limb causing a protective withdrawal response.