Experimental human studies on placebo hypoalgesia and expectation effects show that the descending modulation of pain pathways are mediated primarily through endogenous opioids and dopaminergic signaling mediating negatively reinforcing pain relief or expectations of pain persistence, for example 154–156. Approximately 15 million Americans suffer from alcohol abuse or dependence (National Survey on Drug Use and Health 2015 (“National survey on drug use and health – SAMHSA,” 2015), and an estimated 116 million American adults suffer from chronic pain (Egli, Koob, & Edwards, 2012; Grant et al., 2004). Bidirectional associations between alcohol use disorder (AUD) and chronic pain syndromes also have been reported (Apkarian, Bushnell, Treede, & Zubieta, 2005; Apkarian et al., 2013; Brennan, Schutte, & Moos, 2005; Egli et al., 2012; Zale, Maisto, & Ditre, 2015). The prevalence of AUD is increased in adult patients suffering from chronic pain conditions, partly due to its analgesic properties (Hoffmann, Olofsson, Salen, & Wickstrom, 1995), which may be heightened among individuals with alcohol dependence (Cutter, Maloof, Kurtz, & Jones, 1976). Egli and colleagues (Egli et al., 2012) have even proposed that alcohol dependence itself may stem from aberrant neurobiological substrates of pain, and have conceptualized alcohol dependence as a chronic pain disorder. Chronic pain produces multiple electrophysiological and molecular neuroadaptations in the CeA, a number of which are lateralized to the right CeA (e.g., Carrasquillo and Gereau, 2008; Ji and Neugebauer, 2009).
The pharmacological blockade of DORs with naltrindole in alcohol-naïve mice produced an allodynic effect, and a low dose of naltrindole that did not produce allodynia per se prolonged the duration of alcohol withdrawal-induced allodynia. These findings provide evidence of the participation of DORs (and α2-adrenergic receptors in the spinal cord) in mediating alcohol withdrawal-induced allodynia. 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).
- 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.
- Richter and Campbell (1940) reported that laboratory rats voluntarily consume alcohol when given access to a bottle of water and a bottle of alcohol, a model that is popularly known as the two-bottle choice test.
- This has resulted in increased opioid-related deaths, with ~60% of drug overdose deaths involving opioids in the USA in 2014 (Rudd et al., 2016).
- The PAG along the caudal rostral axis of the midbrain is the most well-characterized pathway involved in descending pain modulation through its connection with the dorsolateral PFC, rostral ACC, hypothalamus, and ventromedial medulla, and spinal cord 71, 153.
- 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).
Chronic Alcohol Consumption Enhances Plantar Incision-Increased CREB Phosphorylation in the Spinal Cord
Sex differences can be seen in studies on transcriptomic analyses, cytokine regulation of the innate and acquired immune system, and regulation of alcohol intake by astrocytes and microglia (for a detailed review see 41). Research on biological sex-dependent neuroimmune mechanisms is likely to provide insight into the relationship between gender and pain such as why woman have more experiences with perceived acute pain and show greater prevalence of some forms of chronic pain (e.g., fibromyalgia) 42. Moreover, changes during aging in pain sensitivity, chronic pain, and the role of molecular mechanisms including via neuroinflammation is still not well characterized 43. By contrast with limited data in humans, alcohol withdrawal-induced hyperalgesia (increased pain evoked by normally painful stimuli) and allodynia (decrease in threshold so that innocuous stimuli are perceived as painful) have been amply demonstrated in laboratory animals.
Opioids
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. While the idea of abstaining completely may feel daunting, there’s a growing cultural shift toward mindful drinking, or how alcohol consumption contributes to chronic pain not drinking.
Preclinical Findings in Rodent models of Alcohol Dependence and Hyperalgesia
Focusing on the CeA as one potential example, chronic alcohol exposure and withdrawal alters MC4R expression in CeA, and site-specific antagonism of MC4Rs in CeA reverses alcohol withdrawal hyperalgesia (Avegno et al., 2018). This information may be especially impactful because prior work showed that intra-nasal delivery of an MC4R antagonist blocks alcohol withdrawal hyperalgesia (Roltsch-Hellard et al., 2017). 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.
Evidence of Curvilinear Associations between Alcohol Consumption and Pain Conditions
Additionally, alcohol-induced mechanical, thermal and chemical hyperalgesia has been observed in C57Bl/6J male mice at 24 hours of ethanol withdrawal after continuous access to 10% ethanol and water for 6 days (Smith et al., 2016a). 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. One caveat with prolonged exposures to alcohol is that this strategy might also give rise to peripheral neuropathy, also known as alcoholic neuropathy. Bridging the preclinical and clinical models presented in this review, future research on chronic pain and AUD would benefit from in depth study of hypersensitivity and whether individuals with AUD and chronic pain experience analagesia or whether alcohol consumption causes greater hypersensitivity to pain among individuals with AUD and chronic pain. Similarly, the preclinical models examining neurobiological mechanisms of alcohol withdrawal-induced hyperalgesia are critical for informing our targets for alcohol relapse prevention among individuals with AUD and chronic pain during early abstinence from alcohol.
Future Research Directions
- Thus, increased pain in the context of alcohol abstinence and withdrawal may have important clinical implications for the treatment of AUD among persons who experience chronic pain.
- In a recent large study (Alford et al., 2016), the investigators identified 589 adult primary care patients who screened positive for illegal drug use and misuse of prescription medications.
- 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.
- 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.
- Experimenter-controlled or no-choice procedures of alcohol administration have allowed researchers to control the amount of administered alcohol and have documented significant hyperalgesia during acute withdrawal.
In one experimental study, male patients with a history of alcohol dependence undergoing alcohol withdrawal displayed reduced tolerance for noxious thermal stimuli (Jochum et al., 2010), with no change in thermal pain threshold. Despite consistent evidence from the animal literature, and well-documented historical use of alcohol as an anesthetic (e.g., Shealy & Cady, 2002), only a few experimental studies have been conducted among humans to test the causal effects of acute alcohol administration on laboratory pain reactivity. Human laboratory pain models allow researchers to mimic signs and symptoms of painful medical conditions without causing lasting damage. Primary outcomes tend to include pain threshold, which is typically defined by the time (e.g., seconds) or stimulus intensity (e.g., volts) at which participants first report pain, and pain tolerance, which represents the duration of exposure or maximum stimulus intensity that a participant is willing to endure (IASP, 1994). However, important features of AUD can be modeled in rodents (Vendruscolo and Roberts, 2014; Tunstall et al., in press).
For example, one study demonstrated that consuming alcohol decreased pain ratings only among participants who met diagnostic criteria for AUD or endorsed problem drinking (Cutter, Jones, Maloof, & Kurtz, 1979). The authors interpreted these results as indicating that customary levels of drinking may provide optimal pain reduction. It is also possible that participants who were considered problem drinkers may have developed a tolerance to alcohol (e.g., Schuckit et al., 2008), which could explain why a higher dose of alcohol was necessary to achieve analgesic effects in that group. However, individuals with OUD need to be fully detoxified prior to naltrexone treatment and compliance with naltrexone treatment is a major issue.
Experimenter-controlled or no-choice procedures of alcohol administration have allowed researchers to control the amount of administered alcohol and have documented significant hyperalgesia during acute withdrawal. Early studies used liquid diet-based approaches to study alcohol-induced hyperalgesia in rats, where 4–10 days of no-choice exposure to a 6.5% ethanol liquid diet or 72-day exposure to escalating 2–5% ethanol liquid diet resulted in hyperalgesia upon withdrawal (Gatch and Lal, 1999; Dina et al., 2006; Gatch, 2006; Narita et al., 2007b). More recently, mechanical hyperalgesia in rats has also been reported after prolonged alcohol vapor exposure (Edwards et al., 2012; Avegno et al., 2018). Alcohol administered by oral gavage (2 or 3 g/kg over the course of 3 weeks) has been shown to induce mechanical allodynia 24 hours following last alcohol exposure in mice (Alongkronrusmee et al., 2016). The goal of the current review was to integrate evidence derived from relevant psychological, social, and biological empirical literatures to generate testable hypotheses that may inform future research and the development of novel interventions. The current review extends previous work by examining associations between pain and various levels of alcohol consumption (including low-to-moderate levels of drinking), and by identifying psychosocial mechanisms that may underlie these relations.
Whether it’s a glass of red wine with dinner or a celebratory cocktail on the weekend, drinking in moderation has long been considered not only socially acceptable but also perhaps even healthy. 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. They are also more likely to already be living with chronic diseases, and to be taking prescription medications that might interact poorly with alcohol. Because women metabolize alcohol differently than men, and tend to have smaller bodies, the same amount of alcohol can have a stronger effect for them.