For example, cough is a nociceptor-driven response that is not typically accompanied with nociceptive-pain 11, 12. Nociceptor activation also plays a role in the protection against muscle injury under normal behavior repertoires by triggering innate motor patterns through spinopallidal circuits independent of the neural circuitry necessary for the cognitive or affective components of pain 13. Because pain has a negative impact on alcohol overconsumption among individuals in treatment for AUD, researchers have investigated whether addressing pain within the context of treatment for alcohol or substance use disorders may be beneficial for drinking outcomes. Among patients receiving pain management cognitive behavioral therapy (CBT), lower pain ratings (Morley et al., 1999) and greater self-efficacy in managing pain, were seen among individuals in treatment for substance use disorders (Ilgen et al., 2011).
Recurrent pain is highly prevalent among treatment seeking problem drinkers (Boissoneault, Lewis, & Nixon, 2018; Sheu et al., 2008), and how alcohol consumption contributes to chronic pain alcoholism is considered a risk factor, both for the development of chronic pain in patients who suffer from AUD, and for relapse in those attempting to remain abstinent. But despite numerous reports on the associations between chronic pain and AUD, the underlying mechanisms involved in linking them remain elusive. AUD may share common neural pathways with chronic pain, which may facilitate pain affecting alcohol use patterns, or facilitate modulatory effects of alcohol on pain processing, thereby precipitating the risk of chronic pain development. It is influenced by a host of familial, biological, environmental, and socioeconomic mediators that affect drinking behavior and susceptibility to pain disorders. Placebo reduction of nociceptive processing at the level of the spinal cord shows the role of cognition in modulating nociceptive-pain at the level of sensory-discrimination dimension 153.
Because the NFR is moderately positively correlated with verbal reports of pain this measure is also used as an indicator of nociceptive-pain 14. However, there are reports of the dissociation between the NFR and nociceptive-pain under clinically relevant (e.g., chronic pain syndromes) and normal situations 15–17. It has also been shown under experimental contexts that stimulus-dependent withdrawal reflexes are influenced by cognitive and emotional factors modulating descending control of spinal circuits 18.
Herein, we begin with a review of the neural bases of pain, and we discuss the influence of alcohol on processes involved in pain perception. We then proceed by proposing some potential mechanisms involved in the development of chronic pain in AUD. 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).
Clinical Models to Investigate the Intersection of AUD and Pain Mechanisms
“This study has uniquely shown that alcohol dependence is not required to worsen pain outcomes and that even moderate drinking can lead to pain pathology, and thus consumption of ethanol is a poor strategy for dealing with pain,” Dr. Nothem told MNT. According to the National Survey on Drug Use and Health, 29.5 million people aged 12 years and older had alcohol use disorder — also known as alcohol abuse, alcohol dependence, or alcohol addiction — in 2021. Alcohol Use Disorder (AUD) and chronic pain are widespread conditions with extensive public health burden. This review seeks to describe neuroanatomical links and major mediating influences between AUD and chronic pain, in the service of identifying factors that predict the risk of chronic pain in precipitating or facilitating AUD. Roberto’s group is continuing studies on how these molecules might be used to diagnose or treat alcohol-related chronic pain conditions.
A prescription for double trouble: how drinking alcohol fuels chronic pain.
Figure 1 shows several of the components of the pain system identified in this review as it relates to Melzack’s conceptualization of the “neuromatrix”. They also found increased levels of IL-6 and activation of ERK44/42 in mice with alcohol withdrawal-related allodynia, but not in mice with alcohol-induced neuropathic pain. Alcohol use disorder (AUD), which encompasses the conditions commonly called alcohol abuse, alcohol dependence and alcohol addiction, affects 29.5 million people in the U.S. according to the 2021 National Survey on Drug Use and Health. Over time, AUD can trigger the development of numerous chronic diseases, including heart disease, stroke, liver disease and some cancers. Additionally, the study sheds light on the pathways involved in alcohol withdrawal-related allodynia and alcohol-induced neuropathic pain. The investigators found that, of the problem drinkers, approximately 43% of men and 44% of women reported experiencing moderate to severe pain, but in nonproblem drinkers, only 28% of men and 33% of women reported that level of pain.
Between 2006 and 2014, the rate of alcohol-related ER visits increased by 47%, an additional 210,000 alcohol-related ER visits. Their aim is to uncover fresh molecular targets that can differentiate between different types of pain and could eventually be employed to create new treatments. Meanwhile, countries including Canada have moved to more cautious recommendations, advising no more than two drinks per week for all adults. With so much data and so many variables, public health recommendations concerning alcohol differ around the world. When newer, larger studies account for these and other variables, the protective effect of alcohol tends to disappear.
Influences of Alcohol on Processes Involved in Pain Perception
It is the latter integrative function that transforms nociceptive information from a basic sensory experience (Melzack’s sensory-discrimination dimension) to a constructed perception that is experienced as pain 66, 72. It is important to note that most of these studies, as with studies on pain and alcohol use and dependence in general, have been conducted with male subjects. More recent evidence, although limited, provide compelling evidence that there are sex differences in neuroimmune signaling and synaptic function as well as the disruptions that occur following chronic alcohol consumption. 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.
Genetic Mechanisms in the Association between Pain and Alcohol Use
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. Behavioral measurement of the differential contributions of somatic versus motivational/affective components of pain may also correspond to distinct neurobiological substrates, and these relationships likely have important ramifications for future therapeutic strategies. Occasional acute physical disturbances or infrequent experiences that may be a potential threat (stressor) result in an adaptive protective response followed by the return to a static but “normal” homeostatic function. Homeostasis makes sense within a physical system that maintains stable features to match an environment that is unchanging notwithstanding irregular and temporary perturbations. However, with the emergence of a chronic environmental stressor or persistent repeated exposures to physical insults the maintenance of a “normal” homeostatic baseline no longer makes sense.
Furthermore, chronic mifepristone treatment decreased alcohol drinking in humans with alcohol use disorder (Vendruscolo et al., 2015). These findings suggest that glucocorticoid receptors play a functional role in dependence-induced pain-like behavior and alcohol drinking. Alcohol can also have robust dose-dependent analgesic properties in healthy human volunteers experiencing experimentally induced nociceptive-pain 50, 51.
Molecular aspects of nociception
The patient began consuming alcohol daily for pain relief, which escalated to an AUD diagnosis and worsened pain due to alcohol-induced hyperalgesia. This study explores the relationship between alcohol use in chronic pain management and the development of AUD through a literature review and a clinical case. Chronic pain is a debilitating condition affecting 20% to 30% of adults globally, with prevalence rates rising to 19% to 38% in Europe. It is often linked to self-medication, particularly through alcohol consumption, due to alcohol’s short-term analgesic properties, which act on the opioid system.
According to an allostatic perspective repeated exposure to alcohol intake (interacting with genetic factors, unique life experiences and psychiatric co-morbidities) can result in maladaptive allostasis leading to pathological states such as alcohol dependence. Koob proposed the psychological construct of hyperkatifeia, an exaggerated negative emotional state (i.e., increased psychological pain and distress) that can occur during periods of alcohol withdrawal to maintain addictive behavior through craving and negative reinforcement 63. This heightened emotional state has a parallel in the pain system in the form of the transition from alcohol-induced analgesia to alcohol-induced hyperalgesia and chronic pain 109. In this narrative review, we aimed to present an overview of the current understanding of the mechanisms of nociception, the sensation of nociceptive-pain, and pain perception to inform and guide research on the contribution of the pain system in alcohol use, misuse, and dependence. Conventional wisdom influenced by the centuries-old Cartesian model of pain views physical hurt as a nociceptive experience that is directly translated into the sensation and perception of pain. However, it has become clear that nociception and pain are closely related but distinct mechanisms of homeostasis in defense against injury and potential injury.
The interrelationship between chronic pain and AUD resides in the intersection of etiological influences, mental experiences, and neurobiological processes. Characterization of the connection between brain and behavioral abnormalities in AUD’s precipitation of chronic pain — and vice versa — allows for early detection and treatment of patients at risk for developing either or both of these conditions, and for preemptive interventional approaches to reduce the risk of consequent vulnerabilities and harm. We propose potential mechanisms involved in the development of chronic pain in AUD, and we consider implications for pain management in recovery from AUD. In dependent mice, allodynia developed during alcohol withdrawal, and subsequent alcohol access significantly decreased pain sensitivity. Separately, about half of the mice that were not dependent on alcohol also showed signs of increased pain sensitivity during alcohol withdrawal but, unlike the dependent mice, this neuropathy was not reversed by re-exposure to alcohol.
- These molecular modulators of nociceptive processing occur at all levels of the pain system including the peripheral nervous system (peripheral nociceptor terminals, dorsal root ganglion) and central nervous system (spinal cord, supraspinal brain circuits) 38.
- More recent evidence, although limited, provide compelling evidence that there are sex differences in neuroimmune signaling and synaptic function as well as the disruptions that occur following chronic alcohol consumption.
- Although experimental nociceptive-pain differs in many ways with clinical pain, there is evidence that the analgesic properties of alcohol may support self-medication behaviors of pain sufferers.
- 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.
In fact, chronic pain and alcohol consumption often combine to create a vicious circle wherein people with chronic pain drink to feel less uncomfortable, but drinking ultimately increases their pain. Pain is a widespread symptom in patients suffering from alcohol dependence and it’s also a reason why people are driven to drink more. Dysfunction in descending pain modulatory circuits is thought to play an important role in the chronification of pain (Ossipov et al., 2014). This circuit, which controls top-down modulation of pain, receives inputs arising from multiple regions in the brain, including the hypothalamus, amygdala, and the rostral anterior cingulate cortex (Figure 2). These regions feed into the rostral ventromedial medulla, which includes the midline nucleus raphe and periaqueductal gray matter that have neural pathways to the spinal dorsal horn. Together, they form the descending pain modulatory system from the brain to the spinal cord and can modulate nociceptive processing by providing a substrate for cortical and subcortical structures to exert their influence.
- It is clear that low or moderate amounts of consumed alcohol also exerts clinically relevant hypoalgesic effects in controlled experimental studies with people and animals 50, 55, 56, 139.
- 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.
- During withdrawal, such somatic symptoms as hyperthermia, anxiogenesis, tremor, and seizures may be observed.
- In fact, chronic pain and alcohol consumption often combine to create a vicious circle wherein people with chronic pain drink to feel less uncomfortable, but drinking ultimately increases their pain.
- 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).
That is, as drug or alcohol use becomes a more frequently relied upon as an efficacious coping strategy, the use can transition to problematic use and addiction. Laboratory experiments also demonstrate the effectiveness of alcohol consumption in reducing experimentally induced stress, although these effects may rely on the influence of prior experience and the type of stressor 134, 135. Preclinical studies demonstrate that rodents will self-medicate with alcohol and some anxiolytics when experiencing aversive emotional states (psychological pain) induced by loss or reduction of expected reward.