Alcohol Use Disorder and Chronic Pain: An Overlooked Epidemic

Abstract

Alcohol use disorder (AUD) and chronic pain disorders are pervasive, multifaceted medical conditions that often co-occur. However, their comorbidity is often overlooked, despite its prevalence and clinical relevance. Individuals with AUD are more likely to experience chronic pain than the general population. Conversely, individuals with chronic pain commonly alleviate their pain with alcohol, which may escalate into AUD. This narrative review discusses the intricate relationship between AUD and chronic pain. Based on the literature available, the authors present a theoretical model explaining the reciprocal relationship between AUD and chronic pain across alcohol intoxication and withdrawal. They propose that the use of alcohol for analgesia rapidly gives way to acute tolerance, triggering the need for higher levels of alcohol consumption. Attempts at abstinence lead to alcohol withdrawal syndrome and hyperalgesia, increasing the risk of relapse. Chronic neurobiological changes lead to preoccupation with pain and cravings for alcohol, further entrenching both conditions. To stimulate research in this area, the authors review methodologies to improve the assessment of pain in AUD studies, including self-report and psychophysical methods. Further, they discuss pharmacotherapies and psychotherapies that may target both conditions, potentially improving both AUD and chronic pain outcomes simultaneously. Finally, the authors emphasize the need to manage both conditions concurrently, and encourage both the scientific community and clinicians to ensure that these intertwined conditions are not overlooked given their clinical significance.

Nearly one in three Americans meets criteria for alcohol use disorder (AUD) during their lifetime (1) and an estimated 29.5 million Americans over the age of 12 met criteria for AUD in the past year (2). Chronic pain, defined as ongoing pain lasting longer than 3 months, also affects approximately one-third of adults in the United States, and frequently co-occurs with AUD (3). Many individuals who do not meet criteria for AUD drink excessively. For example, 21.7% of people age 12 or older report binge drinking in the past month, where binge drinking is defined as having four or more drinks on the same occasion for women and five or more drinks on the same occasion for men, and 5.7% report heavy alcohol use in the past month, defined as binge drinking on five or more days in the past 30 days (2). Taken together, alcohol use and chronic pain pose significant public health challenges and economic burdens. While the link between chronic pain and opioid use disorder has been increasingly studied due to the ongoing opioid epidemic, the relationship between chronic pain and alcohol use has often been overlooked.

As alcohol has analgesic properties, observational data shows that up to 38% of binge drinkers consume alcohol for pain relief (4). Although using alcohol can help individuals cope with physical pain, its analgesic effects are fleeting and subject to tolerance, which can develop shortly after acute consumption (5). Hence, people using alcohol to relieve pain may require increasing amounts to experience the same benefits (6), potentially heightening their risk of developing AUD. Escalating alcohol use, therefore, can be driven by negative reinforcement, when an unpleasant experience (pain) is reduced by the occurrence of a behavior (alcohol drinking) and this increases the frequency of the behavior (6). People with problematic drinking or AUD are more likely to experience moderate to severe or significant recurrent pain (43%–54%) compared to non-problem drinkers or low-risk drinkers (28%–33%) (7, 8). Furthermore, pain intensity among heavy drinkers has been associated with higher levels of alcohol craving (9) and pain interference among those with AUD, and is associated with polysubstance use (10). Yet, effective treatments addressing the intricate relationship between alcohol and pain are presently limited.

In this narrative review, we delve into clinical research on the intersection of AUD and chronic pain. We selected this theme for this special issue due to the stark disparity between its profound clinical relevance and the limited attention it has received. We first examine the interplay between alcohol use and chronic pain, emphasizing the analgesic effect of alcohol during different phases of alcohol intoxication and withdrawal, as well as the underlying neurobiology and mechanisms. To encourage more research, we review pain measurement tools ranging from self-reported measures to lab-based psychophysical methods to enhance pain assessment, particularly in evaluation of treatments for AUD. We then highlight potential dual-action drugs and psychotherapies targeting both AUD and chronic pain, paving the way for innovative therapies to combat this overlooked epidemic.

METHODS

Initially, an unstructured literature search was performed using PubMed, MEDLINE, EMBASE, and ScienceDirect, using terms related to AUD and various pain descriptors. This helped to define terms used subsequently in a structured search which was performed using PubMed and MEDLINE on December 17, 2023 using four search strategies designed to yield studies on the following topics: 1) human laboratory studies investigating the relationship between pain and alcohol consumption; 2) measurement of pain in alcohol use disorder studies; 3) pharmacotherapy for co-occurring alcohol use disorder and chronic pain; and 4) psychotherapy for co-occurring alcohol use disorder and chronic pain. Articles were uploaded to Covidence and duplicate articles were removed. A total of 2,337 unique abstracts were reviewed by a member of the study team. Final determination for article inclusion was made by the first authors (JPD and MES). The online supplement provides a detailed description of the search strategies used.

CLINICAL IMPACT OF AUD AND CHRONIC PAIN: A RECIPROCAL RELATIONSHIP

A few studies have evaluated the interplay between pain and alcohol consumption in the context of treatment for AUD. A secondary analysis of data from two large AUD treatment trials (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence [COMBINE] study and the United Kingdom Alcohol Treatment Trial [UKATT]) found that pain rating at baseline was a predictor of subsequent lapse to heavy drinking, although the effect only remained significant in UKATT but not COMBINE when controlling for covariates such as alcohol dependence severity (11). Higher levels of pain were associated with increased negative affect, and negative affect was a mediator of the association between pain and drinking outcomes (12). Another study investigated this relationship cross-sectionally among 366 alcohol-dependent adults entering abstinence-based inpatient alcohol treatment programs (13). Approximately one-third of the individuals reported moderate to severe pain during the previous 4 weeks, and individuals with moderate to severe pain had greater alcohol use severity, more sleep problems, higher impulsivity, and greater general psychopathology than those with no to mild physical pain (13). A subsequent study in this sample followed patients 12 months after completing the alcohol treatment program. Although baseline pain was not associated with relapse, individuals who reported decreased pain at the 12-month follow-up had an approximately six-fold lower risk of relapse than those with increased or unchanged pain severity (14). Persistent pain has also been associated with higher rates of heavy alcohol use following residential detoxification in individuals whose drug of choice was heroin, alcohol, or cocaine (15). These studies provide clinical evidence that chronic pain is potentially associated with alcohol relapse. Relieving pain through appropriate pain management may curb the motivation to drink following treatment.

Even less is known about how alcohol use might affect the treatment of chronic pain. High levels of pre-injury alcohol consumption increase the risk of chronic pain development following a severe traumatic injury to the lower extremity (16). Similarly, alcohol use is a primary risk factor for the development of chronic pancreatitis (17) and neuropathy (18). Chronic pain in treatment-seeking individuals with AUD is associated with opioid use, depression, and anxiety (8); and higher levels of alcohol use are associated with attenuated central effects of opioids (e.g., reduced pupillary constriction) (19), all of which may affect pain treatment in this population. However, the effects of alcohol consumption on common forms of chronic pain (e.g., low back pain, knee osteoarthritis) and the impact of AUD on pain treatment outcomes remain largely unexplored and warrant further research.

THE NEUROBIOLOGICAL AND CLINICAL OVERLAP BETWEEN ALCOHOL ADDICTION AND CHRONIC PAIN

Addiction has been described as a recurrent three-stage process consisting of binge and intoxication; withdrawal and negative affect; and preoccupation and anticipation (20). This model acknowledges that addiction is not only driven by positive reinforcement due to the hedonic effects of drugs, but also by negative reinforcement to alleviate symptoms of withdrawal and negative affect, as well as by environmental and internal factors that induce craving (21). Each of these three stages has implications for chronic pain, which can drive further alcohol use across the addiction cycle. Below, we examine each stage and its potential interactions with chronic pain.

Alcohol Intoxication, Analgesia, and Acute Tolerance

Acute alcohol intoxication inhibits glutamatergic transmission, increases GABAergic transmission, and induces endogenous opioid release in humans (22), all of which may lead to analgesic effects. During the phase when blood alcohol levels rise (known as the ascending limb), individuals typically experience stimulation and pain relief (5). Conversely, as alcohol levels drop (the descending limb), a reduction of alcohol’s analgesic effects may follow. Supporting these observations, rodent-based preclinical studies have shown that acute alcohol consumption induces increases in pain threshold (analgesia); however, cessation of chronic alcohol intake often leads to a lower pain threshold than baseline (hyperalgesia) (23). In humans, a meta-analysis of experimental studies underscores a dose-response relationship between alcohol intake and attenuation of experimentally-evoked pain: specifically, for every 0.02% increase in breath alcohol concentration (BAC), which is roughly equivalent to one standard drink, there is an amplified analgesic effect for both pain threshold and reduced pain intensity (standardized mean differences of 0.11 and 0.20, respectively) (24). Notably, acute tolerance, defined as a reduced sensitivity to alcohol’s effects within a drinking session, may extend to alcohol’s analgesic effects. In a study by Williams and colleagues, pain threshold, defined as the point at which a heat stimulus first becomes painful, showed evidence of acute tolerance (5). Pain threshold was higher on the ascending limb, indicating greater analgesia at approximately the same BAC compared to the descending limb.

Not only does alcohol consumption affect pain in experimental models, but pain also affects drinking behaviors. Individuals who drink hazardously report greater urge and intention to drink when randomized to experimentally induced pain versus a control condition (25). In individuals who drink socially, men (but not women) drink more rapidly when exposed to painful heat (26). Taken together, these studies show that despite providing initial analgesia, alcohol’s analgesic effects may wane during the descending limb, which may lead individuals with AUD and chronic pain to experience cravings and consume more alcohol to achieve additional pain relief.

Alcohol Withdrawal and Hyperalgesia

Alcohol withdrawal occurs after chronic, persistent heavy alcohol consumption, and is associated with enhanced glutamatergic transmission coupled with reduced GABAergic transmission, both of which may contribute to heightened pain sensitivity. Mice undergoing withdrawal from alcohol experience increased nociception (27). In humans, a cross-sectional study in males employing quantitative sensory testing (QST), a psychophysical technique to reliably assess pain, found that individuals undergoing management of alcohol withdrawal experience altered pain responses, such as lower thermal pain thresholds and tolerances than abstinent individuals with AUD and healthy controls (28). Hence, altered pain responses during alcohol withdrawal, such as hyperalgesia, may increase the risk of relapse, perpetuating symptoms of AUD.

Central Sensitization, Craving, and Preoccupation With Pain

Central sensitization, a phenomenon responsible for the onset and maintenance of chronic pain, refers to the heightened responsiveness of nociceptive neurons in the central nervous system, leading to amplified pain responses even to mildly painful or non-painful stimuli. Chronic pain may change the way the brain responds to pain, leading to activation of distinct neural circuitry (e.g., the medial prefrontal cortex) when compared to acute pain (29). Activation of these brain regions may relate to heightened anticipation of pain, negative emotionality, and intensified pain perception. It is conceivable that this process may be exacerbated by alcohol use (30). As the brain’s reward systems undergo this shift, pain relief and alcohol use are prioritized by the individual. As an example, both AUD and chronic pain sufferers exhibit attentional biases (i.e., automatic cognitive processes) for alcohol and pain cues, respectively (31, 32). Preliminary brain imaging data further suggests that certain aspects of the pain experience in persons with AUD, like pain catastrophizing, are associated with the neural correlates of alcohol craving (33). Craving for alcohol reduces inhibitory control and the ability to resist further drinking (34), leading to heavier alcohol use.

Bridging the Gap: A Framework to Understand Co-Occurring Chronic AUD and Chronic Pain

Taken together, these data suggest that alcohol’s analgesic effects may wane due to acute tolerance, creating the necessity for more alcohol to achieve pain relief. In between episodes of alcohol use, individuals with AUD may experience withdrawal-related hyperalgesia, which further increases the drive to consume alcohol and may heighten relapse risk during attempts at abstinence (Figure 1). Over the long-term, AUD and chronic pain may lead to convergent, kindling neurobiological changes, which sensitize individuals to pain and alcohol cues, increase cravings, and make it harder to inhibit further alcohol consumption. Following repeated cycles of alcohol intoxication and withdrawal, these neuroadaptive changes may influence the activity in ascending nociceptive pathways (bottom-up pain facilitation), and descending inhibitory pathways (top-down pain modulation) that modulate these activities, as well as attention and salience systems that drive maladaptive alcohol use (Figure 2).

FIGURE 1. The cycle of alcohol addiction and chronic pain^a.

^a Acutely, during intoxication, pain threshold is initially elevated, with transient analgesia during the alcohol ascending limb and the eventual development of analgesic tolerance at the descending limb. As withdrawal develops, the pain threshold may lower, potentially intensifying the experience of pain. This, in turn, may lead to an increased preoccupation with alcohol as a means to alleviate pain.

FIGURE 2. Convergent neuroadaptations produced by co-occurring alcohol addiction and chronic pain over time^a.

^a Neuroadaptive changes result from repeated cycles of alcohol intoxication and withdrawal and chronic pain. Individuals with alcohol addiction experience escalating cravings and withdrawal symptoms over time. Concurrently, increased activity occurs in ascending nociceptive pathways that enhance bottom-up pain facilitation while the descending inhibitory pathways responsible for top-down pain modulation are also influenced, potentially disrupting their normal function. Attention and salience system dysfunction may contribute to pain and maladaptive patterns of alcohol use by increasing the salience of alcohol- and pain-related cues and reinforcing the cycle of pain and addiction.

THE IMPORTANCE OF MEASURING PAIN IN PATIENTS WITH AUD

Assessing pain is critical to understanding the relationship between AUD and chronic pain and to providing effective treatment. However, evaluating pain in individuals with AUD can be challenging due to alcohol’s complex time- and dose-dependent analgesic and hyperalgesic effects. For instance, alcohol withdrawal can affect thermal pain thresholds (5), so the timing of pain measurement is important to consider. Standardized assessment tools and data collection methods are needed to enable appropriate comparison and synthesis across studies. A holistic approach to pain assessment, integrating data from multiple disciplines to enhance research and treatment—such as the National Institutes of Health (NIH) Back Pain Consortium and the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Bank data harmonization initiatives—can be crucial to foster consistency across studies (35, 36).

Self-Report Measures

Traditionally, pain has been evaluated using self-report methods. These methods range from pain-specific scales to broader instruments that include pain items. For example, two large AUD clinical trials collected self-report pain data at baseline, and post-hoc analyses examining the association of pain and drinking outcomes were conducted. The COMBINE study assessed pain interference using the 26-item World Health Organization Quality of Life (WHOQOL) assessment and the 12-item Short Form Health Survey (SF-12) (11), and the UKATT assessed pain interference and intensity using items from the European Quality of Life Group EQ-5D and the 36-item Short Form Health Survey (SF-36) (11). In a retrospective study including patients with chronic back pain and over 3 months of disability, Booker and colleagues used the McGill Pain Questionnaire (MPQ), which assesses sensory and affective components of the pain experience; the West Haven-Yale Multidimensional Pain Inventory (MPI), which measures numerous aspects of the pain experience including pain severity, affective distress, pain interference, and significant other support/concern; and the pain Visual Analog Scale (VAS) to assess pain intensity (37). A randomized trial investigating naltrexone versus placebo in women living with HIV with hazardous drinking used a modified version of the Brief Pain Inventory to assess pain in the past week (38). These studies underscore the usefulness of self-report pain assessments in understanding the relationship between pain and alcohol use. Since these measures are also relatively easy to incorporate, there is an urgent need for a broader adoption of self-report pain assessments in both research and clinical settings, given their potential to guide tailored therapeutic strategies. Tools that measure various facets of pain, such as its intensity and functional impact are of particular use and could be adopted more widely.

Psychophysical Measures

For a more reliable and in-depth exploration of pain, particularly in assessing analgesia, hyperalgesia, and pain mechanisms, QST is a highly useful psychophysical technique (39). Growing evidence indicates that QST measures can identify alterations in pain responses in persons with AUD, even in the absence of a chronic pain diagnosis (40, 41). Other studies using QST show a high prevalence of damage induced by alcohol to the peripheral nervous system (42). Vitus and colleagues utilized QST to study alcohol’s analgesic effects in social drinkers with and without chronic jaw pain (43). Participants completed two sessions, one in which they consumed alcohol with a target BAC of 0.08 g/dl and another in which they consumed placebo. During each session, participants’ pain thresholds were determined using pressure algometry. They also rated pain intensity and unpleasantness using a 100mm VAS following removal of the painful stimulus. Participants with chronic jaw pain had lower pain thresholds and reported higher pain intensity than controls. Alcohol consumption was found to increase pain thresholds, reduce pain intensity, and reduce pain unpleasantness regardless of chronic pain status. Another study applied QST to assess how family history of AUD might influence pain modulation (44). Those with a family history of AUD exhibited a pronociceptive response to lab-induced thermal pain compared to those without, indicating evidence of central sensitization. Recently, QST methodologies have played a role in the development of pharmacotherapies for opioid use disorder (45). Their application is poised to offer invaluable insights, especially in detecting early indications of pain-relieving (antinociceptive) effects from AUD medications. Table 1 lists commonly used self-report and psychophysical assessment tools suitable for AUD studies.

TABLE 1.

Overview of self-report and psychophysical measures to assess pain^a

Instrument	Constructs assessed	Advantages
Self-report measures
McGill Pain Questionnaire (MPQ) (37)	Different dimensions of pain: sensory, affective, and evaluative	Designed specifically to assess experience of pain; discriminates between sensory, affective and evaluative dimensions
West-Haven Yale Multidimensional Pain Inventory (37)	Pain severity, pain interference, perceived life control, affective distress, support	Multidimensional; comprehensive assessment of pain impact
Brief Pain Inventory (38)	Pain severity and impact on daily functioning	Multidimensional; assesses functionality impairments
Visual Analog Scale (37)	Pain intensity	Simple and quick to administer; provides continuous, linear measure
PROMIS Pain Instruments (36)	Different dimensions of pain: intensity, inference, behavior	Large item bank allows for tailored assessments
Pain Catastrophizing Scale (9)	Cognitive-affective aspects of pain: rumination, magnification, and helplessness	Brief and easy to administer; designed specifically for pain catastrophizing
SF-36 and SF-12 (11)	Not designed specifically for pain health-related quality of life, including bodily pain severity and impact	Concise; assess physical and mental health
WHOQOL (11)	Specifically design to measure health-related quality-of-life, rather than pain	Comprehensive evaluation of quality of life; includes four specific pain-related questions
Psychophysical and functional measures
Ecological Momentary Assessment	Momentary pain, functioning, behavior	Captures pain fluctuations; can incorporate wearables for objective data
Static QST (42, 43)	Comprehensively evaluates somatosensory function	Measures multimodal pain thresholds and tolerance; applies controlled stimuli to standardize evaluation; provides quantitative measures
Dynamic QST (42, 43)	Assesses both peripheral and central pain modulatory mechanisms	Includes temporal summation and conditioned pain modulation; assesses mechanisms of pain processing
Pedometer	Daily step count, physical activity	Objective measurement of physical activity and pain-related functioning; real-time data

^aPROMIS = Patient-Reported Outcome Measurement Information System; SF-12=12-Item Short Form Health Survey; SF-36=36-Item Short Form Health Survey; QST=Quantitative Sensory Testing; WHOQOL=World Health Organization Quality of Life Scale.

New Horizons in Pain Assessment for AUD Patients

In response to the underdeveloped literature on pain assessment in patients with AUD, there is a clear need to explore more comprehensive and tailored approaches. A tailored tool that efficiently captures the multifaceted nature of pain in AUD, given nociceptive (e.g., pain intensity, frequency of exacerbation of pain episodes), cognitive-affective (e.g., pain catastrophizing), and functional (e.g., the extent to which pain hinders activities of daily living and overall quality of life) components would be of great research and clinical benefit. Specific alcohol-related items could be adapted from the PROMIS Pain Bank to address the intersection between alcohol use and pain (e.g., assessing alcohol-induced pain relief and pain-induced alcohol craving) (36). Further, incorporating emerging digital health technologies, such as wearable devices, could provide objective physical activity and pain-related functioning data (e.g., pedometer count) to complement self-report data. Wearable devices could provide real-time insight into functional changes associated with pain, enriching our understanding of the pain experience of AUD patients. These efforts could significantly advance pain assessment in the field of AUD research and clinical practice.

TREATMENT OPTIONS: CANDIDATE DUAL-ACTION PHARMACOTHERAPIES FOR CO-OCCURRING AUD AND CHRONIC PAIN

As the intertwined nature of alcohol consumption and chronic pain can exacerbate both conditions, dual-action pharmacotherapies may disrupt this cycle by addressing both conditions simultaneously. We focus on medications demonstrating potential efficacy in mitigating both AUD and pain symptoms, excluding medications such as disulfiram due to insufficient evidence of its analgesic effects. Our objective is to identify promising options that could improve outcomes for individuals grappling with both AUD and chronic pain. This streamlined approach to pharmacotherapy, targeting AUD alongside co-occurring conditions, aligns with the priorities set by the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Acamprosate

Acamprosate is considered a first-line pharmacotherapy for AUD. Recent preclinical studies have suggested a role for acamprosate in reducing neuropathic pain (46). In humans, one open-label trial which randomized adult outpatients to brief manualized CBT plus either acamprosate, naltrexone, or disulfiram showed changes in pain in all three groups, but there were no differences by medication group (47), raising the possibility that changes in pain could have been due to reductions in drinking or the psychotherapy component of the study rather than medication effects.

Naltrexone

Naltrexone is an antagonist at the mu-opioid receptor and is an FDA-approved pharmacotherapy for AUD. A meta-analysis of randomized clinical trials of at least 12 weeks’ duration found that naltrexone is associated with lower rates of return to drinking and heavy drinking and that the injectable form of naltrexone is associated with fewer drinking days (48).

At low doses of 1–5 mg daily—referred to as low-dose naltrexone (LDN)—naltrexone is believed to have analgesic and anti-inflammatory properties by modulating glial cells and inflammatory pathways in the central nervous system (49). A recent review highlighted LDN’s potential benefits for chronic pain conditions, such as fibromyalgia, inflammatory bowel diseases, complex regional pain syndrome, and multiple sclerosis. The proposed mechanism involves reducing neuroinflammation and central sensitization (49). A small pilot study tested low-dose naltrexone (4.5 mg, N=8) versus nalmefene (16 mg, N=3), another opioid antagonist that is approved for alcohol dependence in Europe, in patients with chronic pain, HIV, and past-year heavy drinking (50). The primary outcome was tolerability. All three participants in the nalmefene group discontinued the medication within 3 days of initiation, whereas tolerability ratings were high in the LDN group. However, although LDN may be tolerable, these doses are much lower than the 50 mg dose that is FDA-approved for use in AUD; therefore, it is unclear whether this dose would lead to improved AUD outcomes.

Topiramate

Topiramate is an anticonvulsive medication that also holds promise for the treatment of co-occurring AUD and chronic pain. It is well established as a first-line preventive medication for migraines (51). These therapeutic effects are mediated by blocking voltage-gated sodium channels to reduce neuronal excitability, enhancing GABAergic transmission, and antagonizing glutamate receptors to reduce excitatory neurotransmission. Aside from its proven efficacy in migraine prevention, topiramate has been found to relieve chronic low back pain, and its antinociceptive effects are also dovetailed by preclinical evidence (52).

A Bayesian meta-analysis encompassing 13 randomized controlled trials revealed that topiramate significantly reduced heavy drinking days and alcohol craving among individuals with AUD (53). It also prolonged periods of abstinence and reduced gamma-glutamyl transferase (GGT) levels, an indicator of alcohol consumption. However, none of the included studies examined pain outcomes. By alleviating chronic pain, topiramate could mitigate a potential motivating factor for alcohol use in individuals with AUD.

Gabapentinoids

Gabapentin and pregabalin are structurally related compounds, collectively known as gabapentinoids. Both medications are recommended as first-line treatments for neuropathic pain. Gabapentin may be an effective treatment for AUD, especially in individuals with greater alcohol withdrawal symptoms (54). For pregabalin, some trials show reductions in drinking outcomes in individuals with AUD (55, 56), but these studies have been limited by small sample sizes to date.

While the exact mechanisms underlying the therapeutic effects of gabapentinoids for AUD are still not fully understood, they may function by modulating GABA and glutamate levels dysregulated by chronic alcohol exposure (57). These properties may contribute to their putative analgesic, anti-craving, anxiolytic, and anti-drinking properties in individuals with AUD. The effectiveness of gabapentinoids in treating AUD could potentially vary based on the concurrent presence of chronic pain, though this remains unexplored. Notably, a recent meta-analysis found that gabapentin was not associated with lower rates of return to any drinking or heavy drinking compared to placebo, therefore more clinical trials are needed to evaluate its efficacy for AUD (48).

Baclofen

Baclofen is an FDA-approved muscle relaxant used to treat pain due to muscle spasticity (58). While its mechanisms are not understood, evidence suggests that it acts as an agonist at the beta subunit of GABA receptor at presynaptic and postsynaptic receptors, inhibiting excitatory neurotransmitter release.

Baclofen has been considered an off-label treatment for AUD in the United States. Some meta-analyses have shown that baclofen increases abstinence rates, whereas another meta-analysis found no benefit of baclofen over placebo (59). More research is needed to characterize whether baclofen is superior to placebo and to determine whether specific subpopulations benefit from treatment. Given the frequent co-occurrence of chronic pain conditions in patients with AUD, the potential dual efficacy of baclofen for muscle spasticity and AUD should be investigated in individuals with both conditions.

Serotonergic Psychedelics

Psychedelics are emerging as promising pharmacotherapies for both AUD and chronic pain. Classic psychedelics act primarily as agonists or as partial agonists of the serotonin 5-HT2A receptor. A placebo-controlled study found that a single 20 μg dose of LSD significantly increased pain tolerance and decreased subjective pain levels in healthy volunteers during a cold pressor test, a human laboratory model of pain (60). The analgesic effects lasted throughout the entire five-hour testing period. Additionally, an exploratory controlled trial involving individuals with migraines demonstrated that a single 0.143 mg/kg dose of psilocybin led to significant reductions in weekly migraines days over a 2-week follow-up period (61). The antimigraine effects occurred independently of the acute psychedelic effects experienced during the session.

While these studies focused on the analgesic potential of psychedelics, emerging research also indicates that they may help treat AUD. A randomized placebo-controlled trial involving 95 patients with AUD found that two administrations of psilocybin at moderate-high doses of 25–40 mg/70 kg combined with motivational enhancement and CBT produced a significant reduction in the percentage of heavy drinking days over 32 weeks compared to a diphenhydramine control group receiving the same psychotherapy (62). This study did not measure pain-related outcomes.

Taken together, the emerging evidence suggests that psychedelics may simultaneously treat chronic pain and AUD, emphasizing the need for further research to determine optimal doses and understand long-term effects.

NMDA Antagonists

Ketamine, an NMDA receptor antagonist, has long been integral to multimodal pain management approaches, being recognized as a stand-alone treatment option within consensus pain guidelines (63), and more recently, has been proven effective in treating treatment-resistant depression (64). Increasing evidence suggests that ketamine modulates glutamate release in the brain (65) and fosters neuroplasticity (66), potentially facilitating the learning of new coping mechanisms and behaviors. These effects render ketamine a potential therapeutic for co-occurring AUD and chronic pain.

A recent systematic review summarizes clinical studies using ketamine to treat harmful alcohol use, craving, and withdrawal symptoms (67). Among the clinical trials examining alcohol consumption, ketamine reduced drinking quantity (68) while increasing the number of abstinent days (69, 70). Notably, none of these studies assessed pain-related outcomes despite the well-documented evidence of ketamine’s analgesic effect. Further research is needed to address this gap, elucidate mechanisms of action, and identify optimal dosing regimens.

Cannabinoids

The endocannabinoid system is a promising therapeutic target for both pain and addiction (71–73), and some cannabinoid-based treatments, such as nabiximols, are approved for pain management in Canada and Europe (74). However, there are currently no effective cannabinoid treatments for AUD. For instance, the cannabinoid receptor 1 inverse agonist rimonabant was not effective for AUD in clinical trials (75, 76), and research on other cannabinoids for AUD remains limited (73). Hence, future studies are still needed to elucidate the potential of the endocannabinoid system as a treatment target for AUD and chronic pain.

PSYCHOSOCIAL INTERVENTIONS TARGETING CO-OCCURRING ALCOHOL USE DISORDER AND CHRONIC PAIN

Although no specific integrated psychotherapies have been developed targeting co-occurring AUD and chronic pain, some psychotherapeutic approaches have targeted chronic pain and addiction more broadly and reported on alcohol use outcomes. For instance, in a randomized controlled trial, Improving Pain During Addiction Treatment (ImPAT), an approach that combines principles of cognitive behavioral therapy and acceptance-based approaches to pain, was compared to a supportive psychoeducational control to treat of 129 persons (predominantly male U.S. veterans) with co-occurring SUDs and chronic pain (77). ImPAT reduced pain intensity and improved pain-related functioning, while also leading to lower frequency of alcohol consumption than the control group. A subsequent larger trial balanced by gender (N=510, 48.2% women) was conducted comparing ImPAT with a supportive psychoeducational control (78). Improvements in pain tolerance and pain intensity were observed in men and women, respectively, but there were no differences in alcohol or drug use between conditions. Notably, neither trial reported on the percentage of participants who met diagnostic criteria for AUD.

Preliminary open-label studies have investigated integrated treatments for pain and addiction. For instance, a pilot study of a dual-focused CBT program for individuals with pain, a history of SUD, and hepatitis C showed significant improvements in pain and addiction outcomes, but only a small proportion of participants (5 out of 21) met criteria for current SUD (79). Another uncontrolled study evaluating a 10-week integrated group therapy with a cognitive-behavioral approach (N=44) found a reduction in pain severity, but the majority of patients (66%) were diagnosed with opioid use disorder and there were no reductions in drinking days (80). Results from these studies and the ImPAT trials suggest that integrated psychotherapy may more consistently and effectively alleviate pain than substance use. Still, research on psychological interventions specifically targeting alcohol use and pain could potentially yield better outcomes.

Approaches other than cognitive behavioral therapy may also prove effective. A large clinical trial in participants with chronic pain who were misusing opioid medications found that a mindfulness-based approach, Mindfulness-Oriented Recovery Enhancement (MORE), reduced pain severity, pain interference, and opioid misuse compared to supportive psychotherapy (81). Although MORE focuses specifically on opioid misuse and chronic pain, it could conceivably be adapted for use in patients with chronic pain and hazardous alcohol use.

FUTURE DIRECTIONS

Chronic alcohol use alters the brain’s pain processing mechanisms in ways that are still not fully understood. There is a significant lack of human laboratory research modeling the pharmacodynamic and pharmacokinetic effects of alcohol as a function of chronic pain. Most human laboratory research examining the effects of alcohol on pain thus far has been conducted among healthy participants and social drinkers. These data are likely to have limited generalizability for persons with AUD and chronic pain. Future studies should seek to model the effects of alcohol intake on pain in this population. As human laboratory models afford significant control over potential confounding factors (e.g., alcohol use history, chronic pain severity and duration), these laboratory studies can be leveraged to better understand the analgesic effects of alcohol as well as characterize the effects of anti-craving medications with analgesic potential in this population (Figure 3).

FIGURE 3. Future directions for understanding and treating alcohol addiction and chronic pain^a.

^a Three synergistic future strategies for comprehending and addressing alcohol use disorder and chronic pain.

Most epidemiological studies and clinical trials focusing on AUD neglect to assess pain, leading to limited data on the prevalence of AUD and chronic pain. Measuring pain solely in specialized care settings, which may have higher percentages of patients with medical comorbidities and pain, could potentially lead to overestimates of this comorbidity. Broadening pain assessment to various settings and demographics as well as incorporating pain metrics into large-scale surveys is essential for a more accurate understanding of co-occurring AUD and chronic pain. To date, no clinical studies have been designed specifically to explore the effects of pain on trajectories of AUD; rather, pain was included as a secondary or exploratory outcome. The few studies that explored pain outcomes among persons with AUD are characterized by small and highly heterogeneous samples. Future studies should measure multiple components of the pain experience, from the nociceptive component (e.g., psychophysical measures such as multimodal QST), to cognitive (e.g., pain catastrophizing, pain attentional bias), and affective components (e.g., self-efficacy and pain acceptance).

Studies incorporating functional outcomes (e.g., pain interference), preferably using harder and naturalistic measures (e.g., pedometer count), will provide invaluable insights to develop therapies that target AUD and chronic pain simultaneously by elucidating the complex temporal dynamics between the pain experience and urges to drink, thereby identifying the optimal timing for therapeutic intervention. Studies investigating treatments for AUD should minimally include brief measures of pain to characterize pain levels in their samples. Conversely, it is important for researchers studying chronic pain to thoroughly measure alcohol use and assess for the presence of AUD in their participants as heavy alcohol use may affect response to both pharmacological and psychotherapeutic interventions.

It is important to acknowledge that many individuals with AUD suffer from insufficient pain control. There are currently no clinical guidelines for the management of co-occurring AUD and chronic pain and limited scientific evidence that can be used to guide treatment decisions. Future studies should therefore focus on studying pharmacotherapy for AUD with analgesic potential to determine whether such medications can simultaneously treat both conditions. Notably, many of the drugs discussed in this review have shown promise in curbing both alcohol use and chronic pain, offering a potentially parsimonious approach to pharmacotherapy. Integrated psychotherapies targeting both conditions could further enhance the management of pain and AUD and represent another area worthy of further study. Despite the extensive gaps in research identified in this review, a comprehensive assessment and integrated treatment approach to co-occurring AUD and chronic pain will likely lead to improved patient outcomes.

CONCLUSIONS

There is a complex interaction between chronic pain and alcohol use, with alcohol use providing some relief for chronic pain, but also potentially leading to neuroadaptations that heighten pain sensitivity, generating a positive feedback loop of increased pain and alcohol consumption. Methods of measuring pain, ranging from structured questionnaires to psychophysical methods, offer a roadmap to a better understanding, yet they need to be employed much more frequently in clinical AUD research. Given the high prevalence of chronic pain in individuals with AUD and the impact of pain on risk of relapse, it is critical to manage both conditions concurrently. Pharmacotherapy and psychosocial intervention trials addressing both pain and drinking outcomes in patients with AUD and chronic pain are needed to develop treatment strategies that address both conditions. As we strive to understand the complex intersections of AUD and chronic pain, the onus lies on both the scientific community and clinicians to ensure that these intertwined conditions are neither overlooked nor underestimated in their significance.