A Translational Human Laboratory Model to Elucidate Mechanisms of Alcohol's Impact on Pain in Co-Occurring Alcohol Use Disorder and Chronic Pain

About This Grant

PROJECT SUMMARY/ABSTRACT The co-occurrence of alcohol use disorder (AUD) and chronic pain (CP) worsens symptom burden, escalates costs, and increases mortality beyond either condition alone. Despite converging evidence for shared mechanisms, we lack human models that (i) precisely quantify alcohol’s effects on persons with AUD- and CP-induced neuroadaptations, and (ii) link laboratory responses to real-world pain–drinking dynamics to identify dual-action therapeutic targets. This study fills that gap by establishing a mechanistically informed human laboratory model, using a computer-controlled intravenous (IV) alcohol clamp to investigate alcohol’s biphasic effects on pain—analgesia during the ascending limb, and hyperalgesia during the descending limb of alcohol consumption—at standardized breath alcohol concentration (BrAC) windows. Guided by evidence that central sensitization and alcohol withdrawal-related processes may amplify rebound pain in persons with AUD+CP, we test whether co-occurrence yields the most adverse pain response profile and whether laboratory effects translate to everyday coupling of pain and drinking. We will enroll 112 adults in four groups (healthy controls, AUD-only, CP-only, AUD+CP). CP is defined as non-cancer, high-impact chronic low-back pain ≥3 months; analgesics will be stabilized; opioids and benzodiazepines will be excluded. In two counterbalanced, double-blind sessions separated by three days, participants will receive placebo (saline) and an IV alcohol clamp targeting BrAC 0.10 g/dL, with five matched BrAC windows spanning baseline, ascending, peak, and descending limbs. Evoked pain will be assessed primarily via heat pain threshold, with Conditioned Pain Modulation (CPM) and Temporal Summation of Pain (TSP), indexing pain-modulatory mechanisms. Expectancy of Alcohol Analgesia and perceived pain relief will also be assessed. Aim 1 quantifies group differences in (1) ascending-limb analgesia (increase in pain threshold), (2) descending-limb hyperalgesia (decrease in pain threshold), and (3) the net effect (analgesia minus hyperalgesia). We hypothesize that AUD+CP will show the largest descending-limb hyperalgesia and the most negative net effect. Aim 2 tests whether CPM and TSP track the transition from analgesia to hyperalgesia and relate to pain threshold profile (prediction: ascending CPM enhancement followed by descending attenuation; minimal ascending TSP with descending-limb augmentation, strongest in AUD+CP). Aim 3 translates laboratory profiles to two weeks of experience sampling, testing whether greater laboratory hyperalgesia and pronociceptive profiles predict stronger coupling between pain and alcohol use (strongest in AUD+CP). Exploratory aims quantify pro- and anti-inflammatory cytokines at baseline and post-alcohol versus placebo and examine whether expectancy shapes analgesia and diagnosis-specific effects. This integrated model will characterize alcohol–pain mechanisms and identify dual-action targets for intervention— advancing NIAAA’s mechanistic and whole-person health priorities at the pain–alcohol interface.