Effects of Low‐Dose Acetylsalicylic Acid on Spontaneous Pain, Pain Sensitivity, and Central Pain Modulation in Response to a Sleep Restriction Challenge in Healthy Individuals

ABSTRACT Background Poor sleep and pain perpetuate each other through a feed‐forward cycle. While mechanisms driving this cycle remain poorly understood, they appear to involve inflammatory pathways. We investigated whether pre‐emptive administration of low‐dose acetylsalicylic acid (ASA, aspirin), which targets multiple inflammatory pathways, attenuates the pain response to a sleep restriction challenge in healthy adults. Methods Forty‐six participants completed a randomized, double‐blind crossover protocol consisting of three conditions: sleep restriction/ASA, sleep restriction/placebo, and control sleep/placebo. Each participant completed all three conditions in randomized order. Study medication was administered throughout both the 14‐day at‐home phase and the subsequent 11‐day laboratory stay. Sleep restriction consisted of five consecutive nights of 4‐h sleep opportunity. Pain measures included spontaneous daily pain ratings and quantitative sensory testing assessing pain thresholds, pain tolerance, and central pain modulation (inhibition and facilitation). Results Low‐dose ASA intake for 14 days did not affect baseline assessments of spontaneous pain, pain sensitivity, or modulation ( p  > 0.05). However, ASA attenuated the pain response to sleep restriction, as evidenced by lower widespread and muscle pain ratings ( p  = 0.040, p  = 0.009 for condition effect) and less impaired central pain inhibition ( p  = 0.020 for condition × day effect) compared to placebo. Conclusions Pre‐emptive low‐dose ASA attenuated pain responses to sleep restriction, particularly widespread pain and impaired central pain inhibition, consistent with modulation of nociplastic‐like pain mechanisms. Elucidating the mechanisms underlying this effect of ASA could help inform the development of targeted strategies for individuals who experience recurrent short or disrupted sleep and may be at increased risk for chronic pain. Significance Statement Pre‐emptive low‐dose acetylsalicylic acid attenuated increases in spontaneous pain, heat pain sensitivity, and impaired central pain inhibition induced by experimental sleep restriction in healthy individuals. These findings suggest that inflammatory modulation may contribute to pain responses following sleep restriction and highlight a potential pathway for mitigating the sleep‐related pain vulnerability. Trial Registration: ClinicalTrials.gov (NCT03377543)