Treating Pain in Sickle Cell Disease: Design of a Randomized Crossover Controlled Mediterranean Diet Feeding Study

Abstract Objective Sickle cell disease (SCD) is characterized by acute and chronic pain. Adults with SCD often consume diets low in fruits, vegetables, fiber, and whole grains and higher in processed foods and saturated fats, dietary patterns that may worsen disease symptoms, including pain. The gut-brain axis is an underexplored mechanism linking diet to pain. Adherence to a Mediterranean Diet (MedDiet) is associated with favorable changes in the gut microbiome and increased microbial production of short-chain fatty acids (SCFAs), which may support reduced inflammation and pain. The objective is to test the impact of a MedDiet compared with a Habitual Diet Control on chronic pain, the gut microbiome, and microbial metabolites in adults with SCD. Methods This controlled crossover feeding study will randomize 30 adults with SCD and chronic pain to receive a MedDiet and a Habitual Diet Control for 4 weeks each. Blood, stool, anthropometric, and survey data will be collected at the baseline and completion of each diet condition. Results The primary outcome is patient-reported chronic pain. Secondary outcomes include gut microbiome composition, fecal and circulating microbially regulated metabolites, including SCFAs and bile acids, and additional health-related measures. Conclusion This is the first controlled feeding study to test the impact of a MedDiet on chronic pain among adults with SCD. Results will provide preliminary evidence to support dietary strategies for chronic pain management in SCD and inform the design of larger randomized controlled trials.