Adaptive Platform Trial for Pain Management in Sickle Cell Vaso-Occlusive Crisis

Sickle cell disease (SCD) is a severe hemoglobinopathy, characterized by recurrent vaso-occlusive crises (VOC) causing intense pain and frequent hospitalizations in adult patients. Current French and British guidelines recommend rapid administration of strong opioids, primarily through patient-controlled analgesia (PCA), as the reference treatment for hospitalized patients experiencing VOC. However, opioid use is associated with dose-dependent adverse effects, including nausea, constipation, pruritus, sedation, and hypoventilation, the latter representing a risk factor for acute chest syndrome. The hypothesis underlying this study is that multimodal analgesia-combining morphine PCA with co-analgesics such as paracetamol-can significantly reduce morphine consumption during hospitalization compared to opioid-only analgesia, while maintaining effective pain control. Although several co-analgesic agents (paracetamol, NSAIDs, nefopam, tramadol, ketamine) are recommended by expert guidelines, including those from the American Society of Hematology (2020) and French recommendations (2025), the level of evidence supporting their use in adult sickle cell patients remains low or non-existent for most agents, with no randomized controlled trials available for nefopam, tramadol, or ketamine. Using an adaptive platform design, this trial aims to compare multiple analgesic strategies against standard opioid-based care, generating higher-quality evidence to optimize pain management protocols for adult patients experiencing VOC

Inclusion Criteria: * Adult patients (age ≥18 years) * Diagnosed with major sickle cell syndrome (SS homozygous, SC or Sβ° or Sβ+ thalassemia compound heterozygous) * Hospitalized and presenting with a vaso-occlusive crisis (VOC), defined as acute pain or tenderness affecting at least one part of the body, including the limbs, ribs, sternum, head (skull), spine, and/or pelvis, not attributable to other causes * Requiring intravenous morphine or its derivatives * Informed consent obtained from the patient (or from a trusted support person, family member, or relative), or emergency inclusion procedure in cases where the patient is unable to consent and no trusted support person, family member, or relative is available Exclusion Criteria: * Refusal to participate * Pregnant or breastfeeding patient * Administration of one of the interventional group treatments within 4 hours prior to inclusion * Intravenous morphine treatment for more than 24 hours * Patient already included in the study within the previous 3 months * Patient receiving long-term opioid therapy * Not affiliated with a social security scheme, or patient under State Medical Aid (AME) * Patient under legal protection measures (guardianship / family authorization with representation mandate / future protection mandate) or under supervised guardianship (curatelle) * Patient deprived of liberty * Participation in another clinical trial involving a drug * Participation in the PAMAVOC trial within the previous 3 months * Contraindication to standard VOC treatment: * Hypersensitivity to opioids * Opioid-induced hyperalgesia, defined by increased pain on nociceptive testing, topographic extension, or the onset of allodynia with increasing opioid doses * Renal impairment, defined as creatinine clearance ≤30 mL/minute * Hepatocellular impairment, defined as prothrombin time \