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

• Group 02 Paracetamol + Morphine + Ketamine (Drug): Participants receive intravenous paracetamol and morphine via PCA. In case of hyperalgic VOC, low-dose ketamine may be added as a co-analgesic, off-label, according to the treating physician's judgment.
• Group 01 Control: Paracetamol + Morphine (Drug): Participants receive intravenous paracetamol and morphine via patient-controlled analgesia (PCA). In case of hyperalgic VOC, morphine dosage may be increased according to the treating physician's judgment
• Group 03 : Paracetamol + Morphine + Nefopam (Drug): Participants receive intravenous paracetamol, morphine via PCA, and nefopam. In case of hyperalgic VOC, morphine dosage may be increased according to the treating physician's judgment.
• Group 04 : Paracetamol + Morphine + Nefopam + Ketamine (Drug): Participants receive intravenous paracetamol, morphine via PCA, and nefopam. In case of hyperalgic VOC, low-dose ketamine may be added as a co-analgesic, off-label, according to the treating physician's judgment.
• Goup 05 : Paracetamol + Morphine + Tramadol (Drug): Participants receive intravenous paracetamol, morphine via PCA, and tramadol. In case of hyperalgic VOC, morphine dosage may be increased according to the treating physician's judgment.
• Group 6 : Paracetamol + Morphine + Tramadol + Ketamine (Drug): Participants receive intravenous paracetamol, morphine via PCA, and tramadol. In case of hyperalgic VOC, low-dose ketamine may be added as a co-analgesic, off-label, according to the treating physician's judgment.
• Group 7 : Paracetamol + Morphine + Ketoprofen (Drug): Participants receive intravenous paracetamol, morphine via PCA, and ketoprofen. In case of hyperalgic VOC, morphine dosage may be increased according to the treating physician's judgment.
• Group 08 : Paracetamol + Morphine + Ketoprofen + Ketamine (Drug): Participants receive intravenous paracetamol, morphine via PCA, and ketoprofen. In case of hyperalgic VOC, low-dose ketamine may be added as a co-analgesic, off-label, according to the treating physician's judgment.

Primary outcomes

• Time to resolution of vaso-occlusive crisis (VOC) [Up to 14 days after randomization.]: Time to resolution of vaso-occlusive crisis is defined as the time from randomization to discontinuation of intravenous opioid therapy, measured in hours.

Secondary outcomes

• Intravenous Morphine Consumption [From admission to discharge, assessed up to 14 dayss)]: Cumulative dose (mg) and mean daily dose (mg/day) of intravenous morphine.
• Transfusion Requirements [From admission to discharge, assessed up to 14 days]: Number of red blood cell units transfused.
• Intensive Care Unit Admission [From admission to discharge, assessed up to 14 days]: Admission to intensive care unit during hospitalization.
• Morphine-Related Adverse Effects [Within 3 months (+/- 15 days)]: Constipation, sedation (impaired consciousness requiring opioid discontinuation or naloxone administration), vomiting, and secondary acute chest syndrome (new pulmonary infiltrate associated with a clinical sign such as fever, or a respiratory sign such as chest pain or dyspnea).
• Length of Hospital Stay [From admission to discharge, assessed up to 14 days]: Duration of hospitalization, measured in days
• Hyperalgic Vaso-Occlusive Crisis [from randomization to discontinuation of intravenous opioid therapy Up to 14 days]: Uncontrolled pain requiring morphine titration >1 mg/kg or total intravenous morphine consumption >2 mg/kg/24h.
• Refractory Vaso-Occlusive Crisis [From randomization to discontinuation of intravenous opioid therapy Up to 14 days]: Visual analog scale (VAS) score >7/10 after administration of study treatments and a new morphine titration (1 mg/kg).
• Adverse Effects of Investigational Medicinal Products [Within 3 months (+/- 15 days)]: Including nefopam (seizure); NSAIDs (acute kidney injury, KDIGO stage >0; gastrointestinal or other bleeding); tramadol (seizure, liver function abnormalities, impaired consciousness with GCS <14/15); ketamine (liver function abnormalities, hallucinations, impaired consciousness with GCS <14/15, venous access complications).
• In-Hospital Mortality [Duration of hospital stay, assessed up to 14 days]: Death occurring during hospitalization.
• Unplanned Readmission [Within 3 months (+/- 15 days) after discharge]: Unplanned hospital readmission within 3 months following the index hospitalization.

Sex: All, ages: 18 Years to any

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 <40%
* Impaired consciousness, defined as a Glasgow Coma Scale score ≤13/15

Exclusion from a Specific Intervention (randomization possible to other study arms):

* Hypersensitivity to the active substance or to any of the excipients
* Respective contraindications to nefopam, tramadol, ketoprofen, and ketamine, as described in their respective Summaries of Product Characteristics (SmPC)

• Ségolène GENDREAU, MD, PhD, Study chair, Assistance public Hôpitaux de Paris