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Pain, a major comorbidity of sickle cell disease (SCD), has been associated with early mortality. 1 Chronic opioid therapy (COT) is the mainstay for analgesia in SCD. 2 COT has been associated with opioid-induced hyperalgesia (OIH) 3, 4 and reduced survival in humans. 5, 6, 7 We found that chronic morphine treatment of transgenic mice with breast cancer significantly reduced survival. 8 Therefore, it is critical to know whether opioids influence survival and/or cause OIH in SCD. Clinical trials in SCD have remained challenging due to barriers including unpredictable pain episodes. 9 Transgenic homozygous BERK sickle mice show pain characteristics observed clinically in SCD, including increased sensitivity to mechanical and thermal stimuli and increased opioid requirement, and higher circulating substance P and tryptase compared with normal subjects/control mice. 10, 11, 12, 13, 14, 15, 16, 17 Like female …