Review Article| Volume 234, P141-158, August 2021

Pain in sickle cell disease: current and potential translational therapies

  • Author Footnotes
    a VS and AM contributed equally to this manuscript.
    Varun Sagi
    a VS and AM contributed equally to this manuscript.
    School of Medicine, University of Minnesota, Minneapolis, Minnesota
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  • Author Footnotes
    a VS and AM contributed equally to this manuscript.
    Aditya Mittal
    a VS and AM contributed equally to this manuscript.
    School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Huy Tran
    School of Medicine, Kansas City University, Joplin, Missouri
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  • Kalpna Gupta
    Reprint requests: Kalpna Gupta, University of California, Irvine and Southern California Institute for Research and Education, VA Medical Center, 5901 East 7th St, Long Beach, CA 90822.
    Hematology/Oncology, Department of Medicine, University of California, Irvine and Southern California Institute for Research and Education, VA Medical Center, Long Beach, California
    Search for articles by this author
  • Author Footnotes
    a VS and AM contributed equally to this manuscript.
Published:March 09, 2021DOI:
      Pain is a major comorbidity of sickle cell disease (SCD). Patients with SCD may suffer from both acute and chronic pain. Acute pain is caused by recurrent and unpredictable episodes of vaso-occlusive crises (VOC), whereas the exact etiology of chronic pain is still unknown. Opioids are the mainstay for pain treatment, but the opioid epidemic has significantly altered access to prescription opioids and has brought concerns over their long-term use into the forefront, which have negatively impacted the treatment of sickle pain. Opioids remain potent analgesics but growing opioid-phobia has led to the realization of an unmet need to develop nonopioid therapies that can provide relief for severe sickle pain. This realization has contributed to the approval of 3 different drugs by the Food and Drug Administration (FDA) for the treatment of SCD, particularly to reduce VOC and/or have an impact on the pathobiology of SCD. In this review, we outline the challenges and need for validation of side-effects of opioids and provide an update on the development of mechanism-based translational therapies, specifically targeting pain in SCD.


      AU (Action Unit), ACS (Acute Chest Syndrome), AAT (Alpha-1-Antitrypsin), ASH (American Society of Hematology), AV (Audio-visual), CaMKII (Ca2+/calmodulin-dependent protein kinase II), CGRP (Calcitonin Gene-Related Peptide), CBD (Cannabidiol), CB1R (Cannabinoid Receptor 1), CB2R (Cannabinoid Receptor 2), CDC (Centers for Disease Control and Prevention), CNS (Central Nervous System), CCL2 (Chemokine c-c motif Ligand 2), COT (Chronic-Opioid Therapy), CoQ10 (Coenzyme Q 10), CBT (Cognitive Behavioral Therapy), COX2 (Cyclooxygenase-2), DA (Dopamine), DRG (Dorsal Root Ganglion), EA (Electroacupuncture), EEG-fMRI (Electroencephalogram-functional MRI), ER (Emergency Room), FDA (Food and Drug Administration), fMRI (Functional Magnetic Resonance Imaging), GFAP (Glial Fibrillary Acidic Protein), HEAL (Helping to End Addiction Long-term Initiative program), HR (Hypoxia-reoxygenation), IL (Interleukin), MOPR (Mu-opioid Receptor), MGS (Mouse Grimace Scale), NHLBI (National Heart, Lung and Blood Institute), NIH (National Institute of Health), NK1R (Neurokinin 1 Receptor), NOPR (Nociceptin Opioid Receptor), N/OFQ (Nociceptin/orphanin FQ), OIC (Opioid Induced Constipation), OR (Opioid Receptor), OIH (Opioid-induced Hyperalgesia), OTC (Over the Counter), PAMORA (Peripherally Acting Mu Opioid Receptor Antagonist), PDGFR-β (Platelet-Derived Growth Factor-β), qEEG (Quantitative Electroencephalogram), QST (Quantitative Sensory Theory), RCT (Randomized Control Trial), ROS (Reactive Oxygen Species), RBC (Red Blood Cells), 5-HT (Serotonin), SNRI (Serotonin-norepinephrine reuptake inhibitor), SCD (Sickle Cell Disease), SP (Substance P), SIRS (Systemic Inflammatory Response Syndrome), THC (∆9-tetrahydrocannabinol), TLR4 (Toll-like Receptor 4), TCD (Transcranial Doppler Ultrasound), TNF-α (Tumor Necrosis Factor-α), TKI (Tyrosine Kinase Inhibitor), VEGFR2 (Vascular Endothelial Growth Factor Receptor 2), VOC (Vaso-occlusive Crisis), VR (Virtual Reality)
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