Table 1.

Mechanism-based therapies to target sickle cell pain

Intervention	Mechanism	Known Outcomes and Current Clinical Trials
Crizanlizumab	Anti-P-selectin antibody	Reduced the frequency of painful VOC by 45% and tripled the median time of first VOC in patients with SCD; current clinical trial (ClinicalTrials.gov identifier NCT03264989: “Pharmacokinetics and Pharmacodynamics Study of Crizanlizumab in Adult SCD Patients with VOC”)
Sivelestat	Leukocyte elastase inhibitor	Decreased neuronal injury to the DRG and reduced neuropathic pain in BERK sickle mice
Imatinib	cKIT/mast cell inhibitor	Reduced neurogenic inflammation and prevented hypoxia-reoxygenation-induced hyperalgesia in sickle mice; decreased frequency of VOC in patients with SCD
Cromolyn	Mast cell stabilizer	Increased the analgesic effect of a suboptimal dose of morphine in BERK sickle mice
Trifluoperazine	CaMKIIα inhibitor; reduces calpain-1 activity	In a phase I clinical trial, ameliorated neurogenic pain and caused 50% reduction in chronic pain in patients with SCD without severe sedation or supplemental opioid analgesics
Simvastatin	Decreases calpain-1 activation?	In patients with SCD, reduced frequency of pain, oral analgesic use, and markers of inflammation, acting synergistically with hydroxyurea; 4 completed clinical trials are cited on the ClinicalTrials.gov website
CP55,940	Cannabinoid receptor 1 and 2 agonist	Ameliorated chronic and hypoxia-reoxygenation-induced hyperalgesia in sickle mice; mitigated mast cell activation, inflammation, and neurogenic inflammation in sickle mice; current clinical trial (ClinicalTrials.gov identifier NCT01771731: “Vaporized Cannabis for Chronic Pain Associated with SCD”)
Rapamycin everolimus	mTOR inhibitor: increases fetal hemoglobin levels	Ameliorated the nociception phenotype in sickle mice; in 1 renal transplant recipient, increased fetal hemoglobin levels from 4.8 to 15% and was well tolerated
Omega-3 fatty acids	Antioxidant	Reduced frequency of VOC and transfusion requirements in a randomized study of 140 patients in Sudan; current clinical trial (ClinicalTrials.gov identifier NCT02947100: “Omega–3 Fatty Acids in Sickle Cell Disease”)
Curcumin and CoQ10	Anti-inflammatory and antioxidant	Attenuated glial activation, neuroinflammation, and oxidative stress in spinal cords of BERK sickle mice, resulting in attenuation of hyperalgesia; reduced inflammation, oxidative stress, and VOC-associated pain in patients with SCD
AT-200	Nociceptin opioid receptor agonist and mast cell inhibitor	Ameliorated chronic and hypoxia-reoxygenation-induced mechanical, thermal, and deep tissue/musculoskeletal hyperalgesia in BERK sickle mice without causing tolerance
Acupuncture	Inhibits inflammation peripherally and in the spinal cord	In awake BERK sickle mice, reduced inflammatory cytokines, substance P, and neurogenic inflammation in the periphery and signaling pathways of nociception in the spinal cord and potentiated the effect of a suboptimal dose of morphine; acupuncture significantly reduced VOC-associated pain in patients with SCD
Hypnosis	Modulates vascular physiology	Decreased pain intensity and increased peripheral blood flow during anticipation and experience of pain in patients with SCD

CoQ₁₀, coenzyme Q₁₀; DRG, dorsal root ganglion; mTOR, mammalian target of rapamycin; SCD, sickle cell disease; VOC, vasoocclusive crisis.