Pain in sickle cell disease: current and potential translational therapies

Abstract

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.

Figure 1:. Ying and Yang of Opioid use.

Opioids are used to treat severe pain, but their use is associated with several side-effects, which necessitate the need for developing effective non-opioid alternatives to treat severe pain.

Figure 2:. Overview of recently approved therapies and those in development for treating pain in sickle cell disease.

Different treatment strategies are being employed including those which target sickle red blood cell pathology, sensory nerve transmission, and top-down mechanisms of pain. Treatments studied primarily in humans are outlined in blue, whereas those studied primarily in mice are outlined in yellow. For therapies in which both mice and human studies were performed, a green outline is used. AV, Audio-visual relaxation; CaMKII, Ca2+/calmodulin-dependent protein kinase II; CBT, cognitive behavioral therapy; CoQ10, Coenzyme Q10. NOPR, Nociceptin opioid receptor. Created with BioRender.