In a commendable study in this issue of Blood, Kohli and colleagues describe a novel approach to unraveling the complexities of the pathogenesis of sickle cell pain and its management.1  Given the timing of this publication, it can be considered a celebratory centennial of the discovery of sickle cell disease in the United States in 1910.2 

Sickle cell anemia is almost synonymous with pain. Acute painful episodes are its hallmark and the most common cause of hospitalization.3  Vaso-occlusion is believed to be the root cause of the pain; it causes damage to tissues supplied by the occluded vessel and is also responsible for creating a state of chronic vascular inflammation that explains many features of sickle cell pain.4-6  Tissue damage and vascular inflammation generate a number of inflammatory mediators that initiate an electrical impulse of pain transmitted along peripheral nerves (Aδ and C fibers) to the dorsal horn of the spinal cord. The impulse ascends along the contralateral spinothalamic tract to the thalamus, which interconnects reversibly with other centers, most notably with the limbic system (mediator of emotion and memory). At the same time, the central nervous system (CNS) inhibits the transmission of the painful stimulus at the level of the dorsal horn via a descending pathway, with norepinephrine and serotonin as neurotransmitters, which begins in the periaqueductal gray matter of the midbrain. Eventually the modified electrochemical impulse that started at the site of vaso-occlusion is sent to the cerebral cortex, where it is perceived as pain. Pain perception is thus a subjective phenomenon and is the result of a complex interplay among enhancing and inhibiting factors at the level of the CNS in addition to a host of coexisting psychosocial and environmental factors. Given the subjective nature of sickle pain coupled with the lack of experimental models to investigate, it generated an atmosphere of doubt about its authenticity and the reliability of the patients' complaints. The negative attitudes toward patients with painful sickle crises have been compounded by racial stereotypes, the effects of the disease in limiting educational and employment opportunities, suboptimal medical coverage, and the large doses of opioids often required to obtain pain relief. Unlike other types of pain, research support and progress in understanding sickle cell pain followed a sluggish, slothful, almost stagnant, path. In a sense, it has been a situation of retrograde translational medicine working in reverse, where lack of evidence created a barrier to rational clinical management. Hydroxyurea decreases the frequency of painful episodes but it is not an analgesic to treat acute pain directly.7 

In this issue of Blood, Kohli et al take advantage of a transgenic sickle cell mouse model expressing human sickle hemoglobin to characterize the behavioral, neurochemical, and pharmacologic aspects of sickle cell pain as well as to find alternatives to opioid analgesics to treat pain.1  The mice used were the homozygous and hemizygous Berkley strain (BERK and hBERH1), compared with control mice expressing human hemoglobin A (HbA-BERK). Determinants of behavioral change included reduced paw withdrawal threshold to mechanical stimuli, reduced withdrawal latency to thermal stimuli, and decreased grip force in both homozygous and hemizygous mice indicating musculoskeletal and cutaneous hyperalgesia. At the neurochemical level, peripheral nerves and blood vessels were structurally altered in BERK and hBERK1 skin with decreased expression of mu opioid receptors and increased calcitonin gene-related peptide and substance P immunoreactivity. The reduction in innervations is indicative of peripheral neuropathy that may culminate in a central neuropathic pain condition. Similarly, activators of neuropathic and inflammatory pain were increased in the spinal cord of hBERK1 compared with HbA-BERK. These neurochemical changes in the periphery and spinal cord are suggestive of nociceptor and glial activation that may contribute to hyperalgesia in mice, similar to the characteristics of pain observed in patients with sickle cell anemia. Taken together, these findings suggest that the characteristics and severity of sickle cell pain depend on the location, extent, and chronicity of the neurochemical damage that ensues after vaso-occlusion. Thus, depending on whether the damage is peripheral and/or central, the pain may be limited to musculoskeletal and cutaneous hyperalgesia alone or in combination with inflammatory and neuropathic pain. At the pharmacologic level, hyperalgesia in BERK and hBERK1 mice was attenuated by morphine and cannabinoid agonists. This finding implies that the use of medicinal cannabinoids may play an important role in the management of sickle cell pain similar to their reported role in the management of other types of pain.8,9  Used in combination with opioids, cannabinoids may decrease the amount of opioids needed to achieve adequate pain relief.

Another novel aspect of this study is the surprising similarity between the homozygous BERK and hemizygous hBERK1 mice. This is unlike persons with sickle cell trait who are asymptomatic under normal conditions. The reasons for this similarity between the 2 types of mice are unknown and require further future studies.

Some of the findings in this study provide welcome explanations for some of the perplexing observations in patients with sickle cell anemia. We and others, for example, reported that some hospitalized patients with acute painful crises become refractory to treatment with opioids about 3 or 4 days after admission and continue to have severe pain despite the administration of high doses of opioids.3,10  With no good explanation for this phenomenon, some providers attributed it to maladaptive behavior. It is interesting that the study by Kohli et al found decreased expression of mu opioid receptors in both BERK and hBERK1 mice.1  This is a possible explanation for the observed refractoriness to opioids in some patients who may benefit from the use of medicinal cannabinoids. It is unfortunate that so many of the presumed maladaptive behaviors of patients with sickle cell disease have had a plausible explanation later on. Thus, addiction turned out to be pseudo-addiction in many patients resulting from undertreatment of pain. Drug-seeking behavior turned out to be pain relief–seeking behavior resulting from tolerance and hyperalgesia. Refractoriness to opioids, if confirmed in patients, seems to be caused by decreased mu opioid receptors during acute painful episodes.

The present findings are of both basic and clinical value that will facilitate further translational research. Finally, we have an excellent animal model that opens the sluice gates to probe new avenues for understanding and treating sickle cell pain.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

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