**2. Pathogenesis of sickle cell pain**

is affected with sickle cell anemia. The Hb S/S mutation is the most common form of SCD, it accounts for 60–70% of SCD in the United States. Other forms result from a coinheritance of an HbS allele with another abnormal β-globin chain, HbC (Hb S/C) and from a β-thalassemia

of the hemoglobin molecule that is more hydrophobic compared to its normal counterpart (HbB) and is prone to polymerization during episodes of lower oxygen tension, hypothermia or many other stressors. A deoxygenated hemoglobin B (HbB) of patients with SCD will aggregate along its molecular axis leading to distortion of the cell membrane and giving it a sickle shape appearance. A hallmark of sickle cell disease is intermittent vaso-occlusive events (VOE) and chronic hemolytic anemia. VOE in acute and chronic pain as well as organ damage

SCD is a disease that is mostly present in persons of African, Mediterranean, Middle Eastern and Indian ancestry but has been found in individuals of any ethnic background. The prevalence of sickle cell trait, among African Americans in the United States, is 10%, or 3.5 million people, leading to the incidence of SCD among this ethnic group of approximately 1 in 365 live births. More than 100,000 individuals in the United States are estimated to suffer from SCD. In the United Kingdom, the prevalence is about 12,500 people. Globally, it is estimated that about 5–7% of the world's population are carriers of the mutant hemoglobin gene [3, 4], most of which residing on the African continent. As a matter of fact, about 15 million Africans are affected by SCD, more than all other continents combined. And about 200–300,000 affected births per year occur on the African continent [4, 5], accounting for more than 75% of the SCD newborns worldwide. Globally, SCD is one the four most common autosomal recessive

Although in some areas of the world, such as Western African countries, where new treatment modalities are not as widely accessible, SCD accounts for as many as 16% of deaths in children under 5 years old, the death rate has remarkably been reduced in the United States in recent times. In fact, many children did not live to adulthood about half a century ago. With the emergence of hydroxyurea, new born screening, newer and better antibiotics as well as the introduction of the pneumococcal vaccine, the lifespan for sickle cell individuals in the United States has increased substantially to 48 years old for female and 42 years old for male. As a matter of fact, the median survival age of patients with SCD living between 1910 and 1950 was below 20 years of age [6]. By 1980, 50% of children survived beyond 20 years of age; and by 2009, 85% of SCD affect patients did. In England, the trend for hospital admissions related to SCD has been on the rise; from 2001/2002 to 2009/2010, admissions with a diagnosis of SCD

The management of SCD is complex and multidisciplinary. Supportive management includes regular follow-ups with the healthcare providers, adequate diet and sleep. Symptomatic management targets symptoms of the disease and include blood transfusions, pain management, antibiotics for infections among many other possible treatments. Preventive managements include vaccinations, avoidance of stressors that triggers crisis, hydroxyurea treatment, transfusion, etc. Abortive therapy is the attempt at preventing painful crisis from getting worse and leading to other complications. They include nitrous oxide and anti-adhesion factors. The ultimate goal is curative therapy, which can arise from stem cell transplantation, and gene therapy in the future. This chapter focuses solely on the pain management of patients with

SCD and is divided into acute pain, chronic pain and neuropathic pain.

most notably to the bones, spleen, liver, brain, lungs, kidneys and joints [2].

diseases along with cystic fibrosis, thalassemia and Tay-Sachs.

) being the most common among others. The mutation results in a beta chain

(Hb S/β<sup>+</sup>

, Hb S/β<sup>0</sup>

16 Pain Management in Special Circumstances

have risen by more than 50%.

Sickle cell related pain is classified into three categories: acute pain, chronic pain and neuropathic pain [7]. Acute pain is, by far, the most commonly encountered type of pain by healthcare providers and is the precursor of chronic and neuropathic pain. The pathophysiology of sickle cell pain is still not completely understood but is thought to be initiated by stress/ deoxygenation leading to the polymerization of sickle Hb in the red blood cells (RBC) inside the micro and macro-vasculature. This causes the RBC to lose its deformability and adhere to together on the vascular endothelium that in turn gets activated. The latter participates in the recruitment of white blood cells (WBC), which further accentuates the existing vascular occlusion and facilitates tissue ischemia and damage. The activation of endothelial cells along with the tissue damage provokes the release of inflammatory mediators (including arachidonic acid, histamines, bradykinin, H+, K+, cytokines, serotonin, substance P, leukotrienes among others) [8, 9]. The combination of tissue damage and the resulting secondary inflammatory process generated is thought to be the cornerstone of the pain perceived during VOE. They convert chemical and mechanical energy into electrochemical impulse. The release of interleukin-1 activates the cyclo-oxygenase (COX) system that in turns converts arachidonic acid into prostaglandins E2 and I2. This inflammatory soup created interacts to permit and facilitate the transduction and transmission of the painful stimuli from the periphery the central nervous system via the nerve endings, spinal cord and the thalamus. Some of the mediators (Substance P and bradykinin) also cause vasodilatation and extravasation of fluid leading to focal edema and tenderness in the affected areas.

The peripheral nociceptors involved in the painful cascade send their signals via fast acting A-delta and slow acting C fibers to the dorsal horn of the spinal cord by means of the dorsal root ganglion. From the dorsal horn of the spinal cord, the pain signals travel contralaterally through the spinothalamic tract to the thalamus that in turn has multiple interconnections with other systems such as the limbic system (mediator of memory and emotion), the reward system (mediator of pleasure and addiction) and the glia. The signals are then either facilitated or suppressed at the level of the spinal cord by different modulators. The N-methyl-D-aspartate (NMDA) receptor is probably the most important receptor involved in the facilitation of pain transmission. Other important modulators include endogenous endorphins, serotonin and norepinephrine. With knowledge of the implicated factors involved in sickle cell pain, better management can be made targeting the involved transmitters, receptors and modulators.
