Teasing Apart Pain in Sickle Cell Disease

Pain devastates people with sickle cell. Pain destroys quality of life. Pain diagnoses and treatments are problematic. Treatment introduces its own indignities and hurdles. From infancy with its dactylitis, through socially limited adolescence, through erratic pain episodes that destroy the ability to sustain school, work, or relationship, persons with sicklecell disease are burdened by pain. Adults often forgo ED treatment to avoid the interruption of their lives, the stigmatization that pain treatment causes, the interactions with dubious providers at a time the patient cannot be at their most logical and friendly, the lack of effective treatments, and the repeated nature of the pain. Many adult patients have chronic, nearly daily pains, but only a fraction of those choose to go to the ED. When they do go, the pain often is not worse, but rather that the pain has just worn them down. Earlier approaches to treating sickle-cell pain were modeled on terminal cancer care, and possibly reasonable in the time that most patients did not reach twenty. Patients were awash in IV narcotics, kept in hospital for extended times, and missed school, socialization, and work opportunities. Over the last several decades, the increase in life expectancy has turned sickle-cell disease from a childhood fatal disease to a chronic disease fraught with disability, progressive organ failure, and more pain. Now that most patients live well beyond twenty years of age, two challenges have emerged. The first is that many of the adults, those now over about 30 years of age, were treated with prolonged courses of high-dose opioids. Both pain and opioid treatment are causative and concomitant to poor social functioning, worsening school performance, increase risks or morbidity, and even mortality (1). This has been compounded by many patients being told that they would not reach adulthood, keeping them from fully engaging in school and society. Now many of these patients, partly created by the medical treatments of their times, are unmarried and socially isolated with little to look forward to except being alone with their pain. Second, sickle-cell pain is recognized as a unique pain syndrome by the American Pain Society (2), so much pain research may not apply. Mouse models of sickle-cell pain are hard to interpret, limiting the ability to find treatments. The sheer number of proposed guidelines shows the lack of effective treatments (3). Even something as basic as the measurement of pain is a dilemma. Numerous approaches to pain measurement have been used and some have been considered validated, but all miss important impacts of pain on patients’ lives. This was most dramatically shown by the PiSCES study (4), where detailed pain diaries showed more than twenty percent of adults with sickle cell have pain everyday and the majority of patients with pain do not seek medical help. Such observations are pointing to the lack of a coherent understanding of pain as a medical condition. It was noted at the centenary of the recognition of sicklecell disease that although much advance had been made in cataloguing all the organ dysfunction in sickle-cell disease, little has changed over the last hundred years in pain treatment. Fortunately, more attention, observation, and research have concurrently been directed toward the treatment of pain in sickle-cell disease. This year the American Society of Hematology has released research priorities for sickle cell. Enhancing pain research is among them. Furthermore, research into the role of inflammation has added to the concept of red cell plugging of the microvascular the added recognition of pain as a ‘cytokine bomb’. More recent studies of the relationship of sickle-cell pain to asthma, pulmonary hypertension, vitamin D levels, magnesium status, nitric oxide metabolism, poloxamers, selectin inhibitors, and blockers of invariant natural killer T cells reflect the recognition that sickle cell and its manifestations are a reflection of protean and complex interactions of all the components of the blood system, red cells, platelets, white cells, the endothelium, glial activation, reperfusion injuries, and inflammatory changes to many different pathways of pain nociception, potentiation, and modulation. No wonder we are confused. Despite the elucidation over the last decade both of new pathways and more details understanding of known pathways, clinical application of these findings have been slowed by the lack of clinical description of the similarities and differences between the many entities described as ‘pain”. Providers who treat many patients with sickle cell disease soon realize that pain takes on a life of its own and becomes a disease in its own right. In his review of sickle-cell pain in this issue of the Journal (5), Dr. Samir Ballas reviews the current state of the understanding of the different syndromes of sickle-cell pain, of pain pathways, of the use of opioids, and of the possible treatments available. These include delineating between acute and Correspondence Ward Hagar, MD, Children’s Hospital & Research