The Challenge of Painful Crisis in Sickle Cell Disease
Authors: Ronald L. Nagel
Journal: JAMA (2001)

ACUTE PAINFUL CRISIS IN SICKLE CELL DISEASE IS A FREquent complication and considerably diminishes the quality of life of patients with this disease. The pain of sickle cell crisis is one of the most intense in medicine—it has been compared with that of a severe toothache—and affects the extremities, abdomen, lower back, or multiple sites simultaneously. The unpredictability of such painful episodes adds to their discomfort. Some major precipitating factors and aggravating circumstances that contribute to the complex pathophysiology of acute painful crisis include infection, dehydration, excessive exercise, emotional disturbances, or stressful environments. Furthermore, lack of prompt and individualized acute pain treatment increases hospitalization rates as well as the duration and intensity of painful episodes. Even though sickle cell disease was discovered in 1910 and defined at the molecular level in the 1950s, it was not until 1995 that a proven ameliorating therapy was discovered. In a randomized controlled trial, hydroxyurea was shown to decrease the incidence of painful crises. The mechanisms by which hydroxyurea provides benefit are likely to be multiple and complex, including a modest increase in fetal hemoglobin. Efforts are under way to identify a more effective “hydroxyurea-type” approach with administration of arginine butyrate, which induces fetal hemoglobin synthesis more rapidly and more effectively than hydroxyurea. Attempts to develop curative measures for sickle cell disease appear promising but, thus far, have had limited success. Bone marrow transplantation is associated with small but significant mortality, difficulty in identifying donors, and shortand long-term transplant-related complications, particularly among older patients with lifelong complications. Encouraging advances in the prospects for gene therapy for sickle cell disease that involve allogeneic instead of heterologous transplantation have been reported recently. Thus far, testing other potentially ameliorating agents has been relatively unsuccessful. Use of urea was proven to be ineffective, use of cyanate too toxic, the effect of citiedil citrate too modest, and use of methylprednisolone too controversial, with continuing doubts about its efficacy and concerns about adverse effects. In this issue of THE JOURNAL, Orringer and colleagues report the results of a multicenter investigation evaluating the use of purified poloxamer 188 (PP188) for treatment of sickle cell painful crises. Polaxamer 188 is a nonionic surfactant with hemorheological and antithrombotic properties that putatively should improve microvascular flow by reducing bulk viscosity and adhesive frictional forces. In their carefully conducted placebo-controlled trial involving 255 adults and children with painful sickle cell crisis severe enough to require narcotic analgesics and hospital admission, Orringer et al demonstrated a modest reduction in the duration of painful crises (ie, from time of randomization to time of crisis resolution) in the PP188 group (6.4% reduction; 5.5 vs 5.9 days) and report that a greater proportion of patients in the treatment group achieved the protocolspecified end point of resolution of the painful crises within 168 hours (7 days) (51.6% vs 36.6%). Results for children aged 15 years or younger (n=73) were somewhat better, with a statistically significant reduction in painful crisis duration (5.3 vs 6.2 days) and a greater proportion achieving resolution of the painful crisis within 7 days (59.5% vs 27.8%). The results reported by Orringer et al are important but modest, suggesting that it is possible that the potential rheological effects of PP188 were not optimized in this study. However, lack of clear understanding about the mechanism of action of this drug, as acknowledged by the authors, reduces the chances of optimization under the present treatment protocol. Moreover, it would be important not to optimize the untoward effects of PP188 (ie, inhibition of platelet function), particularly since adults with sickle cell disease are at risk of episodes of cerebral hemorrhage. The authors note that the overall incidence of adverse effects of the presently available drug was similar in the treatment and placebo groups and point out that there was no evidence of increased risk of bleeding among patients receiving the study drug. Other efforts directed toward the amelioration of painful sickle cell crisis, such as use of strategies to inhibit vaso-