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Background and Methods The management of episodes of severe pain in patients with sickle cell disease is a difficult clinical problem. We studied 36 children and adolescents with sickle cell disease who had 56 acute episodes of severe pain (44 in 27 patients with sickle cell anemia, 8 in 7 patients with sickle cell-hemoglobin C disease, and 4 in 2 patients with sickle cell-
Results For all episodes of pain, the duration of inpatient analgesic therapy (intravenous and oral) was significantly shorter for the patients who received methylprednisolone than for those given placebo (mean, 41.3 vs. 71.3 hours; P = 0.030). The difference was still significant (31.0 vs. 62.5 hours; P = 0.010) when we excluded seven episodes that were complicated by the chest syndrome (three in the methylprednisolone group and four in the placebo group). The patients who received methylprednisolone had recurrent episodes of pain shortly after the discontinuation of therapy more often than did the patients receiving placebo. No adverse effects of methylprednisolone were observed.
Conclusions A short course of high-dose methylprednisolone decreased the duration of severe pain in children and adolescents with sickle cell disease, but patients who received methylprednisolone had more rebound attacks after therapy was discontinued. On balance, corticosteroids are promising as an adjunct to supportive therapy for painful episodes in children and adolescents with sickle cell disease.
+-thalassemia). The patients were randomly assigned in double-blind fashion to receive an intravenous infusion of either saline placebo or high-dose methylprednisolone (15 mg per kilogram of body weight, to a maximum of 1000 mg) on their admission to the hospital and again 24 hours later. All the patients received intravenous morphine sulfate until severe pain abated and were then given acetaminophen with codeine.
Many features of these episodes of pain are similar to those frequently noted in inflammatory processes, such as an elevated body temperature, local swelling, warmth, erythema, leukocytosis, and an elevated erythrocyte sedimentation rate. In view of the multiple antiinflammatory effects of glucocorticoids,9 we postulated that the administration of high doses of corticosteroids early in a vaso-occlusive crisis might lessen the duration or severity of pain. To test this hypothesis, we undertook a placebo-controlled, double-blind study of the effects of intravenous methylprednisolone in children and adolescents with sickle cell disease who were hospitalized with severe pain.
Methods
Study Population
Patients less than 21 years of age who had sickle cell disease and were being followed in the comprehensive sickle cell clinic at Children's Medical Center of Dallas were eligible for the study if they had acute pain that remained severe despite management at home and in the emergency department with fluids and analgesics. Patients were excluded from the study if pain had been present for more than four days before admission, if a bacterial infection was strongly suspected on the basis of the clinical examination, or if acute chest syndrome (chest-wall pain in association with an acute pulmonary infiltrate, signs of respiratory distress, or both) was present. Fever was not a reason for exclusion. The study protocol was approved by the institutional review board of the University of Texas Southwestern Medical Center at Dallas, and written informed consent was obtained from the parents or guardians of the enrolled patients.
Study Protocol and Patient Care
After their admission to the hospital, the patients were randomly assigned in double-blind fashion to receive the study drug or placebo. Sealed, opaque envelopes were arranged in a computer-generated random order and opened sequentially by the pharmacist to determine the patients' treatment assignments. The treatment consisted of two doses of saline placebo or methylprednisolone at a dose of 15 mg per kilogram of body weight (maximum, 1000 mg), given intravenously over a 30-minute period. The medications were prepared by the pharmacist, packaged identically, and delivered marked as "study medication" to the bedside, so that care givers were unaware of the patients' treatment assignments. The first dose was administered as soon as possible after admission, and the second 24 hours later. Patients were placed on cardiac monitors and received intravenous fluids (5 percent dextrose with 0.45 percent saline) at a maintenance rate. Vigorous hydration was avoided unless the patient was found to be clinically dehydrated. Patients who were febrile at the time of admission received cefuroxime (50 mg per kilogram intravenously every eight hours) after blood was obtained for culture.
Analgesia consisted of morphine sulfate (0.1 mg per kilogram per dose) given by intravenous bolus injection as often as every two hours when needed for moderate-to-severe pain. If pain was poorly controlled at any time during the hospitalization, the dose of morphine was increased to 0.15 mg per kilogram. If pain was severe after 24 hours of hospitalization and the patient had received eight or more bolus injections of morphine, the protocol allowed the use of a continuous infusion of morphine5 at the discretion of the treating physician. After the pain had stopped, intravenous morphine was discontinued and oral acetaminophen with codeine was given as needed. The patient was discharged from the hospital when the patient, his or her parents, and the medical staff agreed that the episode of pain had resolved or could be managed on an outpatient basis with oral analgesics.
Patients were monitored during hospitalization for potential toxic reactions related to steroid use, including headache, psychological disturbances, hypertension, cardiac dysrhythmia, and infectious complications.
Measures of Outcome and Statistical Analysis
The main outcome measures in our study were the number of intravenous doses of morphine given, the need for a continuous infusion of morphine, the duration of intravenous and oral analgesia, and clinical complications such as the chest syndrome. The Mann-Whitney U test was used to evaluate differences between the treatment groups in the number of intravenous analgesic doses required and in age. Because a difference in age was found, analysis of covariance was used to determine age-adjusted group differences in the duration of inpatient administration of analgesic agents. Chi-square analysis was used to evaluate differences in other clinical characteristics and in the incidence of complications.
Results
From February 1990 through October 1991, 36 patients with sickle cell disease were enrolled during 56 episodes of severe pain. Twenty-seven patients (who had a total of 44 episodes) had sickle cell anemia, seven (8 episodes) had sickle cell-hemoglobin C disease, and two (4 episodes) had sickle cell-+-thalassemia. Their ages ranged from 2 to 19 years (mean, 7.7). During 30 episodes the patients received placebo, and during the remaining 26 episodes the patients received methylprednisolone. One patient received both drugs during separate episodes. The two groups were balanced with regard to sex, type of hemoglobinopathy, and duration of pain before hospitalization, but a larger proportion of younger patients were randomly assigned to receive methylprednisolone (P = 0.016) (Table 1). Differences between the groups in the mean duration of administration of analgesic agents were therefore subjected to analysis of covariance to control for the possible confounding by age.
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All 56 episodes of pain in the study patients were included in the analysis. No patient was withdrawn from the study after his or her treatment assignment was determined. The number of hours from the administration of the first dose of the study drug to the last inpatient dose of intravenous or oral pain medication for the same episode is shown in Figure 1. When all 56 episodes were included in the analysis, the age-adjusted duration of inpatient analgesic therapy was significantly longer for patients who received placebo than for those who received methylprednisolone (mean, 71.3 vs. 41.3 hours; P = 0.030). Seven episodes were complicated by the development of the acute chest syndrome (three in the methylprednisolone group and four in the placebo group). When these episodes were excluded from the analysis, the age-adjusted difference between the methylprednisolone and placebo groups remained significant (mean, 31.0 vs. 62.5 hours; P = 0.010).
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Eight patients in the placebo group and seven in the methylprednisolone group had fever on admission. Fever during hospitalization was more common among the patients receiving placebo; 17 patients in the placebo group had fever (mean duration, 3.9 days), as compared with 11 patients receiving methylprednisolone (mean duration, 2.45 days). This difference was not statistically significant. Serial leukocyte counts were not obtained.
After 5 of the 56 study episodes, patients were readmitted for recurrent pain within two weeks of their discharge. One patient readmitted eight days after discharge had received placebo. Four patients who received methylprednisolone were readmitted one, one, two, and six days after discharge and were hospitalized for three, six, eight, and four days, respectively, on readmission.
No complications related to corticosteroid use (such as hypertension, gastrointestinal bleeding, or unusual alterations in behavior) were observed during the study. None of the study patients died.
Discussion
Painful episodes in patients with sickle cell disease are difficult to manage. Some patients with sickle cell disease have few painful events, but others have repeated, severe episodes of pain1,2,3. Management consists of symptomatic measures such as adequate hydration and administration of analgesic agents4,5,6.
Several adjunctive therapies have been used in an effort to ameliorate the severity of painful episodes7,8. In a double-blind study, cetiedil citrate administered during acute episodes shortened the duration of pain and reduced the number of painful sites, as compared with placebo10. Other strategies aimed at preventing vaso-occlusive complications such as pain crisis include the use of hydroxyurea,11,12 butyrate preparations,13 monthly transfusions of packed red cells, and bone marrow transplantation14. The most extensively studied of these treatments, hydroxyurea decreases intracellular hemoglobin polymerization and erythrocyte sickling by increasing the levels of fetal hemoglobin. Further trials of its efficacy are required before hydroxyurea becomes a widely accepted treatment. Although hydroxyurea may prevent painful events, it would not be expected to be effective once vaso-occlusive pain has developed.
Long-term administration of steroid hormones has previously been investigated in sickle cell disease15,16,17,18,19,20,21. In placebo-controlled crossover trials, testosterone, progesterone, and medroxyprogesterone have been studied in both sexes17,20. Steroid-treated patients in all cases had fewer painful episodes than untreated patients. The mechanism was unclear, but it was suggested that the effect of these hormones resulted from effects on the red-cell membrane or improvement in hematologic indexes. Reports of the use of glucocorticoids for acute painful episodes in sickle cell disease are limited and include an anecdotal description by a physician of the effects of dexamethasone in his own children with sickle cell disease22 and an uncontrolled report on the efficacy of hydrocortisone as an adjunct to pain management23.
Nonsteroidal antiinflammatory drugs have also been tried. Diflunisal hastened the resolution of severe pain,24 whereas ketorolac has had promising effects in uncontrolled observations25. Our study also suggests that drugs with antiinflammatory properties may help in painful events.
Since corticosteroids have many effects,9 the precise mechanism by which the duration of severe pain was reduced in our study is unclear. Suppression of the local production and biologic action of cytokines such as interleukin-1 and tumor necrosis factor may have been involved. Serum levels of interleukin-1 and tumor necrosis factor are often elevated in patients with sickle cell disease during painful episodes,26 although one recent study reported undetectable plasma levels of these cytokines in over 85 percent of patients with acute complications of sickle cell disease (Weitman S, Mustafa M: personal communication). It is possible that systemic plasma concentrations may not reflect the local effects of cytokines in ischemic tissue.
Corticosteroids such as methylprednisolone also have analgesic and mood-elevating properties and are useful in the treatment of pain without an inflammatory component, as may occur in cancer27,28,29. Several patients in our study who received methylprednisolone had a rapid reduction in pain. Four of the 26 patients treated with methylprednisolone received opioid analgesics for less than 5 hours after the administration of methylprednisolone, and in 8 others severe pain resolved within 12 hours. High doses of methylprednisolone may have exerted analgesic effects that preceded its antiinflammatory activity.
Caution must be exercised in using high doses of corticosteroids. No adverse effects were observed in our study,30,31,32,33 but it is possible that serious side effects (such as aseptic necrosis of the femoral head) might be encountered, especially if recurrent episodes are treated. There is also concern about the use of high doses of corticosteroids in patients who may have an underlying bacterial infection, even though the administration of high doses of dexamethasone to prevent sequelae of bacterial meningitis in young children was not harmful34,35. In our study, patients who had fever received intravenous antibiotics according to standard practice.
We were not able to perform serial evaluations of the severity of each episode with use of a subjective pain scale, although other investigators have had success with this approach36. Our patients were quite young; 26 of 56 episodes (46 percent) occurred in children four years of age or younger. The clinical assessment of the effects of adjunctive corticosteroids on the severity of pain might be more successful in studies of adolescents or adults.
Our results suggest that two large doses of intravenous methylprednisolone given 24 hours apart shorten the duration of painful vaso-occlusive episodes in young patients with sickle cell disease. There is a risk of recurrent pain after discharge in patients treated with methylprednisolone, however, so the overall advantage of methylprednisolone therapy is not established by our data. This rebound phenomenon suggests that a longer course of treatment might be more beneficial. The dosage of methylprednisolone in our study was arbitrary. Lower doses or other glucocorticoid preparations might also be effective. Our study included too few patients for us to identify any subgroups of patients for whom corticosteroids are more or less efficacious. Many episodes of the chest syndrome are caused by infarcts of the bony thorax,37 and steroid treatment may prevent the development of the chest syndrome during episodes of chest-wall or abdominal pain.
Supported by grants (T-32-CAO9640 and T-32-HD07308) from the National Institutes of Health and by the Sickle Cell Research Fund at Children's Medical Center.
We are indebted to Rebecca Morrison, R.N., P.N.P., to Debbie McBride, R.N., P.N.P., and to all the nurses, house staff members, and hematology-oncology fellows of the Children's Medical Center of Dallas, who assisted with the conduct of this study, and to Ms. Karan Vitale for assistance in the preparation of the manuscript.
Source Information
From the Division of Hematology-Oncology, Department of Pediatrics (T.C.G., G.R.B.), and the Academic Computing Center (D.M.), University of Texas Southwestern Medical Center at Dallas, and the Center for Cancer and Blood Disorders, Children's Medical Center, Dallas (T.C.G., G.R.B.).
Address reprint requests to Dr. Buchanan at the Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9063.
References
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Related Letters:
Treatment of Pain in Sickle-Cell Crisis
Foley K. M., Portenoy R. K., Rosenbloom B. E., Tanaka K. R., Buchanan G. R., Griffin T. C.
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Full Text
N Engl J Med 1994;
331:334-335, Aug 4, 1994.
Correspondence
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