Daily Assessment of Pain in Adults with Sickle Cell Disease

Context Although outpatient, emergency department, and hospital visits have been used as indicators of sickle cell disease severity, the relationship between health care use and pain episodes has not been well described. Contribution Two hundred thirty-two patients with sickle cell disease completed a daily diary for 6 months, providing 31017 patient-days for analysis. Patients reported pain on 56% of total patient-days, crises on 13%, and health care utilization on 4%. Implication Patients with sickle cell disease frequently have pain but usually manage even severe pain without an outpatient, emergency department, or hospital visit. The Editors Pain may be severe and disabling for patients with sickle cell disease, a genetic erythrocyte disorder affecting persons of African, Mediterranean, or Asian descent (1, 2). Pain typically occurs in long bones, joints, the back, the abdomen, and the chest. Although the pathophysiology of pain and its exacerbations is complex and incompletely understood, a complex cascade of ischemia and vaso-occlusion in the microcirculation is believed to be involved (312). Sickle cell disease vaso-occlusive pain is responsible for most sickle cell disease medical contacts. The often episodic nature of these contacts leads many to conclude that patients do not have pain for most of their days. Caregivers have therefore traditionally used the term crisis to describe these contacts and their underlying episodic, acute pain exacerbations and have reserved the term chronic pain syndrome to describe pain from sickle cell disease complications, such as ankle ulcers or avascular necrosis (13). Higher-utilizing adults are at higher risk for death, so measuring medical contacts has clinical meaning (14). However, the relationship among daily reported sickle cell disease pain, crises, and utilization has not been described in large-scale, longitudinal epidemiologic studies. To better understand the epidemiology of daily pain in sickle cell disease, we examined the relationship among self-reported pain, crises, and health care utilization for pain in a cohort study of patients with sickle cell disease. Methods Study Design PiSCES (Pain in Sickle Cell Epidemiology Study) is a longitudinal study of pain in sickle cell disease, with particular emphasis on potentially mutable, causal, nonbiological variables. It is also a methodological study of the relationship among measures of pain, crises, and utilization in sickle cell disease. The methods of PiSCES are described in detail elsewhere (15, 16). In brief, we enrolled 308 patients from July 2002 through August 2004. We collected baseline information (including demographic characteristics and medical history), laboratory data (blood and urine samples), and up to 180 daily pain diaries. We recruited patients 16 years of age or older from across Virginia; most were from the Richmond and Tidewater areas. Sources included statewide sickle cell chapters, clinics and emergency departments, referrals from other patients and health departments, and direct recruiting through health fairs and radio public service announcements. Both the study and our recruitment methods were approved by the institutional review board of Virginia Commonwealth University, Richmond, Virginia. We invited potentially eligible patients for an enrollment visit, at which time we obtained informed consent. Patients received routine care for their sickle cell disease from either community-based physicians or sickle cell specialist physicians associated with academic medical centers (2 physicians at Virginia Commonwealth University serving the Richmond area, and 1 physician associated with Eastern Virginia Medical School, Norfolk, Virginia, serving the Tidewater region). Emergent care for the cohort was provided in emergency departments regardless of the patients' usual source of ambulatory care. No day hospitals for sickle cell disease are located in the region. Diary Data Patients filled out daily diaries for up to 6 months. They were encouraged (at the initial baseline visit and with reminder calls by study staff) to complete the diary each day and return it by mail using provided, stamped envelopes. They received payment for each returned diary, with a higher payment in the latter 2 months of the study to encourage study completion. We modeled the diary after that of the Multicenter Study of Hydroxyurea (17). We asked patients to report the following, among other things, about the previous 24 hours in their diary: their worst sickle cell pain intensity, on a scale from 0 (none) to 9 (unbearable), and whether they were in a sickle cell crisis, had taken medication for their pain (and if so, what), or had gone for an unscheduled physician visit or emergency department visit or had been hospitalized because of sickle cell pain. Crises were self-defined by each patient. Statistical Analysis For analysis, we defined unplanned health care utilization as an unscheduled clinic visit, emergency department visit, or overnight hospitalization. We defined opiate use on home care days as use of any opiates on days when the patient was not seen at the hospital for their sickle cell pain (in either the emergency department or overnight hospitalization). We constructed crisis episodes and utilization episodes by counting groups of 1 or more contiguous crisis days as single crisis episodes and contiguous utilization days as single utilization episodes. Missing diary days that were immediately preceded and followed by crisis days or by utilization days were considered part of the same crisis or utilization episode, respectively. We used generalized estimating equation methods with a logit link (logistic regression, controlling for repeated measures within a patient) to determine whether occurrence of pain, crisis, or unplanned health care utilization varied daily across patient characteristics, controlling for clustering of diary days within patients. We estimated the probability of experiencing the outcomes, along with the 95% CIs, by using the generalized estimating equation parameter estimates and empirical SEs. To study the relationship between the proportion of pain days experienced by patients and the mean intensity of pain, we grouped patients into 6 categories according to their increasing proportion of pain days (calculated as the proportion of diary days with reported pain intensity greater than 0): 5% or less, 6% to 25%, 26% to 50%, 51% to 75%, 76% to 95%, and 96% to 100%. We used mixed-model analysis of variance to evaluate the differences in pain intensity across these groups, controlling for clustering of diary days within patients, and we performed separate analyses for pain days, crisis days, and noncrisis pain days. Least-squares means are reported. To understand the relationship among self-reported pain, crises, and utilization, we placed diary days into 1 of 4 mutually exclusive, ordinal categories by severity. From most to least severe, the categories were days with any unplanned health care utilization for sickle cell disease pain, regardless of self-reported crises; days with self-reported crises without unplanned health care utilization; pain days without utilization or crisis; and pain-free days. We calculated the proportion of all days that fell into these 4 categories, estimating and comparing mean pain intensity across the categories by using mixed-model analysis of variance, which controlled for repeated measures (days within patients). To describe the coincidence of crisis and utilization for each patient, we classified days as to whether the patient had a crisis and whether unplanned health care utilization occurred and computed the percentage of diary days for each of the 4 categories. We then calculated the mean and SD of these percentages over all patients. This method adjusted for the varying number of diaries contributed by each patient. We also used mixed-model regression analysis to see whether unplanned utilization was predictive of self-reported crisis, after controlling for pain intensity. To determine whether crisis and utilization episodes overlapped, we compared the dates when each type of episode occurred and counted the overlap. We used crisis episodes as a denominator, determining how often utilization episodes overlapped with them, then did the same by using utilization episodes as denominator. By counting any missing diary days surrounded on both sides by crisis or utilization days as part of a single episode, we maximized the chance of overlap. Analyses were conducted by using SAS, version 9 for Windows (SAS Institute, Cary, North Carolina). Role of the Funding Source The National Heart, Lung, and Blood Institute provided an unrestricted grant for this project. The funding source had no influence on the planning, conduct, analysis, or publication of this study or its results. Results Three hundred eight patients enrolled in PiSCES and completed baseline surveys. Twenty-three patients (7.5%) sent in no diaries. Of the remaining 285 patients, we excluded 53 (19%) because they completed fewer than 30 diaries. The remaining 232 patients constitute the analysis sample. Patients in the analysis sample were similar to those excluded except for age; the patients who did not complete sufficient diaries tended to be younger (mean age, 28.3 years vs. 32.6 years; P= 0.012). We included a total of 31017 diaries (patient-days) in this analysis. The median number of diaries completed was 158, about 85% of the diaries requested. When patients were grouped by the number of diaries submitted (30 to 59, 60 to 90, and so on), we found no statistically significant differences among groups in terms of pain, crisis, or utilization. Table 1 contains a description of the analysis sample (n= 232), including probabilities of a pain day, crisis day, and utilization day, adjusted for repeated measures within patients. More than half of studied patients were female, 87% graduated f