Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial.

CONTEXT: Sickle cell disease (SCD) can cause severe painful episodes that are often thought to be caused by vaso-occlusion. The current therapy for these uncomplicated painful episodes includes hydration, oxygen, and analgesics. Purified poloxamer 188 may increase tissue oxygenation and thereby reduce inflammation, pain, and the overall duration of such painful episodes in patients with SCD. OBJECTIVE: To compare the duration of painful episodes in patients with SCD treated with purified poloxamer 188 to that of similar episodes experienced by patients who receive a placebo. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, intention-to-treat trial conducted between March 1998 and October 1999 in 40 medical centers in the United States. PARTICIPANTS: Two hundred fifty-five patients with SCD (aged 9-53 years) who had a painful episode sufficiently severe to require hospitalization and narcotic analgesics. INTERVENTION: Patients were randomly assigned to receive an intravenous infusion of purified poloxamer 188, 100 mg/kg for 1 hour followed by 30 mg/kg per hour for 47 hours (n = 127), or a matching volume of saline placebo (n = 128). MAIN OUTCOME MEASURE: Duration of the painful episode, from randomization to crisis resolution. RESULTS: Mean (SD) duration of the painful episodes was 141 (42) hours in the placebo group compared with 133 (41) hours in those treated with purified poloxamer 188, a 9-hour reduction (P =.04). Subset analyses indicated an even more pronounced purified poloxamer 188 effect in children aged 15 years or younger (21 hours; P =.01) and in patients who were receiving hydroxyurea (16 hours; P =.02). Finally, the proportion of patients achieving crisis resolution was increased by purified poloxamer 188 (65/126 [52%] vs 45/123 [37%]; P =.02). Similar results were observed in children aged 15 years or younger (22/37 [60%] vs 10/36 [28%]; P =.009) and in patients who were also receiving hydroxyurea (12/26 [46%] vs 4/28 [14%]; P =.02). CONCLUSIONS: A decrease in the duration of painful episodes and an increase in the proportion of patients who achieved resolution of the symptoms were observed when the purified poloxamer 188-treated patients were compared with the patients receiving placebo. However, the difference between these groups was significant but relatively small. In subgroup analysis, a more significant effect on both parameters was observed in children and in patients who were receiving concomitant hydroxyurea. It is important to confirm both of these observations in further prospective trials.

Activation of sickle red blood cell adhesion via integrin-associated protein/CD47-induced signal transduction.

Peripheral human red blood cells (RBCs) are not generally known to become activated and adhesive in response to cell signaling. We show, however, that soluble thrombospondin via integrin-associated protein (IAP; CD47) increases the adhesiveness of sickle RBCs (SS RBCs) by activating signal transduction in the SS RBC. This stimulated adhesion requires occupancy of IAP and shear stress and is mediated by the activation of large G proteins and tyrosine kinases. Reticulocyte-enriched RBCs derived from sickle-cell disease (SCD) patients are most responsive to IAP-induced activation. These studies therefore establish peripheral SS RBCs as signaling cells that respond to a novel synergy between IAP-induced signal transduction and shear stress, suggesting new therapeutic targets in SCD.

Integrin-associated protein is an adhesion receptor on sickle red blood cells for immobilized thrombospondin.

The adhesive protein thrombospondin (TSP) potentially mediates sickle (SS) red blood cell (RBC) adhesion to the blood vessel wall, thereby contributing to vaso-occlusive crises in sickle cell disease. We previously reported that SS RBCs bind to immobilized TSP under flow conditions, whereas normal (AA) red cells do not. However, the SS RBC receptors that mediate this interaction are largely unknown. Here it is reported that integrin-associated protein (IAP), or CD47, mediates the adhesion of these cells to immobilized TSP under both flow and static conditions. A peptide derived from the C-terminal IAP binding site of TSP also supports sickle cell adhesion; adhesion to this peptide or to TSP is inhibited specifically by the anti-IAP monoclonal antibody, 1F7. Furthermore, these data suggest that IAP on SS RBCs is structurally different from that expressed on AA RBCs but that IAP expression levels do not vary between AA and SS RBCs. This structural difference may contribute to the enhanced adhesion of SS RBCs to immobilized TSP. These results identify IAP as a TSP receptor on SS RBCs and suggest that this receptor and its binding site within TSP represent potential therapeutic targets to decrease vaso-occlusion. (Blood. 2001;97:2159-2164)

Bone marrow necrosis in sickle cell disease: a description of three cases and a review of the literature.

Bone marrow necrosis (BMN) ranges from a localized to a widespread generalized process. Most often seen in patients with leukemia and other malignant conditions, generalized BMN has also been observed in patients with sickle cell disease (SCD), where it is almost certainly a consequence of blood vessel occlusion. Activation of the clotting system seems to play a role in this clinical setting. Systemic fat embolism and acute multi-organ failure syndrome can also complicate BMN in patients with SCD. We describe here 3 cases of BMN associated with SCD. Each patient exhibited an unusually severe vaso-occlusive crisis accompanied by persistent fever, a high level of serum lactate dehydrogenase, leukoerythroblastosis, and large numbers of nucleated red cells. Despite such suggestive clinical features, diagnosis of BMN still requires a bone marrow biopsy. Particularly in patients with SCD, the early institution of transfusion therapy can be life-saving. The ominous prognosis ascribed to generalized BMN seems to reflect the poor outcome of such underlying conditions as leukemia; however, the prognosis of generalized BMN is not so poor in association with SCD and other nonmalignant states.

Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group.

BACKGROUND: The acute chest syndrome is the leading cause of death among patients with sickle cell disease. Since its cause is largely unknown, therapy is supportive. Pilot studies with improved diagnostic techniques suggest that infection and fat embolism are underdiagnosed in patients with the syndrome. METHODS: In a 30-center study, we analyzed 671 episodes of the acute chest syndrome in 538 patients with sickle cell disease to determine the cause, outcome, and response to therapy. We evaluated a treatment protocol that included matched transfusions, bronchodilators, and bronchoscopy. Samples of blood and respiratory tract secretions were sent to central laboratories for antibody testing, culture, DNA testing, and histopathological analyses. RESULTS: Nearly half the patients were initially admitted for another reason, mainly pain. When the acute chest syndrome was diagnosed, patients had hypoxia, decreasing hemoglobin values, and progressive multilobar pneumonia. The mean length of hospitalization was 10.5 days. Thirteen percent of patients required mechanical ventilation, and 3 percent died. Patients who were 20 or more years of age had a more severe course than those who were younger. Neurologic events occurred in 11 percent of patients, among whom 46 percent had respiratory failure. Treatment with phenotypically matched transfusions improved oxygenation, with a 1 percent rate of alloimmunization. One fifth of the patients who were treated with bronchodilators had clinical improvement. Eighty-one percent of patients who required mechanical ventilation recovered. A specific cause of the acute chest syndrome was identified in 38 percent of all episodes and 70 percent of episodes with complete data. Among the specific causes were pulmonary fat embolism and 27 different infectious pathogens. Eighteen patients died, and the most common causes of death were pulmonary emboli and infectious bronchopneumonia. Infection was a contributing factor in 56 percent of the deaths. CONCLUSIONS: Among patients with sickle cell disease, the acute chest syndrome is commonly precipitated by fat embolism and infection, especially community-acquired pneumonia. Among older patients and those with neurologic symptoms, the syndrome often progresses to respiratory failure. Treatment with transfusions and bronchodilators improves oxygenation, and with aggressive treatment, most patients who have respiratory failure recover.

Renal abnormalities in sickle cell disease.

Sickle cell anemia and the related hemoglobinopathies are associated with a large spectrum of renal abnormalities. The patients have impaired urinary concentrating ability, defects in urinary acidification and potassium excretion, and supranormal proximal tubular function. The latter is manifest by increased secretion of creatinine and by reabsorption of phosphorus and beta(2)-microglobulin. Young patients with sickle cell disease (SCD) have supranormal renal hemodynamics with elevations in both effective renal plasma flow (ERPF) and glomerular filtration rate (GFR). These parameters decrease with age as well as following the administration of prostaglandin inhibitors. Proteinuria, a common finding in adults with sickle cell disease, may progress to the nephrotic syndrome. Proteinuria, hypertension, and increasing anemia predict end-stage renal disease (ESRD). While ESRD can be managed by dialysis and/or renal transplantation, there may be an increased rate of complications in renal transplant recipients with SCD. Hematuria is seen in individuals with all of the SCDs as well as with sickle cell trait. In most cases the etiology of the hematuria turns out to be benign. However, there does appear to be an increased association between SCD and renal medullary carcinoma. Therefore, those SCD patients who present with hematuria should initially undergo a thorough evaluation in order to exclude this aggressive neoplasm. Papillary necrosis may occur due to medullary ischemia and infarction. Erythropoietin levels are usually lower than expected for their degree of anemia and decrease further as renal function deteriorates. An abnormal balance of renal prostaglandins may be responsible for some of the changes in sickle cell nephropathy. Acute renal failure is a component of the acute multiorgan failure syndrome (MOFS). Finally, progression of sickle cell nephropathy to ESRD may be slowed by adequate control of hypertension and proteinuria. However, the prevention of the renal complications of SCD will require a cure for this genetic disorder.

Follow-up of coping skills training in adults with sickle cell disease: analysis of daily pain and coping practice diaries.

This study examined the 3-month follow-up effects of a pain coping skills intervention in African American adults with sickle cell disease. Sixty-seven participants were randomly assigned to either a coping skills condition or a disease-education control condition. Multivariate analyses applied to summary measures of coping, laboratory pain perception, and clinical measures indicated that participants in the coping intervention reported significantly lower laboratory pain and significantly higher coping attempts at 3-month follow-up in comparison with the control condition. Multilevel random effects models applied to prospective daily diaries of daily pain, health care contacts, and coping practice indicated that on pain days when participants practiced their strategies, they had less major health care contacts in comparison with days when they did not use strategies.

Depression, disease severity, and sickle cell disease.

The present study examined depressive symptomatology in 440 adults with sickle cell disease (SCD). Participants completed the Center for Epidemiologic Studies--Depression scale (CES-D) as part of their yearly routine visits to the Duke University--University of North Carolina Comprehensive Sickle Cell Center. They also completed questions regarding demographics, disease severity, pain, and health care use. Data analyses revealed that the percentage of patients with SCD exhibiting significant depressive symptomatology dropped from 43 to 18% when a more stringent cutoff was used on the CES-D, suggesting that future studies should determine the most valid cutoff score for identifying depression in patients with SCD. Gender and family income were positively and significantly associated with depressive symptomatology. Also, patients who reported more frequent painful episodes were more likely to report depressive symptoms. Implications for assessment and treatment of depression in adults with SCD are discussed.

Detection of nitrosyl hemoglobin in venous blood in the treatment of sickle cell anemia with hydroxyurea.

The clinical efficacy of hydroxyurea (HU) in the treatment of sickle cell anemia has mainly been attributed to increased levels of fetal hemoglobin (HbF), which reduces the tendency for sickle hemoglobin to polymerize, thereby reducing the frequency of the vaso-occlusive phenomena associated with the disease. However, benefits from HU treatment in patients have been reported in advance of increased HbF levels. Thus, it has been suggested that other hydroxyurea-dependent mechanisms may, in part, account for its clinical efficacy. We have previously demonstrated that HU is metabolized in rats to release nitric oxide and, therefore, postulated the same to occur in humans. However, to our knowledge, evidence of nitric oxide production from HU metabolism in humans has yet to be demonstrated. Here we report that oral administration of HU for the treatment of sickle cell anemia produced detectable nitrosyl hemoglobin. The nitrosyl hemoglobin complex could be detected as early as 30 min after administration and persisted up to 4 h. Our observations support the hypothesis that the ability of HU to ease the vaso-occlusive phenomena may, in part, be attributed to vasodilation and/or decreased platelet activation induced by HU-derived nitric oxide well in advance of increased HbF levels.

Sickle cell adhesion to laminin: potential role for the alpha5 chain.

Sickle red blood cell (RBC) adhesion to the endothelium and to exposed, underlying subendothelial proteins is believed to contribute to vascular occlusion in sickle cell disease. Laminin, a major component of the subendothelium, supports significant adhesion of sickle, but not normal RBCs. The purpose of this study was to define the adhesive region for sickle RBCs within a human laminin preparation using a flow adhesion assay designed to mimic physiologic flow through postcapillary venules. Because sickle RBCs did not adhere to the common laminin contaminants entactin or collagen type IV, neither of these proteins are likely to contribute to the observed adhesion to laminin. Known adhesive regions of laminin neither supported nor inhibited sickle RBC adhesion to laminin, suggesting a mechanism of adhesion previously uncharacterized in other laminin adhesion studies. Moreover, sickle RBCs did not adhere to mouse EHS laminin or to human laminin-2 (merosin), eliminating the alpha1, alpha2, beta1, and gamma1 chains as mediators of sickle cell adhesion. The monoclonal antibody 4C7, which binds at or near the G-domain of the laminin alpha5 chain, significantly inhibited sickle RBC adhesion. These results suggest that an adhesive region for sickle RBCs is contained within the laminin alpha5 chain.

A phase I/II study of polymerized bovine hemoglobin in adult patients with sickle cell disease not in crisis at the time of study.

BACKGROUND: The painful episodes of sickle cell disease (SCD) involve vaso-occlusion and impaired oxygen delivery. HBOC-201, a hemoglobin-based oxygen carrier, has been shown to support oxygen delivery in animal studies and to be safe and well tolerated in normal human volunteers. Therefore, we speculated that it might have a therapeutic role in SCD. METHODS: Eighteen adults with SCD who were asymptomatic at the time of study were enrolled in a Phase I/II single-blind, placebo-controlled, dose-escalation study of HBOC-201. The primary purpose was to assess the safety of the material in this patient population. In addition, as a surrogate marker of efficacy, each subject underwent a variety of exercise tests before and after HBOC-201 was given. RESULTS: All HBOC-201 infusions were well tolerated by the study subjects and no evidence of toxicity was noted. In addition, there was a significant difference in heart rate response to the identical aerobic exercise workload when the study subjects who received HBOC-201 were compared to the subjects who received placebo (p = 0.0061). CONCLUSIONS: HBOC-201 was safely administered to patients with SCD who were not in crisis at the time of study. Furthermore, following infusion of the study material, subjects with SCD performed the identical aerobic exercise-induced workload with an increase in heart rate that was significantly less than the increase observed in the subjects who received an infusion of the saline placebo. These safety and surrogate efficacy data support the notion that HBOC-201 could have efficacy as a treatment for the vasoocclusive episodes of SCD.

Effects of hydroxyurea administration on the body weight, body composition and exercise performance of patients with sickle-cell anaemia.

1. As an ancillary study carried out during the recently completed Multicenter Study of Hydroxyurea, we examined the effect of hydroxyurea on the body weight, body composition and exercise capacity of adult patients with sickle-cell anaemia. 2. The subjects received either hydroxyurea (six males and four females) or placebo (eight males and six females). Data for each subject were generated during four separate 24 h admissions to the General Clinical Research Center. These admissions occurred at baseline and then at 6, 12 and 18 months after the start of study drug (hydroxyurea or placebo) administration. During each admission, body composition was measured by using a dual X-ray absorptiometer, and exercise testing was performed by cycle ergometry. Anaerobic performance was assessed according to a 'Wingate' protocol (20 s at maximal intensity against a cycling resistance of 7.5% body weight). Aerobic performance was examined using a steady state submaximal exercise protocol (10 min cycling time). 3. At baseline, no significant difference in any parameter was found between the hydroxyurea- and placebo-treated groups. At 18 months, the hydroxyurea-treated subjects exhibited an average weight gain of 3.16 kg. The mean weight gain in the placebo-treated subjects was 1.82 kg. Body composition analysis showed that the additional weight in both groups involved both lean and fat body mass components. In anaerobic performance, the subjects given hydroxyurea showed an increase in peak muscle power of 104.9 W. The placebo group also showed an increase, but theirs was a more modest gain of 57.7 W. The most marked improvement in anaerobic performance was observed in the hydroxyurea-treated men (P < 0.05). In aerobic performance, the hydroxyurea-treated subjects exhibited a decrease in peak heart rate response to a standardized workload of 15.2 beats/min, as compared with a decrease of only 4.3 beats/min in the placebo-treated patients. 4. Taken together, the overall weight gain, combined with increases in both anaerobic muscular performance and aerobic cardiovascular efficiency, provides objective data to support the subjective impression that hydroxyurea administration produces an improvement in the physical capacity of patients with sickle-cell anaemia.

Cholecystectomy in sickle cell anemia patients: perioperative outcome of 364 cases from the National Preoperative Transfusion Study. Preoperative Transfusion in Sickle Cell Disease Study Group.

Cholecystectomy is the most common surgical procedure performed in sickle cell anemia (SCA) patients. We investigated the effects of transfusion and surgical method on perioperative outcome. A total of 364 patients underwent cholecystectomy: group 1 (randomized to aggressive transfusion) 110 patients; group 2 (randomized to conservative transfusion) 120 patients; group 3 (nonrandomized nontransfusion) 37 patients; and group 4 (nonrandomized transfusion) 97 patients. Patients were similar except group 3 patients were more likely to be female, over 20 years old, smokers, and more healthy by American Society of Anesthesiologists (ASA) physical status score. Total complication rate was 39%: sickle cell events 19%; intraoperative or recovery room events 11%; transfusion complications 10%; postoperative surgical events 4%; and death 1%. Group 3 patients had the highest incidence of sickle cell events (32%). Open cholecystectomies were performed in 58% and laparoscopic in 42%. Laparoscopic patients were younger and more healthy by ASA score. Laparoscopic patients had longer anesthesia time (3.2 v 2.9 hours), but shorter hospitalization time (6.4 days v 9.8). Complications were similar between these two groups. We conclude that SCA patients undergoing cholecystectomy have a high perioperative morbidity, and the incidence of sickle cell events may be higher in patients not preoperatively transfused. We recommend a conservative preoperative transfusion regimen, and we encourage the use of the laparoscopic technique for SCA patients undergoing elective cholecystectomy.

Case report: splenomegaly and splenic sequestration in an adult with sickle cell anemia.

Splenomegaly in adult patients with homozygous sickle cell anemia (HbSS) is uncommon and splenic sequestration crises are rare. This paper describes a patient with HbSS who, at the age of 24, began to experience acute splenic sequestration crises. These episodes occurred with sufficient frequency and severity to warrant splenectomy. This case is presented to emphasize that, although rare, splenomegaly can persist in adults with homozygous HbSS and can be associated with severe and even life-threatening splenic sequestration. The incidence of splenomegaly in adults with HbSS and the factors linked to it will be discussed and the published reports of splenic sequestration crises in this patient population reviewed. It appears that high hemoglobin F (HbF) levels and alpha-thalassemia may be important etiologic factors in causing persistence of splenomegaly and predisposing patients to splenic sequestration crises.

Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia.

Painful crises in patients with sickle cell anemia are caused by vaso-occlusion and infarction. Occlusion of blood vessels depends on (at least) their diameter, the deformability of red cells, and the adhesion of blood cells to endothelium. Deoxygenated sickle cells are rigid because they contain linear polymers of hemoglobin S (Hb S); polymerization is highly concentration dependent, and dilution of Hb S by a nonsickling hemoglobin such as fetal hemoglobin (Hb F) would be expected to lead ultimately to a decrease in the frequency of painful crises. It might also be expected to decrease the severity of anemia, although the pathogenesis of anemia in sickle cell anemia (SS disease) is not clearly understood. Reversion to production of fetal rather than adult hemoglobin became practical with the discovery that HU was an orally effective and relatively safe "switching agent." Preliminary dose-ranging studies led to a double-blind randomized controlled clinical trial, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), designed to test whether patients treated with HU would have fewer crises than patients treated with placebo. The MSH was not designed to assess the mechanism(s) by which a beneficial effect might be achieved, but it was hoped that observations made during the study might illuminate that question. The 2 MSH treatment groups were similar to each other and were representative of African-American patients with relatively severe disease. The trial was closed earlier than expected, after demonstration that median crisis rate was reduced by almost 50% (2.5 versus 4.5 crises per year) in patients assigned to HU therapy. Hospitalizations, episodes of chest syndrome, and numbers of transfusions were also lower in patients treated with HU. Eight patients died during the trial, and treatment was stopped in 53. There were no instances of alarming toxicity. Patients varied widely in their maximum tolerated doses, but it was not clear that all were taking their prescribed treatments. When crisis frequency was compared with various clinical and laboratory measurements, pretreatment crisis rate and treatment with HU were clearly related to crisis rate during treatment. Pretreatment laboratory measurements were not associated with crisis rates during the study in either treatment group. It was not clear that clinical improvement was associated with an increase in Hb F. Crisis rates of the 2 treatment groups became different within 3 months. Mean corpuscular volumes (MCVs) and the proportion of Hb F containing red cells (F cells) rose, and neutrophil and reticulocyte counts fell, within 7 weeks. When patients were compared on the basis of 2-year crisis rates, those with lower crisis rates had higher F-cell counts and MCVs and lower neutrophil counts. Neutrophil, monocyte, reticulocyte, and platelet counts were directly associated, and F cells and MCV were inversely associated, with crisis rates in 3-month periods. In multivariable analyses, there was strong evidence of independent association of lower neutrophil counts with lower crisis rates. F-cell counts were associated with crisis rate only in the first 3 months of treatment; MCV showed an association over longer periods of time. Overall, the evidence that decreased neutrophil counts played a role in reducing crisis rates was strong. Increased F cells or MCV and evidence of cytoreduction by HU were also associated with decreased crisis rates, but no definitive statement can be made regarding the mechanism of action of HU because the study was not designed to address that question. Future studies should be designed to explore the mechanism of action of HU, to identify the optimal dosage regimen, and to study the effect of HU when combined with other antisickling agents.

Glycoprotein IV-independent adhesion of sickle red blood cells to immobilized thrombospondin under flow conditions.

The abnormal adherence of red blood cells (RBC to the blood vessel wall is believed to contribute to the vascular occlusion observed in patients with sickle call anemia. The cell adhesion receptors GPIV (CD36) and integrin alpha 4 beta 1 (CD49d/CD29) were previously identified on circulating sickle reticulocytes, and shown to mediate sickle RBC adhesion to the endothelium. The presence of damaged endothelium in these patients suggests that exposed extracellular matrix proteins could provide a potential substrate for sickle RBC adhesion. To determine whether RBC adhesion receptors could mediate adhesion to extracellular matrix proteins, we tested their ability to adhere to a variety of immobilized, purified proteins under flow conditions. Neither sickle nor normal RBC adhered to fibronectin, vitronectin, fibrinogen, or collagen. In contrast, we observed substantial adhesion of sickle but not normal RBC to thrombospondin (TSP). The adhesion was not inhibited with known antagonists of the GPIV-TSP interaction, nor by inhibitors of several other known binding domains in TSP. Moreover, the adhesion was resistant to inhibition by soluble TSP, suggesting that immobilization of TSP exposes an adhesive site that is cryptic on TSP in solution. However, the glycosaminoglycans, chondroitin sulfate A, and dextran sulfate were potent inhibitors of this adhesion. These results suggest that a mechanism distinct from GPIV is responsible for sickle RBC adhesion to immobilized TSP under flow conditions.

Case report: splenic sequestration and multiorgan failure as the presenting manifestation of hemoglobin SC disease.

Acute splenic sequestration, a well recognized complication of the various sickle cell syndromes, is characterized by increasing splenomegaly and a sudden fall in hemoglobin concentration. In this article, the authors describe a 21-year-old woman with previously undiagnosed hemoglobin SC disease whose initial presentation was that of acute, severe splenic sequestration. Despite the severity of her illness, prompt diagnosis and appropriate therapy led to a complete recovery. The splenic sequestration in this case was apparently exacerbated by a recent hepatitis B infection. To date, this presentation of hemoglobin SC disease has not been described in the medical literature.

Effects of cognitive coping skills training on coping strategies and experimental pain sensitivity in African American adults with sickle cell disease.

The present study examined whether training in cognitive coping skills would enhance pain coping strategies and alter pain perception in adults with sickle cell disease (SCD). Sixty-four African Americans with SCD were randomly assigned to either a cognitive coping skills condition (three 45-min sessions in which patients were trained to use 6 cognitive coping strategies) or a disease-education control condition (three 45-min didactic-discussion sessions about SCD). Pain sensitivity to calibrated noxious stimulation was measured at pre- and posttesting, as were cognitive coping strategies, clinical pain, and health behaviors. Results indicated that, compared with the randomly assigned control condition, brief training in cognitive coping skills resulted in increased coping attempts, decreased negative thinking, and lower tendency to report pain during laboratory-induced noxious stimulation.