A randomized, controlled clinical trial of ketoprofen for sickle-cell disease vaso-occlusive crises in adults

Abstract

Vaso-occlusive crisis (VOC) is the primary cause of hospitalization of patients with sickle-cell disease. Treatment mainly consists of intravenous morphine, which has many dose-related side effects. Nonsteroidal antiinflammatory drugs have been proposed to provide pain relief and decrease the need for opioids. Nevertheless, only a few underpowered trials of nonsteroidal antiinflammatory drugs for sickle-cell VOC have been conducted, and conflicting results were reported. We conducted a phase 3, double-blind, randomized, placebo-controlled trial with ketoprofen (300 mg/day for 5 days), a nonselective cyclooxygenase inhibitor, for severe VOC in adults. A total of 66 VOC episodes were included. The primary efficacy outcome was VOC duration. The secondary end points were morphine consumption, pain relief, and treatment failure. Seven VOC episodes in each group were excluded from the analysis because of treatment failures. No significant between-group differences were observed for the primary outcome or the secondary end points. Thus, although ketoprofen was well-tolerated, it had no significant efficacy as treatment of VOC requiring hospitalization. These findings argue against its systematic use in this setting. IntroductionPain is the most frequent manifestation of sickle-cell disease (SCD) and is thought to be a consequence of sickle-cell vaso-occlusion. Vaso-occlusive crisis (VOC) is the primary cause of hospitalization of patients with SCD and is among the main causes of death in affected adults. 1,2 To date, no specific therapeutic agents have been approved for VOC, and treatment of uncomplicated VOC is merely symptomatic: bed rest, analgesics and hydration. According to American and British recommendations,3,4 severe pain of VOC that requires hospitalization should be treated with intravenous morphine. However, pain relief is not easily obtained during episodes of VOC, and morphine has many dose-related side effects, including sedation, nausea, constipation, pruritus, and hypoventilation. In addition, it might contribute to the development of acute chest syndrome. 5 In light of these potentially severe adverse events, many physicians are still reluctant to administer high doses of potent narcotics, and many medical texts do not provide adequate information for the treatment of pain. 6 A drug that would provide pain relief in patients with SCD and decrease the need for narcotics would be of obvious benefit.According to the results of 2 trials, 7,8 corticosteroids had a potentially beneficial effect on VOC by reducing the duration of analgesics, but corticosteroids have been shown to induce recurrent pain episodes. 7-11 Pilot trials with inhaled nitric oxide 12 and poloxamer 188 13 yielded promising results but were experimental, and those treatments are not yet available for routine use.Nonsteroidal antiinflammatory drugs (NSAIDs) are an effective treatment to decrease surgical and posttraumatic pain. 14-21 NSAIDs and opioid analgesics have a synergic effect, 22 thereby achieving better pain control and an ...

Delayed hemolytic transfusion reaction in adult sickle‐cell disease: presentations, outcomes, and treatments of 99 referral center episodes

“…Furthermore, our study results indicated high ACS frequency during DHTR, estimated at 50%, while only 20% of VOC suffers developed secondary ACS. 18 The extent of intravascular hemolysis in severe DHTR could partly explain the vascular reaction leading to ACS. Indeed, physiological findings demonstrated that cell-free plasma Hb was associated with endothelial dysfunction and PHT.…”

“…VOC was defined as pain, affecting at least one part of the body, including limbs, ribs, sternum, head (skull), spine, and/or pelvis, which required antalgics and was not attributable to other causes. 18 The diagnosis of ACS was based on the association of a respiratory symptom (dyspnea or chest pain), an abnormal lung sound at auscultation, and a new pulmonary infiltrate on the chest radiograph. In some cases, we have jointly used the rate of decline in hemoglobin (HbA)…”

Score Predicting Acute Chest Syndrome During Vaso-occlusive Crises in Adult Sickle-cell Disease Patients

“…The primary endpoint was ACS onset within 15 days of admission, defined as the appearance of an auscultatory abnormality (crepitants and/or bronchial breathing) and/or chest pain and an infiltrate on chest film and/or thoracic computed-tomography (CT) scan but excluding atelectasia. Secondary endpoints were: hospitalization duration, BT, morphine consumption, visual analog scale (VAS: 0 mm, none; 100 mm, worst possible) for pain and our categorical pain score (CPS: range 0–3 points: 0, no pain; 1, mild pain, unaffected by mobilization; 2, moderate pain, increased by mobilization; 3, severe pain with disability) (Bartolucci et al, 2009) evaluations, BT, intensive care unit admission and mortality. Medical history and precipitating factors were systematically recorded on a standardized form.…”

Le syndrome thoracique aigu : complication pulmonaire aiguë des patients adultes atteints d’un syndrome drépanocytaire majeur

“…Le nefopam est quelque fois utilisé en association avec ces deux drogues. Les benzodiazépines ne sont pas recommandées dans ce contexte aigu en raison de leurs effets centraux associés aux morphiniques et les anti-inflammatoires non stéroï-diens n'ont pas montré d'intérêt en association systématique avec les morphiniques dans le contrôle des douleurs des crises vaso-occlusives [19]. Le protoxyde d'azote et, dans des cas exceptionnels la kétamine, peuvent être utilisés comme appoint dans les crises hyperalgiques.…”