The Moral of the StoryKlass, Perri
doi: 10.1056/NEJMp0802542pmid: 18509118
A 20-month-old boy was brought in to the clinic because he was vomiting. Two nights before, the child had fallen down some stairs. Dr. Perri Klass writes about the worry that set in after she saw the boy and about the voices that can echo in your head after even a simple clinical decision.
Methylnaltrexone for Opioid-Induced Constipation in Advanced IllnessThomas, Jay; Karver, Sloan; Cooney, Gail Austin; Chamberlain, Bruce H.; Watt, Charles Kevin; Slatkin, Neal E.; Stambler, Nancy; Kremer, Alton B.; Israel, Robert J.
doi: 10.1056/NEJMoa0707377pmid: 18509120
BackgroundConstipation is a distressing side effect of opioid treatment. As a quaternary amine, methylnaltrexone, a μ-opioid–receptor antagonist, has restricted ability to cross the blood–brain barrier. We investigated the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness.MethodsA total of 133 patients who had received opioids for 2 or more weeks and who had received stable doses of opioids and laxatives for 3 or more days without relief of opioid-induced constipation were randomly assigned to receive subcutaneous methylnaltrexone (at a dose of 0.15 mg per kilogram of body weight) or placebo every other day for 2 weeks. Coprimary outcomes were laxation (defecation) within 4 hours after the first dose of the study drug and laxation within 4 hours after two or more of the first four doses. Patients who completed this phase were eligible to enter a 3-month, open-label extension trial.ResultsIn the methylnaltrexone group, 48% of patients had laxation within 4 hours after the first study dose, as compared with 15% in the placebo group, and 52% had laxation without the use of a rescue laxative within 4 hours after two or more of the first four doses, as compared with 8% in the placebo group (P<0.001 for both comparisons). The response rate remained consistent throughout the extension trial. The median time to laxation was significantly shorter in the methylnaltrexone group than in the placebo group. Evidence of withdrawal mediated by central nervous system opioid receptors or changes in pain scores was not observed. Abdominal pain and flatulence were the most common adverse events.ConclusionsSubcutaneous methylnaltrexone rapidly induced laxation in patients with advanced illness and opioid-induced constipation. Treatment did not appear to affect central analgesia or precipitate opioid withdrawal. (ClinicalTrials.gov number, NCT00402038.)
A Placebo-Controlled Trial of Prucalopride for Severe Chronic ConstipationCamilleri, Michael; Kerstens, René; Rykx, An; Vandeplassche, Lieve
doi: 10.1056/NEJMoa0800670pmid: 18509121
BackgroundIn this 12-week trial, we aimed to determine the efficacy of prucalopride, a selective, high-affinity 5-hydroxytryptamine4 receptor agonist, in patients with severe chronic constipation.MethodsIn our multicenter, randomized, placebo-controlled, parallel-group, phase 3 trial, patients with severe chronic constipation (≤2 spontaneous, complete bowel movements per week) received placebo or 2 or 4 mg of prucalopride, once daily, for 12 weeks. The primary efficacy end point was the proportion of patients having three or more spontaneous, complete bowel movements per week, averaged over 12 weeks. Secondary efficacy end points were derived from daily diaries and validated questionnaires completed by patients. Adverse events, clinical laboratory values, and cardiovascular effects were monitored.ResultsEfficacy was analyzed in 620 patients. The proportion of patients with three or more spontaneous, complete bowel movements per week was 30.9% of those receiving 2 mg of prucalopride and 28.4% of those receiving 4 mg of prucalopride, as compared with 12.0% in the placebo group (P<0.001 for both comparisons). Over 12 weeks, 47.3% of patients receiving 2 mg of prucalopride and 46.6% of those receiving 4 mg of prucalopride had an increase in the number of spontaneous, complete bowel movements of one or more per week, on average, as compared with 25.8% in the placebo group (P<0.001 for both comparisons). All other secondary efficacy end points, including patients' satisfaction with their bowel function and treatment and their perception of the severity of their constipation symptoms, were significantly improved with the use of 2 or 4 mg of prucalopride as compared with placebo, at week 12. The most frequent treatment-related adverse events were headache and abdominal pain. There were no significant cardiovascular effects of treatment.ConclusionsOver 12 weeks, prucalopride significantly improved bowel function and reduced the severity of symptoms in patients with severe chronic constipation. Larger and longer trials are required to further assess the risks and benefits of the use of prucalopride for chronic constipation. (ClinicalTrials.gov number, NCT00483886.)
Precocious PubertyCarel, Jean-Claude; Léger, Juliane
doi: 10.1056/NEJMcp0800459pmid: 18509122
The parents of a 6-year-old girl bring her to a pediatrician because of breast development. Her medical history is unremarkable. The parents are of average height, and the mother reports first menstruating when she was 11 years old. On physical examination, the girl is 125 cm tall (in the 97th percentile for her age), weighs 28 kg, and has a body-mass index of 17.9 (90th percentile for her age). Her breast development is classified as Tanner stage 3, and she has Tanner stage 2 pubic hair. Review of her previous growth data indicates that she has grown 8 cm during the past year. How should her condition be evaluated and managed?