title: Once-daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study.
abstract: BACKGROUND
  Randomized controlled trials can answer questions of efficacy, but long-term pharmacovigilance studies generate complementary safety data.
  
  
  OBJECTIVE
  Level I evidence supports short-term efficacy of opioids in reducing chronic refractory dyspnea. This study aimed to determine the minimum effective once-daily dose of sustained-release morphine, and whether net clinical benefits are sustained safely.
  
  
  METHODS
  In a Phase II dose increment study, 10mg daily of sustained-release morphine was administered, and increased in nonresponders by 10mg daily each week to a maximum of 30 mg daily. The participant was withdrawn if there were unacceptable side effects or no response to maximum dose. If participants had a 10% improvement in dyspnea over their own baseline, they joined a long-term Phase IV effectiveness/safety study at that dose. Complying with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines, response and side effects are described, with demographic and clinical characteristics of responders.
  
  
  RESULTS
  Eighty-three participants (53 males, mean age 75 years, 54% with chronic obstructive pulmonary disease) provided more than 30 patient-years of data. Fifty-two participants derived ≥ 10% benefit (on average 35% improvement over baseline), giving a response rate of 62% (number needed to treat of 1.6: number needed to harm 4.6); for 70%, this dose was 10mg/24h. Benefit was maintained at three months for 28 (33%) people. Ranking of breathlessness was reduced significantly (P<0.001), but constipation increased (P<0.001) despite laxatives. There were no episodes of respiratory depression or hospitalizations as a result of the sustained-release morphine. Overall, one in three people continued to derive benefit at three months.
  
  
  CONCLUSIONS
  Ten milligrams of sustained-release oral morphine once daily is safe and effective for most people who respond.
authors: Discipline, Palliative and Supportive Services, Flinders University, Bedford Park, SA, Australia. david.currow@flinders.edu.au
authors: David C
authors: DC
authors: Currow
authors: Christine
authors: C
authors: McDonald
authors: Sheila
authors: S
authors: Oaten
authors: Bernadette
authors: B
authors: Kenny
authors: Peter
authors: P
authors: Allcroft
authors: Peter
authors: P
authors: Frith
authors: Michael
authors: M
authors: Briffa
authors: Miriam J
authors: MJ
authors: Johnson
authors: Amy P
authors: AP
authors: Abernethy
mesh_terms: D000368:Aged; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D004417:Dyspnea / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000627:therapeutic use; D060735:Pharmacovigilance; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D009020:Morphine