title: [Long-term opioid therapy in chronic noncancer pain. A systematic review and meta-analysis of efficacy, tolerability and safety in open-label extension trials with study duration of at least 26 weeks].
abstract: BACKGROUND
  The efficacy and safety of long-term (≥ 6 months) opioid therapy (LtOT) in chronic noncancer pain (CNCP) is under debate. A systematic review with meta-analysis of the efficacy and harms of opioids in open-label extension studies of randomized controlled trials (RCTs) has not been conducted until now.
  
  
  METHODS
  We screened MEDLINE and clinicaltrials.gov (through to December 2013), as well as reference sections of systematic reviews of long-term RCTs of opioids in CNCP. We included open-label extension trials with a study duration ≥ 26 weeks of RCTs of ≥ 2 weeks duration. Using a random effects model, pooled estimates of event rates for categorical data and standardized mean differences (SMD) for continuous variables were calculated.
  
  
  RESULTS
  We included 11 open-label extension studies with 2445 participants with nociceptive (low back, osteoarthritis) and neuropathic (radicular, polyneuropathy) pain. Median study duration was 26 (range 26-108) weeks. Four studies tested oxycodone, two studies tramadol and buprenorphine; hydromorphone, morphine, oxymorphone and tapentadol were each tested in one study. Of the patients randomized at baseline, 28.5 % (95 % confidence interval, CI, 17.9-39.2 %) finished the open-label period; 53.5 % (95 % CI 38.1-68.2 %) of patients entering the open-label period finished the open-label period. In sum, the total loss was 71.5 % (95 % CI 60.9-83.1 %) of all patients primarily included into the RCT. A total of 4.9 % (95 % CI 2.9-8.2 %) of patients dropped out due lack of efficacy; 16.8 % (95 % CI 11.0-24.8 %) dropped out to due adverse events (AE) in the open-label period and 0.08 % (95 % CI 0.001-0.05 %) of patients died during the open-label period. Only one study systematically assessed aberrant drug behavior of the patients: 5.7 % (95 % CI 3.4-9.6 %) showed aberrant drug behavior in the opinion of the investigators and 2.6 % (95 % CI 1.2-5.8 %) were judged to show aberrant drug behavior by independent expert assessment. There was no significant change (p = 0.50) in pain intensity between the end of the randomized period and the end of open-label phase (SMD 0.19 [- 0.03, 0.41]; six studies with 1360 participants).
  
  
  CONCLUSIONS
  Only a minority of patients selected for opioid therapy at randomization finished the long-term open-label study. However, sustained effects of pain reduction could be demonstrated in these patients. LtOT can be considered in carefully selected and monitored CNCP patients who experience clinically meaningful pain reduction with at least tolerable AE in short-term opioid therapy. The English full-text version of this article is freely available at SpringerLink (under "Supplementary Material").
authors.affiliation: Innere Medizin I, Klinikum Saarbrücken gGmbH, Winterberg 1, 66119, Saarbrücken, Deutschland, whaeuser@klinikum-saarbruecken.de.
authors.forename: W
authors.initials: W
authors.lastname: Häuser
authors.forename: K
authors.initials: K
authors.lastname: Bernardy
authors.forename: C
authors.initials: C
authors.lastname: Maier
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000627:therapeutic use*; D002047:Buprenorphine / Q000009:adverse effects / Q000627:therapeutic use; D059350:Chronic Pain / Q000188:drug therapy*; D004091:Hydromorphone / Q000009:adverse effects / Q000627:therapeutic use; D008134:Long-Term Care; D009020:Morphine / Q000009:adverse effects / Q000627:therapeutic use; D010098:Oxycodone / Q000009:adverse effects / Q000627:therapeutic use; D010111:Oxymorphone / Q000009:adverse effects / Q000627:therapeutic use; D010147:Pain Measurement / Q000187:drug effects; D010636:Phenols / Q000009:adverse effects / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D000077432:Tapentadol; D014147:Tramadol / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D010636:Phenols; D014147:Tramadol; D002047:Buprenorphine; D009020:Morphine; D010111:Oxymorphone; D010098:Oxycodone; D000077432:Tapentadol; D004091:Hydromorphone