• Brett Doleman, Jo Leonardi-Bee, Thomas P Heinink, Debamita Bhattacharjee, Jon N Lund, and John P Williams.
• Department of Surgery and Anaesthesia, Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Uttoxeter New Road, Derby, UK, DE22 3DT.
• Cochrane Db Syst Rev. 2018 Dec 3; 12: CD012624.

BackgroundPostoperative pain is a common consequence of surgery and can have deleterious effects. It has been suggested that the administration of opioid analgesia before a painful stimulus may improve pain control. This can be done in two ways. We defined 'preventive opioids' as opioids administered before incision and continued postoperatively, and 'pre-emptive opioids' as opioids given before incision but not continued postoperatively. Both pre-emptive and preventive analgesia involve the initiation of an analgesic agent prior to surgical incision with the aim of reducing intraoperative nociception and therefore postoperative pain.ObjectivesTo assess the efficacy of preventive and pre-emptive opioids for reducing postoperative pain in adults undergoing all types of surgery.Search MethodsWe searched the following electronic databases: CENTRAL, MEDLINE, Embase, AMED, and CINAHL (up to 18 March 2018). In addition, we searched for unpublished studies in three clinical trial databases, conference proceedings, grey literature databases, and reference lists of retrieved articles. We did not apply any restrictions on language or date of publication.Selection CriteriaWe included parallel-group randomized controlled trials (RCTs) only. We included participants aged over 15 years old undergoing any type of surgery. We defined postincision opioids as the same intervention administered after incision whether single dose (as comparator with pre-emptive analgesia) or continued postoperatively (as comparator with preventive analgesia) (control group). We considered studies that did and did not use a double-dummy placebo (e.g. intervention group received active drug before incision and placebo after incision; control group received placebo before incision and active drug after incision).Data Collection And AnalysisWe used the standard methodological procedures expected by Cochrane. Our primary outcomes were: early acute postoperative pain (measured within six hours and reported on a 0-to-10 scale) and respiratory depression. Our secondary outcomes included: late acute postoperative pain (24 to 48 hours and reported on a 0-to-10 scale), 24-hour morphine consumption, and adverse events (intraoperative bradycardia and hypotension). We used GRADE to assess the quality of the evidence for each outcome.Main ResultsWe included 20 RCTs, including one unpublished study with 1343 participants. Two studies were awaiting classification as the full text for these studies was not available. One study evaluated pre-emptive opioids, and 19 studies evaluated preventive opioids. We considered only one study to be at low risk of bias for most domains. The surgeries and opioids used varied, although roughly half of the included studies were conducted in abdominal hysterectomy, and around a quarter used morphine as the intervention. All studies were conducted in secondary care.Pre-emptive opioids compared to postincision opioidsFor pre-emptive opioids in dental surgery, there may be a reduction in early acute postoperative pain (mean difference (MD) -1.20, 95% confidence interval (CI) -1.75 to -0.65; 40 participants; 1 study; low-quality evidence). This study did not report on adverse events (respiratory depression, bradycardia, or hypotension). There may be a reduction in late acute postoperative pain (MD -2.10, 95% CI -2.57 to -1.63; 40 participants; 1 study; low-quality evidence). This study did not report 24-hour morphine consumption.Preventive opioids compared to postincision opioidsFor preventive opioids, there was probably no reduction in early acute postoperative pain (MD 0.11, 95% CI -0.32 to 0.53; 706 participants; 10 studies; I2 = 61%; moderate-quality evidence). There were no events of respiratory depression in four studies (433 participants). There was no important reduction in late acute postoperative pain (MD -0.06, 95% CI -0.13 to 0.01; 668 participants; 9 studies; I2 = 0%; moderate-quality evidence). There may be a small reduction in 24-hour morphine consumption (MD -4.91 mg, 95% CI -9.39 mg to -0.44 mg; 526 participants; 11 studies; I2 = 82%; very low-quality evidence). There may be similar rates of bradycardia (risk ratio (RR) 0.33, 95% CI 0.01 to 7.88; 112 participants; 2 studies; I2 = 0%; low-quality evidence) and hypotension (RR 1.08, 95% CI 0.25 to 4.73; 88 participants; 2 studies; I2 = 0%; low-quality evidence).Authors' ConclusionsDue to the low quality of the evidence, we are uncertain whether pre-emptive opioids reduce postoperative pain. Based on the trials conducted thus far, there was no clear evidence that preventive opioids result in reductions in pain scores. It was unclear if there was a reduction in morphine consumption due to very low-quality of evidence. Too few studies reported adverse events to be able to draw any definitive conclusions. Once assessed, the two studies awaiting classification may alter the conclusions of the review.

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