Cochrane in CORR®: Pre‐emptive and Preventive Opioids for Postoperative Pain in Adults Undergoing All Types of Surgery

Importance of the Topic

Approximately 88% of patients with acute postoperative pain following surgery report moderate, severe or extreme pain levels [9]. Ineffective acute-pain management during the postoperative period can result in patient dissatisfaction, increased morbidity, impaired physical function and quality of life, increased risk of chronic postsurgical pain, and prolonged opioid use during and after hospitalization [3, 4, 10, 15, 22]. A growing body of evidence supports the use of multimodal analgesia—a combination of different classes of analgesics targeting multiple mechanisms simultaneously and acting in additive or synergistic manner—for postoperative pain [11, 17, 21]. Even so, opioids still are used in most patients undergoing surgery [1].

Opioid use and its associated harms have become a major concern for patients, clinicians, and the public. The range of adverse effects associated with opioid use include hypotension, bradycardia, vomiting, constipation, respiratory depression, suppression of immune function, as well as hyperalgesia, addiction/dependence, and death [6, 23, 24]. Orthopaedic-specific harms include concerns about opioids affecting bone healing after a fracture, as well as increased risk of fractures associated with patient falls [2, 14, 19]. Improving strategies for pain management now is seen as an essential component in the care of patients undergoing surgery.

The timing of administration of analgesics might be an important factor in providing improved pain relief, and if it is, Doleman and colleagues [5] believe it could have substantial implications for postoperative pain management. Pre-emptive analgesia (before surgical incision) or preventive analgesia (before surgical incision and continued after surgery) may reduce intraoperative nociception to the central nervous system, and thus may reduce pain more effectively than if the same analgesic was given after incision [5]. The last systematic review addressing this topic was published more than a decade ago [16]; the current Cochrane review from 2018 [5] presents an updated review of the evidence.

Upon Closer Inspection

This systematic review and meta-analysis of 20 randomized trials including 1343 participants evaluated the effects of pre-emptive opioids (one trial) and preventive opioids (19 trials) for reducing early postoperative pain in adults undergoing any type of surgery [5]. The sole study evaluating the effects of pre-emptive opioids was conducted in patients undergoing dental surgery [18]. This study including 40 participants showed that pre-emptive opioids had, on average, an important reduction in early acute (within 6 hours postoperatively; mean difference (MD) = 1.20; 95% CI -1.75 to - 0.65) and late acute postoperative (24 to 48 hours postoperatively; MD = - 2.10; 95% CI - 2.57 to - 1.63) pain compared to postincision opioids. Unfortunately, owing to concerns over risk of bias and imprecision resulting from a lack of a double-dummy-blinded design and small study sample size, respectively, the authors deemed this study to be of low-quality evidence for both outcomes.

The authors found moderate-quality evidence suggesting preventive opioids were no different than post-incision opioids in terms of providing reduction in early acute (MD = 0.11; 95% CI -0.32 to 0.53, 10 trials) or late acute (MD = - 0.06; 95% CI - 0.13 to 0.01, 9 trials) postoperative pain [5]. As the authors themselves have correctly noted, given the no-difference findings on this point, and the fact that the effect of bias resulting from lack of blinding are more likely to produce exaggerated effect estimates than underestimates, it is unlikely that higher-quality evidence will alter the conclusions of this review in terms of early and late acute postoperative pain [5].

That being said, to explore high heterogeneity (I = 61%) in the meta-analysis for early acute postoperative pain, the authors performed meta-regression, an extension to subgroup analyses, which allows the investigation of how one or more continuous or categorical study characteristics are associated with the intervention effects in meta-analysis. Meta-regression analysis found the type of opioid administered explained nearly all of the observed heterogeneity, with longer-acting opioids proving most effective. This finding suggests that preventive intermediate- and long-acting opioids may indeed provide adequate pain relief in the early acute postoperative period.

Also, although this review found a small reduction in 24-hour morphine consumption (MD = - 4.91 mg; 95% CI - 9.39 mg to - 0.44 mg) with preventive opioids, it did not exceed the predefined threshold of importance (10 mg), and the evidence was of low quality due to concerns over risk of bias, possible publication bias and unexplained high heterogeneity. Again, these kinds of biases would tend to lead to inflated treatment-effect benefits, and so it seems reasonable to conclude that the use of preventative opioids does not result in a clinically important reduction in the amount of morphine equivalents a patient will consume in the first day after surgery.

The authors took a pragmatic approach to this review, including trials evaluating all types of opioids, at any dose, at any time within the specified definition for pre-emptive and preventive, via any route of administration in patients with varying baseline pain/opioid consumption [24]. While this increases the generalizability of the results of this review, the wide eligibility criteria also introduced between study differences that lead to differences across the effects of opioids on some of the outcomes (so-called heterogeneity). Although the authors were able to explain statistical heterogeneity for early acute postoperative pain, the unexplained high heterogeneity for 24-hour morphine consumption lowered the authors’ confidence in the results. Moreover, most of the included studies evaluating preventive opioids were conducted in women undergoing hysterectomy, and thus it is unclear whether the results can be generalized to other types of procedures. Similarly, the single study assessing the effects of pre-emptive opioids was conducted in dental surgery under local anesthetic, and therefore we are uncertain if this evidence can be applied to more complicated surgeries or surgeries conducted under general anesthesia.

Take-home Messages

This review found no compelling evidence that preventive opioids provide important reductions in early or late acute postoperative pain, as well as for other key outcomes including reduction in morphine consumption and time to first analgesic request. Despite the lack of efficacy shown in this review, future randomized trials might focus on determining the effects of intermediate and long-acting opioids, as the authors found these types of opioids may be effective in providing early acute postoperative pain relief.

The few studies that reported on complications of postoperative opioids found that the risk of respiratory depression [7, 8, 13], intraoperative bradycardia [12, 20], or intraoperative hypotension [8, 20] were similar between treatment groups. However, data were insufficient to make definitive conclusions regarding adverse effects. Only one low-quality study evaluated the effects of pre-emptive opioids on postoperative pain, but did not report on other important outcomes such as adverse effects and morphine consumption [16]. Therefore, the results of this study should be interpreted with caution and future trials should focus on evaluating this strategy further.

Mounting evidence suggests acute postoperative pain is best treated through a multimodal approach consisting of a combination of different classes of analgesics; this Cochrane review suggests that there is little, if any, benefit to pre-emptive or preventative dosing of opioid analgesics prior to surgery.