Estimating relative efficacy in acute postoperative pain: network meta-analysis is consistent with indirect comparison to placebo alone

Abstract

Network meta-analysis uses direct comparisons of interventions within randomized controlled trials and indirect comparisons across them. Network meta-analysis uses more data than a series of direct comparisons with placebo, and theoretically should produce more reliable results. We used a Cochrane overview review of acute postoperative pain trials and other systematic reviews to provide data to test this hypothesis. Some 261 trials published between 1966 and 2016 included 39,753 patients examining 52 active drug and dose combinations (27,726 given active drug and 12,027 placebo), in any type of surgery (72% dental). Most trials were small; 42% of patients were in trials with arms <50 patients, and 27% in trials with arms ≥100 patients. Response to placebo in third molar extraction fell by half in studies over 30 to 40 years (171 trials, 7882 patients given placebo). Network meta-analysis and Cochrane analyses provided very similar results (average difference 0.04 number needed to treat units), with no significant difference for almost all comparisons apart from some with small patient numbers or small effect size, or both. Network meta-analysis did not detect significant differences between effective analgesics. The similarity between network meta-analysis and Cochrane indirect analyses probably arose from stringent quality criteria in trials accepted in Cochrane reviews (with consequent low risk of bias) and consistency in methods and outcomes. Network meta-analysis is a useful analytical tool that increases our confidence in estimates of efficacy of analgesics in acute postoperative pain, in this case by providing similar results.

Figure 1.

Distribution of the percentage with at least 50% maximum pain relief related to the number of patients given placebo (red line shows overall average of 12%, N = 7882). Size of symbol indicates the number of patients (inset scale).

Figure 2.

Response rate with placebo over time.

Figure 3.

All data for all drugs, doses, and combinations, and for all surgery types for Network Meta Analysis of analgesic response. The size of the symbols refers to the number of patients treated with particular drugs, and the thickness of lines is proportional to the numbers in each possible comparison.

Figure 4.

Results using all available data for the comparison of active drug with placebo, presented as odds ratio, risk difference, and NNT. Horizontal bars represent the width of the 95% confidence interval, and colour change the point estimate. NNT, number needed to treat.

Figure 5.

Results using all available data for the comparison of active drug with diclofenac K 100 mg, presented as odds ratio and risk difference. Horizontal bars represent the width of the 95% confidence interval, and colour change the point estimate. Horizontal bars crossing the red vertical line indicate no significant difference. OR, odds ratio.

Figure 6.

Difference between the NMA indirect and Cochrane indirect estimates of NNT, plotted against the Cochrane indirect estimate NNT. Size of symbol indicates the number of patients (inset scale). NMA, network meta-analysis; NNT, number needed to treat.