The VAS score at the different postoperative time
A total of 9 studies (599 patients) were included to compare the VAS score at different postoperative times between IVIB and placebo (25, 26, 29, 32, 37, 46-48, 53). The results indicated that IVIB was significant effective in reducing VAS scores at postoperative 0min (MD, -3.53; 95% CI, -4.32 to -2.75, 5 trials, low certainty), 1h (MD, -1.94; 95% CI, -2.66 to -1.22, 7 trials, moderate certainty), 2h (MD, -1.69; 95% CI, -2.29 to -1.09, 6 trials, low certainty), 4h (MD, -1.24; 95% CI, -1.80 to -0.68, 5 trials, low certainty), 8h (MD, -1.69; 95% CI, -2.65 to -0.73, 5 trials, low certainty), 12h (MD, -1.04; 95% CI, -1.63 to -0.45, 6 trials, low certainty), and 24h (MD, -0.96; 95% CI, -1.35 to -0.57, 8 trials, moderate certainty) (Figure 4, Supplementary Table 7). Subgroup analysis showed that IVIB (800 mg) was administered preoperatively and continued every 6 h or 8h postoperatively was associated with lower VAS scores (29, 46, 53) (Supplementary Figure 1). Additionally, five studies (25, 26, 32, 37, 48) reported the VAS score at different postoperative times between single-dose IVIB (800 mg) 30min preoperative group and placebo, the results did not change except for 4h and 8h (Supplementary Figure 2). Only one study (47) compared the single-dose IVIB (400 mg) with placebo, the results showed that IVIB was associated with lower pain scores in the postoperative 24h period. Subgroup analyses were further performed for different surgery types in the postoperative VAS score (Supplementary Table 4).
Four studies (26, 29, 31, 46) including 260 patients compared the VAS score at different postoperative times between IVIB and intravenous acetaminophen. The results showed that VAS scores within postoperatively 24h were reduced in the IVIB group (Supplementary Figure 3). Although there were no statistical differences in terms of VAS scores at 1h (MD, -1.77; 95% CI, -3.98 to 0.45, 2 trials, low certainty) and 24h (MD, -0.36; 95% CI, -0.80 to 0.08, 4 trials, low certainty), the point estimates in IVIB group were associated with lower pain intensity.
Considering the differences in the effect indicators, including the area under the VAS pain curve (VAS-AUC), median value, and numeric rating scale (NRS), we conducted the descriptive analyses to show the results. Compared with placebo, Southworth et al (52) reported that IVIB (800 mg) q6h was associated with significant reduction in postoperative pain across three time periods (VAS-AUC, 1-24h, 6-24h, 12-24h, P < 0.01), while IVIB (400 mg) provide effectively pain relieve within 6-24h and 12-24h periods. Three studies (33, 39, 45) compared the postoperative analgesic effect of IVIB (800 mg) versus acetaminophen (1000 mg). Viswanath et al showed that the median postoperative pain scores in the IVIB group were significantly lower than those in the IV acetaminophen group at 4 hours (P = 0.004) and 24 hours (P = 0.019), respectively (33). Kayhan et al indicated that the usage of IVIB was associated with a reduction in pain at 1-24h and 12-24h (VAS-AUC, P < 0.05) (45). However, Ucar et al (39) indicated that there were no differences in pain intensity between IVIB and acetaminophen (P = 0.428). Additionally, Lubis et al found the pain score in the walking phase based on NRS in the IVIB group was lower than that in the acetaminophen group (5.6 ± 0.5 vs 7.3 ± 1.2, P < 0.001), while there is no significant difference in the resting state (38). Dwarica et al reported that there was no statistically significant difference in the pain VAS scores within postoperative 24h between IVIB and intravenous ketorolac group (at rest: 2.30 ± 2.10 vs 2.68 ± 2.34, P = 0.20; at ambulation: 3.94 ± 2.57 vs 4.16 ± 2.73, P = 0.57, respectively) (51).
Cumulativeconsumption of opioid medication
Fifteen studies (26, 27, 29, 31, 32, 34, 35, 37, 42, 46-48, 50, 52, 53) and six studies (26, 29, 31, 35, 45, 46) compared the differences in the cumulative opioid consumption between IVIB and placebo or acetaminophen during postoperative 24h, respectively. The opioids include tramadol, fentanyl, and morphine. As shown in Figure 5, compared to placebo, IVIB (800 mg) could significantly reduce fentanyl (MD, -0.23 mg; 95% CI, -0.39 to -0.07, 4 trails, low certainty) and morphine consumption (MD, -10.14 mg; 95% CI, -15.33 to -4.95, 6 trails, moderate certainty), but could not reduce tramadol consumption (MD, -45.03 mg; 95% CI, -132.00 to 41.94, 3 trails, low certainty).There was no statistically significance between IVIB (400 mg) and placebo in terms of morphine consumption (MD, -5.76 mg; 95% CI, -13.60 to 2.07, 3 trails, moderate certainty). Only two studies (42, 47) reported that IVIB (400 mg) reduced fentanyl consumption compared with placebo (553.00 µg ± 257.04 vs 303.33 µg ± 132.08, P<0.001 (47); median consumption: 12.5 µg vs 37.5 µg, P = 0.004 (42)).
When compared to acetaminophen, IVIB (800 mg) was associated with lower fentanyl (MD, -0.09 mg; 95% CI, -0.17 to -0.01, 2 trails, low certainty) and morphine (MD, -5.49 mg; 95% CI, -7.04 to -3.94, 2 trails, moderate certainty) consumption, except for tramadol (MD, -33.28 mg; 95% CI, -67.30 to 0.74, 2 trails, moderate certainty) (Supplementary Figure 4, Supplementary Table 7). Two studies reported the median opioid consumption after postoperative 24h. Ucar et al (39) found IVIB (800 mg) was associated with lower tramadol consumption than intravenous acetaminophen (195 mg vs 325 mg, P = 0.031). Lubis et al (38) indicated that no statistical difference was found in the median total morphine consumption between IVIB (800 mg) and acetaminophen group (9.0 mg vs 15.0 mg, P = 0.391). Only one study (42) reported IVIB (400 mg) was associated with lower fentanyl consumption than acetaminophen (12.5µg vs 32.5µg, P=0.016).
In terms of the cumulative opioid consumption during postoperative 48h, IVIB (800 mg) group was associated with lower fentanyl (255.45± 171.429 µg and 748.85 ± 155.645 µg, P < 0.001) (44) and morphine (MD, -20.65 mg; 95% CI, -28.06 to -13.24, 2 trials, moderate certainty) (28, 34) consumption than the placebo group, respectively (Supplementary Figure 5).