## 4 Discussion  
Our study revealed the potential clinical benefits of willlow bark for pain relief and the improvement of physical function in patients with arthritis. In addition, there were no significant differences in the risk of adverse events among patients with arthritis between the willlow bark and analgesics or placebo groups. These adverse events mainly consisted of skin and appendage disorders, gastrointestinal system disorders, and infections associated with using willlow bark. In our study, the most common adverse event of willlow bark was gastrointestinal system disorders (\(n=14\)) and central and peripheral nervous system disorders (\(n=14\)) followed by skin and appendage disorders (\(n=9\)). However, no severe adverse event was noted. In our study, there were no significant differences in the risk of adverse events in arthritis patients between using willlow bark and analgesics or placebo groups. Previous review articles reported that the most common adverse events of willlow bark were gastrointestinal system disorders, including upper abdominal pain, nausea, gastric disorder, and dysppesia [13], and this result was compatible with our findings. The potential toxicity and adverse effects of willlow bark extraction included anaphylactic reaction, gastrointestinal upset, and a remarkable capacity to concentrate heavy metals, especially cadmium [43]. Components in willlow bark may interact with anticoagulants (increase bleeding tendency), beta-blockers and diuretics (decrease the effect of the drugs), and NSAIDs (increase the risk of stomach bleeding) [33]. Only a limited number of case  
Figure 8: Post hoc analysis of only studies including WOMAC physical function scores comparing willlow bark and placebo. A better effect of physical improvement is shown in favor of willlow bark over placebo. See refs. [34; 37; 38]. Figure 6: Post hoc analysis of only studies including WOMAC pain scores comparing willlow bark and placebo. Better pain control is shown in favor of willlow bark over placebo. See refs. [34; 37; 38]. Figure 7: Post hoc analysis of only studies including WOMAC stiffness scores comparing willlow bark and placebo. A better effect of stiffness relief is shown in favor of willlow bark over placebo. See refs. [34; 37; 38]. reports indicated serious adverse events including anaphylactic reaction [44] and acute respiratory distress syndrome [45]. The use of willow bark as a medicine should be carefully assessed for those with a history of allergy to salicates. Additionally, children under the age of 16 were suggested to avoid using willow bark with the concern of Reye syndrome [33]. Our study showed potential benefits in treating arthritis with willow bark. Nonetheless, some limitations were present in our study. Only five studies with six RCTs qualified for meta-analysis, so the sample size was relatively small. In addition, there was no standard regimen of willow bark for arthritis. The designs of these trials were also different. Some studies used willow bark extract alone as medication, the others used compound drugs with other components, which might have an impact on its analgesic effect. There were three studies containing other compounds because the authors designed these studies and thought it was a complete regimen for therapeutic effect. Since willow bark was still the primary substance in the regimen, and other compounds were regarded as adjuvant, we still included these three studies in the analysis. However, potential analgesic effects may be presented in other botanical substances. Clinical heterogeneity should be also noted when interpreting our study results. To solve this condition, we used the GRADE system in our analysis. In addition, all six RCTs used subjective patient-reported outcome scales. Both WOMAC and pain scores (e.g., VAS, NRS, or BPI) were not objective. Although there were many studies to verify the validity and reliability of WOMAC, it still had limitations [46], especially for the convergent validity of the stiffness subscale [47].