Nonsteroidal antiinflammatory drugs versus tramadol in pain management following transsphenoidal surgery for pituitary adenomas: a randomized, double-blind, noninferiority trial

Abstract

OBJECTIVE Opioid-minimizing or nonopioid therapy using nonsteroidal antiinflammatory drugs (NSAIDs) or tramadol has been encouraged for pain management. This study aimed to examine the noninferiority of NSAIDs to tramadol for pain management following transsphenoidal surgery for pituitary adenomas in terms of analgesic efficacy, adverse events, and rescue opioid use. METHODS This was a randomized, single-center, double-blind noninferiority trial. Patients 18–70 years old with planned transsphenoidal surgery for pituitary adenomas were randomly assigned (in a 1-to-1 ratio) to receive NSAIDs (parecoxib injection and subsequent loxoprofen tablets) or tramadol (tramadol injection and subsequent tramadol tablets). The primary outcome was pain score assessed by a visual analog scale (VAS) for 24 hours following surgery; the secondary outcomes were VAS scores for 48 and 72 hours. Other prespecified outcomes included nausea, vomiting, dizziness, upset stomach, skin rash, peptic ulcer, gastrointestinal bleeding, and pethidine use to control breakthrough pain. Noninferiority of NSAIDs to tramadol was established if the upper limit of the 95% confidence interval (CI) of the VAS score difference was < 1 point and the rate difference of adverse events and pethidine use < 5%. The superiority of NSAIDs was assessed when noninferiority was verified. All analyses were performed on an intention-to-treat basis. RESULTS Two hundred two patients were enrolled between November 1, 2020, and May 31, 2021 (101 in the NSAIDs group, 101 in the tramadol group). Baseline characteristics between groups were well balanced. Mean VAS scores for 24 hours following transsphenoidal surgery were 2.6 ± 1.8 in the NSAIDs group and 3.5 ± 2.1 in the tramadol group (−0.9 difference, 95% CI −1.5 to −0.4; p value for noninferiority < 0.001, p value for superiority < 0.001). Noninferiority and superiority were also achieved for both secondary outcomes. VAS scores improved over time in both groups. Incidences of nausea (39.6% vs 61.4%, p = 0.002), vomiting (3.0% vs 42.6%, p < 0.001), and dizziness (12.9% vs 47.5%, p < 0.001) were significantly lower, while incidence of upset stomach (9.9% vs 2.0%, p = 0.017) was slightly higher in the NSAIDs group compared with the tramadol group. The percentage of opioid use was 4.0% in the NSAIDs group and 15.8% in the tramadol group (−11.8% difference, 95% CI −19.9% to −3.7%; p value for noninferiority < 0.001, p value for superiority = 0.005). CONCLUSIONS NSAIDs significantly reduced acute pain following transsphenoidal surgery, caused few adverse events, and limited opioid use compared with tramadol.