NSAIDs as First-Line Treatment for Acute Pain in Children

Source: Olejnik L, Lima JP, Sadeghirad B, et al. Pharmacologic management of acute pain in children: a systematic review and network meta-analysis. JAMA Pediatr. 2025;179(4):407-417; doi: 10.1001/jamapediatrics.2024.5920.Investigators from multiple institutions in Canada conducted a systematic review and network meta-analysis to assess the effectiveness and harms of different medications for relief of acute pain in children. For the study, they identified randomized controlled trials in which patients <18 years old who presented with acute pain to outpatient providers were enrolled, and the effectiveness of pharmacologic agents in relieving pain were compared to placebo or each other. For the included studies, measures of pain severity were transformed to a 10-cm visual analogue scale. Additional outcome data abstracted from the selected trials included need for rescue medication, symptom relief (defined as elimination of pain or achieving minimal pain), and occurrence of gastrointestinal or neurologic adverse drug events (ADEs). For the primary outcome, pain relief, data from multiple studies were to calculate the weighted mean difference (WMD) and 95% confidence interval (CI) compared to placebo. For secondary outcomes, data also were pooled to calculate risk ratios (RR) and 95% CI, compared to placebo. Based on the calculated outcome value and study characteristics, results were classified by certainty using a systematic process.Data on 4,935 children enrolled in 41 trials were analyzed. Of the 41 included trials, 35 (85%) were conducted in emergency departments (EDs). Medications assessed were non-steroidal anti-inflammatory drugs (NSAIDs), mid- to high-potency opioids, ketamine, midazolam, tramadol, acetaminophen, codeine, and combination drugs. Pain relief was assessed in 33 trials that included 3,482 patients. There was moderate certainty that NSAIDs (WMD, -1.29; 95% CI, -1.89, -0.70), ketamine (WMD, -1.12; 95% CI, -2.09, -0.14), mid- to high-potency opioids (WMD, -1.19; 95% CI, -1.83, -0.55) were more effective than placebo in reducing pain. There was low certainty that midazolam + opioid, acetaminophen, and tramadol were effective. There was no evidence that codeine or other combination agents were more effective than placebo. In 13 trials of 1,525 patients, only NSAIDss were associated with a significantly reduced risk of need for rescue medication compared to placebo (RR, 0.31; 95% CI, 0.14, 0.68). Achieving symptom relief was assessed 8 trials that included 1,310 patients. None of the medications evaluated were associated with a significantly greater chance of achieving symptom relief than placebo. Adverse drug events were documented in 41 trials and 4,935 children. Compared to placebo, neither NSAIDs (RR, 0.69; 95% CI, 0.31, 1.55) or acetaminophen (RR, 0.63; 95% CI, 0.21, 1.87) were associated with an increased risk of a GI ADE. Among the medications assessed, only midazolam + opioid was associated with a significantly increased risk of a neurologic ADE (RR, 7.03; 95% CI, 1.02, 48.55).The authors conclude that among the drugs evaluated, NSAIDs provided the greatest benefits and least harm for treating acute pain in children.Dr Bechtel has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Providing timely, effective analgesia to children with acute painful conditions is paramount.1 Historically, the safety profile of opioids to provide analgesia has been a concern in children due to their ADEs and addictive potential.2 The results of a 2012 study comparing non-opioid and opioid treatment for analgesia showed that acetaminophen was comparable to opioids in children undergoing operative treatment of supracondylar fractures. (See AAP Grand Rounds. 2024;51[3]:31.)3The current large meta-analysis provides further evidence that non-opioid treatment with NSAIDs provides the most benefit and least harm compared to opioids and ketamine, making them the preferred choice for acute pain management in pediatric patients. Even more importantly, NSAIDs effectively reduced acute pediatric pain and the need for rescue medication compared to placebo. While ketamine and opioids are effective for pain relief, NSAIDs are more effective in reducing the need for rescue medication and have a better safety profile, making them the preferred first-line therapy for acute pain in children.The current study has a few limitations. First, there is limited direct evidence to support many comparisons. Second, since 85% of the trials were based in EDs, the findings may have limited generalizability to non-ED outpatient clinics. Third, the researchers did not assess long-term harms such as opioid misuse or severe ADEs (eg, GI bleeding).NSAIDs are an effective first-line therapy for acute pain management in children.