Background: A range of pharmacologic options is available for acute migraine treatment, yet the efficacy and safety of commonly used over-the-counter (OTC) therapies relative to newer prescription agents remain unclear. Given the scarcity of direct head-to-head trials, this network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluated selected OTC therapies against newer oral agents, including CGRP antagonists and the 5-HT ₁ F receptor agonist. Methods: A comprehensive literature search was conducted in PubMed, Embase, and CENTRAL for RCTs of acute migraine therapies published between January 1990 and July 2025. Primary outcomes were 2-h (2 h) pain relief and pain freedom; secondary outcomes included 2-h photophobia, phonophobia and nausea. Effect sizes were calculated as relative risks (RRs) with 95% confidence intervals (CIs). A frequentist NMA was conducted to estimate comparative efficacy and safety across the treatment network. Results: This NMA synthesized evidence from 25 RCTs, including 5 different interventions across 19 dose categories, involving a total of 22,100 participants with migraine. Compared with placebo, acetaminophen, aspirin, and caffeine (AAC) combination showed superior 2 h pain relief (RR, 1.76; 95% CI, 1.61–1.94; p-score = 0.96), followed by ibuprofen 400 mg and 200 mg. For 2 h pain freedom, AAC, ibuprofen 400 mg, and lasmiditan 200 mg showed broadly comparable favorable effects versus placebo, with similar RRs and p-scores. AAC also produced the greatest reductions in photophobia and phonophobia at 2 h (photophobia: RR, 1.99; 95% CI, 1.62–2.45; p-score = 0.97; phonophobia: RR, 1.53; 95% CI, 1.28–1.84; p-score = 0.89), while ibuprofen Liquigel 400 mg provided additional meaningful benefit. For nausea, rimegepant 75 mg demonstrated the strongest effect (RR, 1.15; 95% CI, 1.08–1.22; p-score = 0.85), followed by ibuprofen Liquigel 400 mg and AAC. Conclusion: In this NMA, OTC therapies showed meaningful efficacy and favorable safety for acute episodic migraine versus placebo, with ibuprofen and AAC demonstrating consistent benefits across 2 h pain and secondary outcomes. These findings support their use as effective, accessible options alongside newer oral agents. Larger trials and patient-level analyses are needed to refine efficacy, optimize dosing, and personalize migraine management. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261325571 , Identifier CRD420261325571.

Objective: The objective of the current post hoc analysis is to evaluate whether the combination of acetaminophen, aspirin, and caffeine (AAC) is more effective than placebo in relieving the pain intensity for and improving the quality-of-life (QoL) of subjects with menstrual migraine (MM). Methods: This analysis evaluated the impact of AAC (n = 85) versus placebo (n = 100) in relieving the pain intensity for and improving the QoL of subjects with MM during baseline and at 0.5, 1, 2, 3, 4, and 6 h post treatment. Subjects reported their pain intensity using a 4-point scale and QoL using a 5-point scale. A lower score indicates reduced pain intensity and improved QoL. Results: A statistically significant difference between the AAC and placebo groups (p ≤ 0.001) was observed in pain relief after 1 h (40% vs. 14%), 2 h (56.5% vs. 24%), 3 h (63.5% vs. 31%), 4 h (65.9% vs. 34%), and 6 h (64.7% vs. 31%) post treatment. Similarly, a significantly higher proportion of subjects reported improved QoL at 1 h (48.2% vs. 28.0%; p ≤ 0.005), 2 h (61.2% vs. 40.0%; p ≤ 0.005), 3 h (68.2% vs. 44.0%; p ≤ 0.001), 4 h (67.9% vs. 39.0%; p ≤ 0.001), and 6 h (64.3% vs. 37.0%; p ≤ 0.001) post treatment. The mean pain intensity and QoL scores reduced, while the relative pain intensity and QoL (difference between the AAC and placebo groups) increased with time and was sustained for 6 h. Conclusions: The rapid onset and sustained effect of AAC make it a potential option for managing headaches and other symptoms, and to improve the QoL of subjects with MM.