We tested two low-dose naltrexone/acetaminophen combinations and each component in the acute treatment of migraine . The patients use a single-dose of the study medication for a moderate or severe pain intensity migraine attack . Patients were adults with migraine with or without aura experiencing 2 to 20 (average 6.4) monthly migraine days . The co-primary endpoints were pain-freedom and absence of prospectively-identified most bothersome migraine-associated symptom 2 hours after dosing . We randomized 92 patients; 72 completed the study (mean age , 43 years; 75% women). Pain-freedom at 2 hours was 10.2% higher than placebo with naltrexone 2.25 mg/acetaminophen 325 mg , 10.9% with naltrexone 3.25 mg/acetaminophen 325 mg , 17.3% with naltrexone 2.25 mg, and 31.3% with acetaminophen 325 mg . The treatment groups' migraine burden was unbalanced due to randomized patients' uneven study completion . The acetaminophen group had the lowest migraine burden, giving its results lower credibility . The naltrexone and the placebo groups were the largest and had a balanced disease burden, lending higher credibility to the naltrexone group results . We found low-dose naltrexone/acetaminophen, low-dose naltrexone, and acetaminophen had higher response rates than placebo in treating headache pain . Saliently, Low-dose naltrexone alone (n=19) had a 17.3% higher response rate than placebo (n=17) for headache pain-freedom at 2 hours . The most commonly reported adverse events were sedation, nausea, and dizziness . We postulate that naltrexone's toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines' production, leading to the trigeminal ganglion neurons becoming``overactive"and migraine . Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), we postulate mid-dose naltrexone (MDN) (defined as 6 - 10 mg/day) may offer a greater acute migraine control.