Low-Dose Naltrexone/Acetaminophen Combinations and Each Component in the Acute Treatment of Migraine: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial

Toledano, A. C.

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.