Naltrexone/Acetaminophen for Migraine Headaches

(AT-06 Trial)

Overseen By Annette C Toledano, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Annette C. Toledano MD

Must not be taking: Opioids, Benzodiazepines, Barbiturates, others

Disqualifiers: Pregnancy, Uncontrolled hypertension, Diabetes, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for people with migraines, using two medications: naltrexone (an opioid receptor antagonist) and acetaminophen (a common pain reliever). The goal is to determine if this combination can effectively reduce migraine pain. In the first stage, participants will receive either the combination, each medication alone, or a placebo. Individuals diagnosed with migraines who do not use certain medications like opioids or marijuana may be suitable for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial requires that you do not use opioids, marijuana, benzodiazepines, or excessive alcohol. If you use medications to treat headaches or other pain more than 10 days a month, you may not be eligible. The protocol does not specify other medication restrictions, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using naltrexone and acetaminophen together has been safe in past studies. In one study, four out of six patients using this combination experienced fewer migraine days, indicating potential effectiveness and safety. Other research found that both low-dose naltrexone and acetaminophen, when used separately, reduced headache pain more effectively than a placebo. These findings suggest the combination is likely safe for people, though individual results may vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the Naltrexone-Acetaminophen combination because it offers a potential new way to tackle migraines by combining two active ingredients. Unlike typical migraine treatments such as triptans and NSAIDs, this combination leverages naltrexone, which can modulate the nervous system's response to pain, alongside the pain-relieving effects of acetaminophen. This dual-action approach not only targets pain relief but may also reduce the frequency or severity of migraine attacks. Additionally, by exploring varying doses, researchers hope to optimize the balance between efficacy and any potential side effects, offering a personalized treatment option for migraine sufferers.

What evidence suggests that this trial's treatments could be effective for migraines?

Research has shown that combining naltrexone and acetaminophen can significantly reduce migraine days. One study found that 66.7% of participants using this combination experienced a 75% reduction in migraine days, compared to just 16.7% of those who did not use it. This trial will assess the effectiveness of the naltrexone/acetaminophen combination, as well as naltrexone and acetaminophen individually, in reducing migraine symptoms. Acetaminophen is already known for relieving pain, while low-dose naltrexone may help by adjusting pain signals in the brain. Overall, these findings suggest that this combination could be a promising option for treating migraines. ^{1 2 3 6 7}

Who Is on the Research Team?

Annette C Toledano, MD

Principal Investigator

Allodynic Therapeutics, Inc

Natalia Belikova, MD PhD

Principal Investigator

Keystone Clinical Research

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with a history of migraines, diagnosed before age 50. Participants must have experienced migraines lasting 4-72 hours and occurring 2-8 times per month over the last year. They should not be using opioids, marijuana, benzodiazepines, or excessive alcohol and must have a BMI below 34. Those on stable migraine prevention medication can join if they maintain their dosage.

Inclusion Criteria

My BMI is 36 or less.

I can avoid opioids for the duration of the study and 7 days after.

I have had migraines for at least a year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-in

Participants complete a run-in period, documenting a migraine attack without study medication

1 week

1 visit (in-person)

Stage 1 Treatment

Participants receive one dose of either the combination therapy, each individual component, or placebo for a qualifying migraine attack

1 week

1 visit (in-person)

Stage 2 Treatment

Participants test three doses of the combination therapy for a qualifying migraine attack

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Naltrexone-Acetaminophen Combination

Trial Overview

The study tests a new combination therapy for acute migraine in two stages: Stage 1 compares Naltrexone/Acetaminophen combo to each component alone and placebo; Stage 2 finds the best dose of the combo. Participants will treat one attack per stage after documenting an untreated attack.

How Is the Trial Designed?

Group I: Stage 2: Naltrexone/Acetaminophen-medium dose Experimental Treatment 1 Intervention

One dose for a qualifying migraine attack

Group II: Stage 2: Naltrexone/Acetaminophen-low dose Experimental Treatment 1 Intervention

One dose for a qualifying migraine attack

Group III: Stage 2: Naltrexone/Acetaminophen-high dose Experimental Treatment 1 Intervention

One dose for a qualifying migraine attack

Group IV: Stage 1: Naltrexone/Acetaminophen Experimental Treatment 1 Intervention

One dose for a Qualifying Migraine Attack

Group V: Stage 1: Naltrexone Active Control 1 Intervention

One dose for a Qualifying Migraine Attack

Group VI: Satge 1: Acetaminophen Active Control 1 Intervention

One dose for a Qualifying Migraine Attack

Group VII: Stage 1: Placebo Placebo Group 1 Intervention

One dose for a Qualifying Migraine Attack

Group VIII: Stage 2: Placebo Placebo Group 1 Intervention

One dose for a qualifying migraine attack

Who Is Running the Clinical Trial?

Annette C. Toledano MD

Lead Sponsor

Trials

2

Recruited

380+

Allodynic Therapeutics, LLC

Lead Sponsor

Trials

6

Recruited

450+

Allodynic Therapeutics, Inc

Lead Sponsor

Trials

7

Recruited

540+

Published Research Related to This Trial

The combination of acetaminophen, aspirin, and caffeine significantly reduces migraine headache pain intensity compared to placebo, with 59.3% of patients experiencing pain relief to mild or none within 2 hours, and 79% by 6 hours after taking the medication.

This nonprescription treatment not only alleviates headache pain but also improves associated symptoms like nausea and sensitivity to light and sound, demonstrating a strong safety profile and good tolerability among the 1250 patients who took the study medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain: three double-blind, randomized, placebo-controlled trials. Lipton, RB., Stewart, WF., Ryan, RE., et al.[2019]

In a study of 179 patients with severe headaches, a fixed combination of acetylsalicylic acid (ASA), paracetamol, and caffeine was found to provide significantly faster pain relief compared to a placebo, with a p-value of 0.0008.

The combination treatment was effective across various measures, including pain intensity reduction and daily activity impairment, and was well tolerated with a low incidence of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and tolerability of a fixed combination of acetylsalicylic acid, paracetamol, and caffeine in patients with severe headache: a post-hoc subgroup analysis from a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study. Diener, HC., Peil, H., Aicher, B.[2013]

In a clinical trial involving 60 patients with post-trauma headaches, intravenous paracetamol provided faster relief compared to morphine, with an average treatment duration of 37.43 minutes versus 71.93 minutes for morphine.

Paracetamol significantly reduced headache severity more effectively than morphine within 30 minutes of administration, indicating it is a safe and effective option for managing trauma-related headaches in emergency settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of paracetamol (apotel®) and morphine in reducing post pure head trauma headache. Shams Vahdati, S., Morteza Baghi, HR., Ghobadi, J., et al.[2021]

Acute treatment for migraines aims to quickly restore function with minimal side effects, using specific vasoconstrictive drugs like triptans and dihydroergotamine, as well as nonspecific options like NSAIDs and paracetamol.

NSAIDs are highlighted as a strong alternative for patients who cannot use triptans due to vascular issues, while narcotics should be avoided due to their high risk of leading to chronic daily headaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute treatment of migraines. Da Silva, AN., Tepper, SJ.[2021]

In a study of 173 patients, the combination of rizatriptan and acetaminophen provided significantly better pain relief within 2 hours compared to placebo and acetaminophen alone, achieving a 90% relief rate.

The combination treatment was well tolerated, showing no significant differences in adverse events compared to the individual medications, although it did not demonstrate superior efficacy over rizatriptan alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of coadministration of rizatriptan and acetaminophen vs rizatriptan or acetaminophen alone for acute migraine treatment. Freitag, F., Diamond, M., Diamond, S., et al.[2019]

The updated treatment guidelines for acute migraine emphasize that migraine-specific triptans and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most effective first-line treatments, based on a review of recent evidence and trials.

Combination therapies, such as using a triptan with an NSAID, have been shown to provide better efficacy than using either treatment alone, while the use of opiates is discouraged due to potential serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medical Treatment Guidelines for Acute Migraine Attacks. Hsu, YC., Lin, KC., Taiwan Headache Society, TGSOTHS.[2018]

In a clinical trial involving 346 adults with moderate to severe migraines, acetaminophen 1000 mg was found to be significantly more effective than placebo, with 52% of patients reporting mild to no pain after 2 hours compared to 32% in the placebo group.

Acetaminophen not only reduced headache pain but also improved associated migraine symptoms like nausea and sensitivity to light and sound, making it a well-tolerated and effective nonprescription treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, placebo-controlled trial of acetaminophen for treatment of migraine headache. Prior, MJ., Codispoti, JR., Fu, M.[2022]

In a study of 1555 participants, a combination of acetaminophen, acetylsalicylic acid, and caffeine (AAC) was found to provide significantly better pain relief for severe migraines compared to a placebo and was more effective than ibuprofen (IB) at multiple time points.

AAC not only relieved pain faster than IB, with patients experiencing meaningful relief 16 minutes sooner, but also showed superior results in reducing headache symptoms and functional disability within three hours post-dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a multicenter, double-blind, randomized, parallel-group, placebo-controlled, single-dose study comparing the fixed combination of acetaminophen, acetylsalicylic acid, and caffeine with ibuprofen for acute treatment of patients with severe migraine. Goldstein, J., Hagen, M., Gold, M.[2014]

Citations

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medrxiv.org

medrxiv.org/content/10.1101/2021.03.23.21254186v3.full-text

The Preventive Treatment of Migraine with Low-Dose ...

Four out of 6 (66.7%) naltrexone and acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7%) ...

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medrxiv.org

medrxiv.org/content/10.1101/2021.03.23.21254186v2.full.pdf

Dose Naltrexone/Acetaminophen Combination

Oral naltrexone/acetaminophen combination, if proven effective, may provide greater efficacy/tolerability ratio than existing migraine ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT03194555

The Preventive Treatment of Migraine With Low-Dose ...

Randomized, double-blind, study to assess low-dose naltrexone and acetaminophen combination in the prevention of episodic migraine in adults.

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connect.careboxhealth.com/en-US/trial/listing/444000

Single-Site Study of Naltrexone/Acetaminophen for the ...

This two-stage clinical trial will assess a novel combination therapy for acute migraine. In Stage 1 (factorial), participants will receive the combination, ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT03061734

Study Details | NCT03061734 | Low-Dose Naltrexone and ...

Efficacy and safety of acetaminophen in the treatment of migraine: results of a randomized, double-blind, placebo-controlled, population-based study. Arch ...

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medrxiv.org/content/10.1101/2021.03.22.21254145v1.full-text

Low-Dose Naltrexone/Acetaminophen Combinations and ...

We found low-dose naltrexone/acetaminophen, low-dose naltrexone, and acetaminophen had higher response rates than placebo in treating headache pain.

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ctv.veeva.com

ctv.veeva.com/study/the-preventive-treatment-of-migraine-with-low-dose-naltrexone-and-acetaminophen-combination

The Preventive Treatment of Migraine With Low-Dose ...

A small, randomized, double-blind, and placebo-controlled clinical trial with an open-label extension for none-responders.