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

300 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Naltrexone-Acetaminophen Combination for treating migraine headaches?

Research shows that acetaminophen, a component of the combination, is effective in treating migraine headaches. Studies have demonstrated that acetaminophen alone or in combination with other drugs can help alleviate migraine pain. ^{1 2 3 4 5}

How does the Naltrexone-Acetaminophen drug differ from other migraine drugs?

The Naltrexone-Acetaminophen combination is unique because it combines naltrexone, which is typically used to treat addiction, with acetaminophen, a common pain reliever, offering a novel approach to migraine treatment that differs from standard options like triptans or NSAIDs (non-steroidal anti-inflammatory drugs). ^{1 2 6 7 8}

What is the purpose of this trial?

* This two-stage clinical trial will assess a novel combination therapy for acute migraine. In Stage 1 (factorial), participants will receive the combination, each individual component, or placebo. In Stage 2 (dose-finding), they will test three doses of the combination. Before both stages, participants will complete a run-in period, documenting a migraine attack without study medication. They will then treat one migraine attack in each stage. * 4 visits * Requirements: Migraine Diagnosis. BMI below 34. Read, write, and speak English. No opioids, marijuana, benzodiazepines, or excessive alcohol.

Research Team

Annette C Toledano, MD

Principal Investigator

Allodynic Therapeutics, Inc

Natalia Belikova, MD PhD

Principal Investigator

Keystone Clinical Research

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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 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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of coadministration of rizatriptan and acetaminophen vs rizatriptan or acetaminophen alone for acute migraine treatment. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

A randomized, placebo-controlled trial of acetaminophen for treatment of migraine headache. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Comparison of paracetamol (apotel®) and morphine in reducing post pure head trauma headache. [2021]

4. United States 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. [2019]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Acute treatment of migraines. [2021]

6. China (Republic : 1949- ) pubmed.ncbi.nlm.nih.gov

Medical Treatment Guidelines for Acute Migraine Attacks. [2018]

7. England 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. [2013]

8. England 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. [2014]