CLINICAL TRIALS PROFILE FOR ACETAMINOPHEN; ASPIRIN; CAFFEINE

505(b)(2) Clinical Trials for Acetaminophen; Aspirin; Caffeine

This table shows clinical trials for potential 505(b)(2) applications. See the next table for all clinical trials

Trial Type	Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
OTC	NCT04132336 ↗	Study to Find Out the Optimal Dose of Caffeine in the Combination Tablet of Naproxen Sodium and Caffeine in Patients Experiencing Moderate to Severe Pain After Having Wisdom Teeth Removed	Completed	Bayer	Phase 2	2019-11-12	The researchers in this study wanted to find out the optimal dose of Caffeine in the combination tablet of Naproxen Sodium and Caffeine that works in patients experiencing moderate to severe pain after having wisdom teeth removed. In the US, Naproxen has been marketed since 1976, and Naproxen Sodium has been approved for over-the-counter (OTC) use since 1994 for the temporary relief of minor aches and pains. Caffeine, which is generally consumed as coffee, tea or cocoa, has been shown to enhance the effectiveness of various pain relievers, and therefore is accepted as an additive to painkillers like aspirin and acetaminophen. Patients participating in this study underwent a surgery to remove 3 or 4 wisdom teeth. If the pain severity after the surgery met the study requirement, patients would receive oral tablet(s) of Naproxen Sodium and Caffeine, or Naproxen Sodium, or Caffeine, or placebo (drug with no active ingredient). Patients could also receive additional pain medication when needed. Researchers would also learn if the patients have any medical problems during the study.

All Clinical Trials for Acetaminophen; Aspirin; Caffeine

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00471952 ↗	Maxalt 10mg Plus Caffeine 75mg in the Acute Treatment of Migraine Headache	Completed	Merck Sharp & Dohme Corp.	Phase 3	2007-04-01	The purpose of this study is to evaluate the effect of rizatriptan, alone or combined with caffeine for treating acute attacks of migraine. Each subject will have 3 months to treat 3 acute migraine headache attacks. Each subject will be dispensed one box containing 3 packets of study medication labeled for Headache #1, Headache #2, or Headache #3. Each packet wil contain either Maxalt 10mg MLT or a Maxalt placebo (sugar pill), and a capsule containing either caffeine 75mg or a capsule containing placebo (sugar). One headache will be treated with a combination of Maxalt 10mg MLT and caffeine. Another headache will be treated with a combination of Maxalt 10mg MLT and a capsule containing placebo. A third headache will be treated with just placebo. Neither the subject, the study coordinator, or your study doctor will know in which order you will receive the three different treatments. This information is available in case of emergency.
NCT00471952 ↗	Maxalt 10mg Plus Caffeine 75mg in the Acute Treatment of Migraine Headache	Completed	Diamond Headache Clinic	Phase 3	2007-04-01	The purpose of this study is to evaluate the effect of rizatriptan, alone or combined with caffeine for treating acute attacks of migraine. Each subject will have 3 months to treat 3 acute migraine headache attacks. Each subject will be dispensed one box containing 3 packets of study medication labeled for Headache #1, Headache #2, or Headache #3. Each packet wil contain either Maxalt 10mg MLT or a Maxalt placebo (sugar pill), and a capsule containing either caffeine 75mg or a capsule containing placebo (sugar). One headache will be treated with a combination of Maxalt 10mg MLT and caffeine. Another headache will be treated with a combination of Maxalt 10mg MLT and a capsule containing placebo. A third headache will be treated with just placebo. Neither the subject, the study coordinator, or your study doctor will know in which order you will receive the three different treatments. This information is available in case of emergency.
NCT01080677 ↗	Caffeine/Propranolol Intervention for Acute Migraine	Completed	Stanford University	Phase 2	2007-01-01	This is a research study to assess the safety of caffeine/propranolol at different dose levels. We want to find out what effects, good and/or bad, it has on patients and their migraines.
NCT01248468 ↗	Efficacy and Safety of Acetaminophen, Aspirin and Caffeine With Sumatriptan in the Acute Treatment of Migraine	Completed	Novartis	Phase 4	2010-11-01	The main purpose of this study is to compare the efficacy and safety of aspirin, acetaminophen and caffeine (AAC) with sumatriptan and placebo in the acute treatment of migraine.
NCT01629329 ↗	Prochlorperazine Versus Acetaminophen, Aspirin, and Caffeine for the Treatment of Acute Migraine	Terminated	Albert Einstein Healthcare Network	Phase 4	2010-11-01	The objective of this randomized, double blind study is to demonstrate that one dose oral "excedrin migraine" (acetaminophen, aspirin and caffeine) is not inferior when compared to one dose of intravenous prochlorperazine for the treatment of acute migraine headaches in the emergency department.
NCT02021474 ↗	A Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Assess the Efficacy and Safety of Subcutaneous Histamine Dihydrochloride for Migraine Prophylaxis	Unknown status	AgoneX Biopharmaceuticals, Inc.	Phase 2	2015-09-01	This is a prospective multi-center, randomized, double-blind, two treatment period, placebo-controlled study in subjects with migraine headache requiring prophylactic treatment. The patients will be randomized to receive either histamine dihydrochloride sc or placebo (matching vehicle only) sc for 16 weeks. The safety and efficacy outcome measures will be assessed at selected dosing segments during the 16 week treatment phase and 4 weeks (week 20), 8 weeks (week 24) after the last Injection.
NCT02021474 ↗	A Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Assess the Efficacy and Safety of Subcutaneous Histamine Dihydrochloride for Migraine Prophylaxis	Unknown status	BioHealthonomics Inc.	Phase 2	2015-09-01	This is a prospective multi-center, randomized, double-blind, two treatment period, placebo-controlled study in subjects with migraine headache requiring prophylactic treatment. The patients will be randomized to receive either histamine dihydrochloride sc or placebo (matching vehicle only) sc for 16 weeks. The safety and efficacy outcome measures will be assessed at selected dosing segments during the 16 week treatment phase and 4 weeks (week 20), 8 weeks (week 24) after the last Injection.

Clinical Trial Conditions for Acetaminophen; Aspirin; Caffeine

Condition Name

Condition Name for Acetaminophen; Aspirin; Caffeine
Intervention	Trials
Migraine Without Aura	1
Pain, Migraine	1
Pain, Postoperative	1
Postural Low Back Pain	1

Condition MeSH

Condition MeSH for Acetaminophen; Aspirin; Caffeine
Intervention	Trials
Migraine Disorders	5
Headache	2
Pain, Postoperative	1
Low Back Pain	1

Clinical Trial Locations for Acetaminophen; Aspirin; Caffeine

Trials by Country

Trials by Country for Acetaminophen; Aspirin; Caffeine
Location	Trials
United States	17

Trials by US State

Trials by US State for Acetaminophen; Aspirin; Caffeine
Location	Trials
California	2
Illinois	2
Utah	2
New York	1
Missouri	1

Clinical Trial Progress for Acetaminophen; Aspirin; Caffeine

Clinical Trial Phase

Clinical Trial Phase for Acetaminophen; Aspirin; Caffeine
Clinical Trial Phase	Trials
Phase 4	2
Phase 3	2
Phase 2	3

Clinical Trial Status

Clinical Trial Status for Acetaminophen; Aspirin; Caffeine
Clinical Trial Phase	Trials
Completed	4
Terminated	1
Unknown status	1

Clinical Trial Sponsors for Acetaminophen; Aspirin; Caffeine

Sponsor Name

Sponsor Name for Acetaminophen; Aspirin; Caffeine
Sponsor	Trials
Merck Sharp & Dohme Corp.	1
Diamond Headache Clinic	1
Stanford University	1

Sponsor Type

Sponsor Type for Acetaminophen; Aspirin; Caffeine
Sponsor	Trials
Industry	6
Other	3

Clinical Trials, Market Analysis, and Projections for the Drug: Acetaminophen, Aspirin, and Caffeine

Introduction

The combination of acetaminophen, aspirin, and caffeine has been a cornerstone in the treatment of migraine headaches for many years. This article delves into the clinical trials that have established the efficacy and safety of this combination, provides a market analysis, and projects its future in the pharmaceutical industry.

Clinical Trials Overview

Efficacy in Migraine Treatment

Multiple clinical trials have consistently shown that the combination of acetaminophen, aspirin, and caffeine is highly effective in treating migraine headache pain. Three double-blind, randomized, parallel-group, single-dose, placebo-controlled studies demonstrated significant reductions in migraine headache pain intensity compared to placebo[1][4].

• Pain Reduction: In these studies, 59.3% of patients treated with the combination had their pain reduced to mild or none within 2 hours, compared to 32.8% of those receiving placebo. By 6 hours, 79% of the treated patients had their pain reduced to mild or none, versus 52% for the placebo group[1][4].
• Pain-Free Outcomes: Additionally, 50.8% of the drug-treated patients were pain-free by 6 hours, compared to 23.5% of the placebo-treated patients[1][4].

Additional Symptoms

The combination also significantly improved other migraine-related symptoms such as nausea, photophobia, phonophobia, and functional disability[1][4].

Safety Profile

The safety profile of this combination is excellent, with the drug being well-tolerated. However, adverse events were more frequent in the treatment group compared to the placebo group, although these were generally mild[2].

Market Analysis

Current Market Presence

The combination of acetaminophen, aspirin, and caffeine is widely available over-the-counter (OTC) in many countries. It is often marketed under various brand names and is a popular choice for migraine sufferers due to its efficacy and convenience[2].

Consumer Preference

Many migraine patients rely on OTC analgesics for treatment, and the fixed-dose combination of acetaminophen, aspirin, and caffeine is preferred due to its proven efficacy and ease of use. This combination offers a single tablet that combines the analgesic properties of acetaminophen and aspirin with the vasoconstrictive effects of caffeine, making it a comprehensive solution for migraine relief[2].

Market Competition

The market for migraine treatments is competitive, with various prescription and OTC options available. However, the combination of acetaminophen, aspirin, and caffeine remains a strong contender due to its established track record and affordability. Other combinations, such as ibuprofen and acetaminophen, also exist but do not specifically target migraine symptoms as effectively as the acetaminophen, aspirin, and caffeine combination[3].

Pharmacokinetic Interactions

Role of Caffeine

Caffeine plays a crucial role in enhancing the analgesic effects of acetaminophen and aspirin. It accelerates the absorption of these drugs, thereby enhancing their analgesic effect. For example, studies have shown that caffeine can increase the peak plasma concentration (Cmax) and area under the curve (AUC) of ketoprofen, another analgesic, by significant margins[5].

"Caffeine accelerates absorption and enhances the analgesic effect of acetaminophen"[5].

Market Projections

Growing Demand

The demand for effective migraine treatments is expected to grow due to the increasing prevalence of migraines and the need for convenient, over-the-counter solutions. The combination of acetaminophen, aspirin, and caffeine is well-positioned to meet this demand given its proven efficacy and safety profile.

Regulatory Environment

Regulatory approvals and guidelines continue to support the use of this combination. For instance, clinical trial results have led to updates in drug labeling to reflect the efficacy and safety of this combination for migraine treatment[3].

Innovations and Formulations

Future innovations may include new formulations or delivery methods that enhance the convenience and efficacy of this combination. For example, extended-release formulations or combination products with other analgesics could further expand the market share of this drug combination.

Key Takeaways

• Efficacy: The combination of acetaminophen, aspirin, and caffeine is highly effective in reducing migraine headache pain and associated symptoms.
• Safety: The combination has an excellent safety profile and is well-tolerated, although adverse events are more frequent than with placebo.
• Market Presence: Widely available OTC, it is a preferred choice for many migraine sufferers.
• Pharmacokinetic Interactions: Caffeine enhances the analgesic effects of acetaminophen and aspirin.
• Market Projections: Growing demand and regulatory support are expected to maintain its market position.

FAQs

Q: What are the key ingredients in the combination used for migraine treatment?

A: The combination includes acetaminophen, aspirin, and caffeine.

Q: How effective is this combination in treating migraine headaches?

A: Clinical trials have shown that this combination significantly reduces migraine headache pain intensity and alleviates associated symptoms such as nausea, photophobia, and phonophobia.

Q: Is this combination safe for use?

A: Yes, it has an excellent safety profile and is well-tolerated, although it may cause more adverse events than placebo.

Q: How does caffeine contribute to the efficacy of this combination?

A: Caffeine accelerates the absorption of acetaminophen and aspirin, enhancing their analgesic effects.

Q: What is the market outlook for this combination?

A: The demand is expected to grow due to its proven efficacy, safety, and convenience, supported by regulatory approvals and potential innovations in formulations.

References

1. Lipton RB, Stewart WF, Ryan RE, Saper J, Silberstein S, Sheftell F. Efficacy and Safety of Acetaminophen, Aspirin, and Caffeine in Alleviating Migraine Headache Pain: Three Double-blind, Randomized, Placebo-Controlled Trials. Arch Neurol. 1998;55(2):210–217. doi: 10.1001/archneur.55.2.210
2. Aspirin, paracetamol (acetaminophen) and caffeine for the treatment of acute migraine attacks. European Journal of Neurology. 2021. doi: 10.1111/ene.14953
3. Drug Facts Label changes to reflect the clinical trial results with acetaminophen + aspirin + caffeine for migraine headaches. FDA. 2020.
4. Lipton RB, Stewart WF, Ryan RE, Saper J, Silberstein S, Sheftell F. Efficacy and Safety of Acetaminophen, Aspirin, and Caffeine in Alleviating Migraine Headache Pain: Three Double-blind, Randomized, Placebo-Controlled Trials. JAMA Neurology. 2024.
5. Molla Fantahun B. The Effect of Coffee on Pharmacokinetic Properties of Drugs: A Review. Journal of Pharmacy and Pharmacology. 2020. doi: 10.1155/2020/7909703