CLINICAL TRIALS PROFILE FOR ACETAMINOPHEN, ASPIRIN AND CAFFEINE

505(b)(2) Clinical Trials for ACETAMINOPHEN, ASPIRIN AND 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 AND 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.

Clinical Trial Conditions for ACETAMINOPHEN, ASPIRIN AND CAFFEINE

Condition Name

Condition Name for ACETAMINOPHEN, ASPIRIN AND CAFFEINE
Intervention	Trials
Migraine With Aura	1
Migraine Without Aura	1
Pain, Migraine	1
Pain, Postoperative	1

Condition MeSH

Condition MeSH for ACETAMINOPHEN, ASPIRIN AND CAFFEINE
Intervention	Trials
Migraine Disorders	5
Headache	2
Low Back Pain	1
Back Pain	1

Clinical Trial Locations for ACETAMINOPHEN, ASPIRIN AND CAFFEINE

Trials by Country

Trials by Country for ACETAMINOPHEN, ASPIRIN AND CAFFEINE
Location	Trials
United States	17

Trials by US State

Trials by US State for ACETAMINOPHEN, ASPIRIN AND CAFFEINE
Location	Trials
Utah	2
California	2
Illinois	2
Pennsylvania	1
Washington	1

Clinical Trial Progress for ACETAMINOPHEN, ASPIRIN AND CAFFEINE

Clinical Trial Phase

Clinical Trial Phase for ACETAMINOPHEN, ASPIRIN AND CAFFEINE
Clinical Trial Phase	Trials
Phase 4	2
Phase 3	2
Phase 2	3

Clinical Trial Status

Clinical Trial Status for ACETAMINOPHEN, ASPIRIN AND CAFFEINE
Clinical Trial Phase	Trials
Completed	4
Terminated	1
Unknown status	1

Clinical Trial Sponsors for ACETAMINOPHEN, ASPIRIN AND CAFFEINE

Sponsor Name

Sponsor Name for ACETAMINOPHEN, ASPIRIN AND CAFFEINE
Sponsor	Trials
Stanford University	1
Novartis	1
Albert Einstein Healthcare Network	1

Sponsor Type

Sponsor Type for ACETAMINOPHEN, ASPIRIN AND CAFFEINE
Sponsor	Trials
Industry	6
Other	3

Clinical Trials Update, Market Analysis, and Projection for Acetaminophen, Aspirin, and Caffeine Combination

Last updated: October 28, 2025

Introduction

The combined formulation of acetaminophen, aspirin, and caffeine remains a notable segment within over-the-counter (OTC) analgesics and headache medications. With extensive historical use, evolving clinical research, and market dynamics influenced by regulatory scrutiny, consumer preferences, and emerging therapeutic alternatives, it is imperative to analyze current developments, clinical trial status, and the future market outlook. This report provides a comprehensive update on clinical trial initiatives, a detailed market analysis, and projections for this combination product.

Clinical Trials Landscape for Acetaminophen, Aspirin, and Caffeine

Current Clinical Trials Status

Over the past two years, the number of ongoing clinical trials involving combination therapies of acetaminophen, aspirin, and caffeine has remained limited but strategically targeted. Most trials focus on efficacy, safety, and comparative effectiveness in tension-type headaches, migraines, and other acute pain indications.

A 2022 clinical trial registry search (e.g., ClinicalTrials.gov) indicates approximately 12 active or recruiting studies globally. These are primarily phase II and phase III trials designed to evaluate formulations with enhanced bioavailability, reduced adverse effects, and optimized dosing regimens. Notably:

• Efficacy in Migraine Management: Several trials are assessing the combination’s efficacy in acute migraine relief compared to monotherapies or placebo.
• Safety Profiles: Studies evaluate the hepatotoxic risk associated with acetaminophen and cardiovascular risks linked to aspirin use.
• Formulation Innovations: Trials exploring sustained-release formulations aim to improve patient compliance and duration of effect.

Clinical Trial Highlights and Outcomes

1. Efficacy and Safety in Headache Relief
   Recent phase III data demonstrate that combination formulations offer superior pain relief within two hours versus placebo, with comparable safety profiles to individual components when administered at recommended doses (e.g., 650 mg acetaminophen, 500 mg aspirin, 65 mg caffeine). Adverse events are primarily gastrointestinal, with low incidence of hepatotoxicity and bleeding episodes.

2. Novel Formulation Trials
   Development of fixed-dose combinations with reduced acetaminophen content aims to mitigate hepatotoxic concerns while maintaining analgesic efficacy. These trials show promising results, indicating potential for safer OTC options.

3. Post-marketing Surveillance Data
   Post-approval observational studies highlight that these formulations maintain a consistent safety record over large patient populations, aligning with pre-market clinical data.

Market Analysis

Historical Market Overview

The global analgesics market was valued at approximately USD 22 billion in 2021, with acetaminophen, aspirin, and caffeine-containing products constituting a significant share. Key consumers include OTC consumers, healthcare providers, and institutional healthcare settings.

• Acetaminophen: Dominates the OTC pain relief segment due to its favorable safety profile and widespread acceptance.
• Aspirin: Sustains relevance for cardiovascular prophylaxis and analgesia despite declining use in pain management owing to bleeding risk concerns.
• Caffeine: Predominantly used as an adjuvant ingredient to enhance analgesic efficacy; consumption driven by acute headache relief products.

Market Drivers and Challenges

• Increasing Prevalence of Headache and Migraine Disorders: WHO estimates suggest over a billion people globally suffer from headaches, fueling demand for effective OTC analgesics.
• Consumer Preference for Multi-Ingredient OTC Medications: Consumers favor combination products for convenience and rapid relief.
• Regulatory Scrutiny: Rising concerns over acetaminophen-induced hepatotoxicity and aspirin-associated bleeding risks have prompted tighter regulations, influencing formulation innovation and marketing.

Competitive Landscape

Major players include Johnson & Johnson (Tylenol), Bayer, Johnson & Johnson (Advil), and various generic manufacturers. The market's competitive edge hinges on formulation innovation, safety profile, consumer brand loyalty, and regulatory compliance.

Market Segmentation and Regional Analysis

• North America: Largest market, driven by high awareness, strong OTC medication sales, and regulatory oversight.
• Europe: Similar trends with a focus on safety, particularly concerning aspirin use among the elderly.
• Asia-Pacific: Rapid growth driven by rising healthcare awareness, urbanization, and expanding OTC OTC market penetration.
• Emerging Markets: Growth potential remains high owing to increasing disposable income and healthcare infrastructure enhancements.

Future Market Projections

The OTC analgesics market incorporating acetaminophen, aspirin, and caffeine is projected to grow at a CAGR of approximately 4-5% from 2023 to 2030. Key factors influencing this trajectory include:

• Product Innovation: Development of low-dose formulations and novel delivery systems.
• Regulatory Policies: Tightened regulations on acetaminophen content and labeling are likely to reshape product offerings.
• Consumer Trends: Preference for fast-acting, safe, and multi-benefit OTC solutions sustains demand.

Regulatory and Industry Outlook

Regulatory agencies like the FDA (United States) and EMA (Europe) are emphasizing safety monitoring for acetaminophen and aspirin. Recent warnings about liver toxicity have prompted manufacturers to reformulate products with lower acetaminophen doses or combined agents with hepatoprotective features.

Industry players are proactively working on:

• Enhanced Safety Profiles: Utilizing new formulation technologies to reduce adverse effects.
• Digital Engagement: Leveraging digital channels for consumer education and compliance reinforcement.
• Strategic Partnerships: Collaborations for clinical development and regulatory approval to expedite market entry.

Key Market Opportunities and Risks

Opportunities

• Expanding use for pediatric and elderly populations with tailored formulations.
• Entering emerging markets with increasing healthcare accessibility.
• Innovating in sustained-release or combination therapies targeting multiple pain pathways.

Risks

• Regulatory constraints on acetaminophen dose levels.
• Competitive pressures from emerging analgesic modalities (e.g., CGRP inhibitors for migraines).
• Public perception concerns regarding safety, especially in light of recent hepatotoxicity warnings.

Conclusion and Future Outlook

The combination of acetaminophen, aspirin, and caffeine maintains a substantial role in OTC pain management, supported by ongoing clinical research and evolving consumer preferences. While regulatory challenges persist, product innovation and safety improvements offer pathways for sustained market growth. The next decade will likely see increased commercialization of low-dose, safer formulations, with strategic focus on regulatory compliance and targeted therapeutic applications.

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Key Takeaways

• Clinical Efficacy: Current clinical trials validate the effectiveness of acetaminophen, aspirin, and caffeine combinations in acute headache relief, with ongoing efforts to optimize safety.
• Market Dynamics: The global analgesics market remains robust, with growth driven by demand for convenient, multi-ingredient OTC products and regional expansion.
• Regulatory Landscape: Heightened safety concerns, especially regarding acetaminophen, are prompting reformulations and stricter regulations, impacting product development.
• Innovation Opportunities: Developments in sustained-release formulations and dose optimization present significant growth avenues.
• Growth Projections: The market is expected to grow at a compound annual rate of 4-5% from 2023 to 2030, driven by innovation, expanding consumer base, and emerging markets.

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FAQs

1. What are the primary clinical benefits of combining acetaminophen, aspirin, and caffeine?
The combination delivers rapid and potent analgesic effects, especially for headaches and migraines, by synergistically targeting pain pathways. Caffeine acts as an adjuvant to enhance absorption and efficacy.

2. Are there safety concerns associated with this combination therapy?
Yes. Acetaminophen carries a risk of hepatotoxicity at high doses, while aspirin increases gastrointestinal and bleeding risks. Clinical trials indicate low adverse event rates at recommended doses, but regulatory scrutiny continues.

3. How is regulatory oversight impacting product formulations?
Regulators are emphasizing dose limits and warning labels, prompting manufacturers to develop lower-dose or reformulated versions that balance efficacy and safety.

4. What market segments are expected to see the most growth in this drug category?
Emerging markets in Asia-Pacific, pediatric and elderly populations, and sustained-release formulations are anticipated to experience significant growth.

5. What future innovations could influence this market?
Development of targeted, low-dose, extended-release formulations and combination products with enhanced safety profiles will shape future market trends.

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References

1. ClinicalTrials.gov. Various trial data on combination analgesics.
2. MarketWatch. Global analgesics market analysis, 2021–2030.
3. FDA. Safety communications on acetaminophen and aspirin.
4. WHO. Global headache and migraine prevalence studies.
5. IQVIA. Consumer trends in OTC medication use.