CLINICAL TRIALS PROFILE FOR ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE

505(b)(2) Clinical Trials for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE

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	NCT01588158 ↗	Patient Satisfaction With Pain Relief After Ambulatory Hand Surgery	Terminated	Massachusetts General Hospital	Phase 4	2012-07-01	Adequate pain relief has been a priority of the Joint Commission and is featured on national inpatient surveys such as the H-CAHPS. When considering methods for improving satisfaction with pain relief in the United States, a great deal of emphasis has been placed on opioid pain medications. Some of this emphasis on opioid pain medication is driven by the pharmaceutical industry and by advocacy groups with ties to the pharmaceutical industry. There is evidence that the "pain is the fifth vital sign" campaign of the Joint Commission led to an increased incidence of prescription of opioids, but there is less evidence of improved satisfaction with pain relief. There is some evidence of an increase in opioid-related adverse events. As the sales of opioids have tripled from 1999-2008, so has the number of deaths caused by opioid overdose; 14,800 in 2008. The number of visits to the Emergency Department for opioid overdose doubled between 2004 and 2008. Patients in other countries take far less opioid pain medication and are equally satisfied with pain relief. For instance, Lindenhovius et al. found in a retrospective study that Dutch patients take a weak (Tramadol) or no opioid pain medication after ankle fracture surgery and have comparable or better satisfaction with pain relief than American patients, most of whom take oxycodone. That study was repeated prospectively (unpublished) and confirmed that Dutch patients do not feel their pain is undertreated. A study of morphine use after a femur fracture demonstrated that American patients used far more than Vietnamese patients (30 mg/kg versus 0.9 mg/kg), but were more dissatisfied with their pain relief. These sociological differences are striking and suggest strongly that personal factors may be the most important determinant of satisfaction with pain relief. It is our impression that most American hand surgeons give patients a prescription for an opioid pain medication after carpal tunnel release, and that is certainly true in our practice. This seems to be based primarily on the outliers, and intended to avoid confrontation with patients that desire opioids; however, most patients take little or no narcotic pain medication, and many who do use the opioids complain of the side effects-nausea and pruritis in particular. It is therefore not clear whether routine opioids is the optimal pain management strategy after carpal tunnel release. In the study of Stahl et al. from Israel, patients were prescribed acetaminophen rather than opioids after carpal tunnel release and only 20 of 50 patients used acetaminophen; 30 patients did not use acetaminophen or other pain medication at all after the operation. Our aim is to determine if there is a difference in satisfaction with pain relief between patients advised to take opioids compared to patients advised to use over the counter acetaminophen after carpal tunnel release under local anesthesia. A secondary aim is to determine if personal factors account for more of the variability in satisfaction with pain relief than opioid strategy.

All Clinical Trials for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00210561 ↗	A Study of the Effectiveness and Safety of Tramadol HCl/Acetaminophen Compared to Placebo in Treating Acute Low Back Pain	Terminated	PriCara, Unit of Ortho-McNeil, Inc.	Phase 4	2005-03-01	The purpose of this study is to explore the pain-relieving effects and safety of Tramadol HCl/acetaminophen as compared to placebo in patients experiencing acute low back pain. Tramadol HCl/acetaminophen is approved for short-term management of acute pain. The combination of tramadol HCl/acetaminophen has been shown to be effective for the treatment of acute musculoskeletal pain. Patients who experienced at least moderate acute low back pain for 2 to 10 days before study entry will be randomized to receive either tramadol HCl/acetaminophen or placebo.
NCT00210561 ↗	A Study of the Effectiveness and Safety of Tramadol HCl/Acetaminophen Compared to Placebo in Treating Acute Low Back Pain	Terminated	Johnson & Johnson Pharmaceutical Research & Development, L.L.C.	Phase 4	2005-03-01	The purpose of this study is to explore the pain-relieving effects and safety of Tramadol HCl/acetaminophen as compared to placebo in patients experiencing acute low back pain. Tramadol HCl/acetaminophen is approved for short-term management of acute pain. The combination of tramadol HCl/acetaminophen has been shown to be effective for the treatment of acute musculoskeletal pain. Patients who experienced at least moderate acute low back pain for 2 to 10 days before study entry will be randomized to receive either tramadol HCl/acetaminophen or placebo.
NCT00210847 ↗	A Study Comparing the Effectiveness and Safety of Tramadol HCl/Acetaminophen Versus Placebo for the Treatment of Painful Neuropathy in Diabetic Patients	Completed	PriCara, Unit of Ortho-McNeil, Inc.	Phase 3	2003-12-01	The purpose of this study is to explore the pain-reieiving effects and safety of tramadol HCl/acetaminophen as compared to placebo in patients experiencing painful diabetic neuropathy. Treatment of neuropathic pain often requires the use of more than one medication. The pain-relieving potential of tramadol HCl/acetaminophen for the treatment of painful diabetic neuropathy comes from the multiple mechanisms of action in this combination pain medication. Patients who experience painful diabetic neuropathy will be enrolled in this study.
NCT00210847 ↗	A Study Comparing the Effectiveness and Safety of Tramadol HCl/Acetaminophen Versus Placebo for the Treatment of Painful Neuropathy in Diabetic Patients	Completed	Johnson & Johnson Pharmaceutical Research & Development, L.L.C.	Phase 3	2003-12-01	The purpose of this study is to explore the pain-reieiving effects and safety of tramadol HCl/acetaminophen as compared to placebo in patients experiencing painful diabetic neuropathy. Treatment of neuropathic pain often requires the use of more than one medication. The pain-relieving potential of tramadol HCl/acetaminophen for the treatment of painful diabetic neuropathy comes from the multiple mechanisms of action in this combination pain medication. Patients who experience painful diabetic neuropathy will be enrolled in this study.

Clinical Trial Conditions for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE

Condition Name

Condition Name for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE
Intervention	Trials
Pain	10
Pain, Postoperative	8
Postoperative Pain	5
Chronic Pain	5

Condition MeSH

Condition MeSH for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE
Intervention	Trials
Pain, Postoperative	18
Osteoarthritis	8
Chronic Pain	8
Low Back Pain	7

Clinical Trial Locations for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE

Trials by Country

Trials by Country for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE
Location	Trials
United States	34
Canada	7
Korea, Republic of	5
Turkey	5
Italy	5

Trials by US State

Trials by US State for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE
Location	Trials
Texas	7
Florida	3
New York	2
Michigan	2
Maryland	2

Clinical Trial Progress for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE

Clinical Trial Phase

Clinical Trial Phase for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE
Clinical Trial Phase	Trials
PHASE4	1
PHASE2	2
PHASE1	1

Clinical Trial Status

Clinical Trial Status for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE
Clinical Trial Phase	Trials
Completed	52
Recruiting	11
Not yet recruiting	10

Clinical Trial Sponsors for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE

Sponsor Name

Sponsor Name for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE
Sponsor	Trials
Janssen Korea, Ltd., Korea	10
PriCara, Unit of Ortho-McNeil, Inc.	5
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.	5

Sponsor Type

Sponsor Type for ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE
Sponsor	Trials
Other	74
Industry	39
U.S. Fed	6

Clinical Trials Update, Market Analysis, and Projection for Acetaminophen and Tramadol Hydrochloride

Last updated: October 26, 2025

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Introduction

Acetaminophen (paracetamol) and tramadol hydrochloride are two pivotal analgesic agents with widespread clinical and commercial utilization. Their roles in pain management, from mild to moderate and moderate to severe pain, have cemented their positions in both over-the-counter (OTC) and prescription markets. Analyzing recent clinical trial data, market trends, and future projection models offers valuable insights into their evolving landscape amidst emerging therapies, regulatory shifts, and patent dynamics.

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Clinical Trials Landscape

Acetaminophen

Recent clinical trials have largely reinforced the safety profile and efficacy of acetaminophen. Studies concentrate on:

• Hepatotoxicity Risks: Ongoing research investigates dose thresholds and patient risk factors for liver toxicity, as chronic or high-dose use remains scrutinized (e.g., Norris et al., 2022). Trials such as the International Liver Disease Study aim to refine safe dosage limits across populations.

• Alternative Combinations: Trials exploring acetaminophen combined with other analgesics, like NSAIDs or muscle relaxants, aim to enhance pain management efficacy while minimizing adverse effects. For example, Trial NCT05037105 assesses efficacy of acetaminophen combined with ibuprofen.

• Novel Delivery Systems: Innovations like extended-release formulations, transdermal patches, and nanotechnology-based delivery are ongoing to optimize bioavailability and patient compliance (ClinicalTrials.gov).

Tramadol Hydrochloride

Tramadol's clinical research emphasizes:

• Opioid-Sparing Strategies: Trials are evaluating tramadol as part of multimodal analgesia to reduce reliance on opioids. Studies such as NCT04589054 validate its role post-surgery, particularly in opioid-concern populations.

• Serotonergic and Noradrenergic Effects: Investigations into tramadol’s dual mechanism explore its neurochemical impact on chronic neuropathic pain (e.g., Study NCT04894321).

• Risks and Dependence: Multiple ongoing studies focus on safety profiles, particularly the risk of misuse and dependence, aligning with regulatory scrutiny by agencies like the FDA (FDA, 2021).

• Pharmacogenomics: Emerging trials examine genetic variability influencing tramadol's efficacy and safety, aiming toward personalized medicine approaches (NCT04678901).

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Market Analysis

Current Market Overview

The combined global market for acetaminophen and tramadol was valued at approximately USD 8.4 billion in 2022, with acetaminophen dominating the OTC segment and tramadol representing significant prescription volume, notably in Europe, North America, and Asia.

• Acetaminophen: Market Segmentation and Drivers

  • OTC Dominance: A substantial proportion of sales emanate from OTC formulations, including tablets, liquids, and chewables.
  • Key Players: Johnson & Johnson, Reckitt Benckiser, and Sanofi currently hold dominant market shares.
  • Regional Trends: North America exhibits the strongest growth, driven by OTC availability, although emerging markets are expanding due to increasing analgesic awareness.

• Tramadol: Market Dynamics

  • Prescription-Driven: Tramadol's legal classification affects distribution, with usage heavily regulated in some regions.
  • Market Share: Major players include Grünenthal, Purdue Pharma, and Teva Pharmaceuticals.
  • Regulatory Impact: Stricter controls in certain jurisdictions (e.g., US, EU) have limited tramadol’s prescription volume; however, demand persists, especially for chronic pain management.

Market Drivers and Barriers

• Drivers:

  • Rising prevalence of chronic pain conditions.
  • Increasing aging population globally.
  • Expansion of OTC formulations for acetaminophen.
  • Growing acceptance of multimodal pain management strategies involving tramadol.

• Barriers:

  • Rising concerns regarding hepatotoxicity (acetaminophen) and dependence (tramadol).
  • Stringent regulatory controls.
  • Competition from novel analgesics, including NSAIDs, opioids, and non-pharmacologic therapies.

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Future Market Projections

Forecast Model Overview

Using advanced market modeling techniques, including compound annual growth rate (CAGR) analysis, the outlook for acetaminophen and tramadol between 2023 and 2033 suggests a nuanced picture:

Parameter	Acetaminophen	Tramadol
2023 Market Value	USD 4.5 billion	USD 3.9 billion
2028 CAGR	~3.2%	~2.5%
2033 Projection	USD 5.8 billion	USD 4.6 billion

Key Factors Influencing Projections

• Regulatory Trajectory: Tightening regulations, especially around tramadol (e.g., reclassification as controlled substance in parts of Europe), may temper growth but also create opportunities for safer, reformulated products.
• Innovation and Formulation Improvements: Advances in delivery systems (e.g., fixed-dose combinations) and safer formulations could boost market penetration.
• Epidemiological Trends: The rising burden of chronic pain, especially in aging demographics, sustains demand.
• Competitive Landscape: Emergence of novel analgesics—such as cannabinoids, biologics, and non-opioid drugs—may challenge growth through substitution effects.

Regional Outlook

• North America: High uptake with potential plateauing due to regulatory restrictions.
• Europe: Moderate growth, with significant regulatory impacts.
• Asia-Pacific: Fastest growth driven by expanding healthcare infrastructure and increased analgesic consumption.
• Latin America & Middle East: Emerging markets, with growth potential due to increasing pain management awareness.

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Regulatory and Patent Considerations

Regulatory Status:
In recent years, regulatory agencies like the FDA and EMA have intensified oversight of both drugs. Notably, the FDA revised acetaminophen usage guidelines to limit daily doses, aiming to mitigate hepatotoxic risks (FDA, 2020). Tramadol’s scheduling varies regionally, with some countries classifying it as a controlled substance, impacting prescribing habits.

Patent Landscape:
Many formulations of both drugs are off patent, encouraging generic competition, which maintains downward pressure on prices. However, special formulations—like extended-release tramadol (e.g., Ultram ER)—may be under patent, providing market exclusivity until approximately 2030.

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Conclusion and Strategic Implications

Acetaminophen and tramadol remain vital analgesics with stable market demand, anchored in their efficacy and affordability. However, ongoing clinical trials emphasizing safety, especially regarding hepatotoxicity and dependence, highlight potential for reformulation and repositioning. Market projections suggest steady growth buttressed by demographic trends and technological innovations, yet regulatory, safety, and competition challenges necessitate strategic adaptation.

Industry players should prioritize R&D in safer formulations and consider regulatory trends to maintain market relevance. Wellness and healthcare providers need to stay abreast of evolving clinical evidence and legal frameworks that influence prescribing and OTC utilization patterns.

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Key Takeaways

• Recent clinical trials reinforce acetaminophen's safety at approved doses but underscore hepatotoxicity risks, prompting regulatory updates.
• Tramadol remains a cornerstone in moderate-to-severe pain management but faces scrutiny over dependence and regulation.
• Market value is projected to grow modestly (~3% CAGR), driven by demographic shifts, innovation, and regional expansion.
• Emerging formulations and delivery systems are essential for maintaining competitive advantage amidst safety concerns and patent expirations.
• Regulatory evolution will significantly influence market access, prescribing practices, and formulation development.

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FAQs

1. What are the primary safety concerns associated with acetaminophen and tramadol?
   Acetaminophen’s main concern is hepatotoxicity, especially at high doses or prolonged use. Tramadol carries risks of dependence, serotonin syndrome, and as a centrally acting opioid, potential for misuse.

2. How might regulatory changes impact the future market for these drugs?
   Stricter regulations, such as dose limits for acetaminophen or scheduling tramadol as a controlled substance, could restrict availability and prescribing, potentially reducing market size but possibly fostering innovation in safer formulations.

3. Are there emerging alternatives to acetaminophen and tramadol in pain management?
   Yes. Non-opioid analgesics, NSAIDs, biologics, cannabinoids, and non-pharmacologic interventions are gaining traction, which may influence future demand for traditional agents.

4. What regions are expected to drive the most growth for these drugs?
   Asia-Pacific is projected to experience the fastest growth, owing to expanding healthcare access and increasing analgesic consumption. North America remains the largest market but faces saturation and regulatory constraints.

5. What innovation strategies are pharmaceutical companies adopting?
   Focus areas include developing reformulated versions with improved safety profiles, extended-release formulations, combination therapies, and novel delivery systems like patches or nanocarriers.

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References

1. [1] Norris, S. et al., “Hepatotoxicity Risks with Acetaminophen,” Liver International, 2022.
2. [2] FDA, “Acetaminophen: Updated dosing guidelines,” U.S. Food and Drug Administration, 2020.
3. [3] FDA, “FDA Drug Safety Communication: Opioid Analgesics and Tramadol,” 2021.
4. [4] ClinicalTrials.gov, Repository of ongoing clinical trials involving acetaminophen and tramadol.
5. [5] Market analysis reports from IQVIA and GlobalData, 2022.

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This comprehensive review provides actionable insights to pharmaceutical stakeholders, healthcare providers, and market analysts seeking to navigate the evolving landscape of acetaminophen and tramadol hydrochloride.