CLINICAL TRIALS PROFILE FOR TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN

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

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 That study was repeated prospectively (unpublished) and confirmed that Dutch patients do not feel their pain is undertreated.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 TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN

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.

Clinical Trial Conditions for TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN

Condition Name

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

Condition MeSH

Condition MeSH for TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN
Intervention	Trials
Pain, Postoperative	18
Osteoarthritis	8
Chronic Pain	8

Clinical Trial Locations for TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN

Trials by Country

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

Trials by US State

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

Clinical Trial Progress for TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN

Clinical Trial Phase

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

Clinical Trial Status

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

Clinical Trial Sponsors for TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN

Sponsor Name

Sponsor Name for TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN
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 TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN
Sponsor	Trials
Other	74
Industry	39
U.S. Fed	6

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

Last updated: October 28, 2025

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Introduction

The combination of Tramadol Hydrochloride and Acetaminophen continues to hold a significant position within the analgesic pharmaceutical landscape. This opioid and non-opioid mixture addresses moderate to severe pain, offering a dual mechanism that enhances analgesic efficacy while aiming to reduce opioid dosage requirements. As the landscape of pain management evolves amidst regulatory shifts and digital health advancements, comprehensive insights into clinical developments, market dynamics, and future projections are critical for stakeholders.

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Clinical Trials Updates

Current State of Clinical Research

Recent clinical trials have focused on reaffirming the safety, efficacy, and tolerability profiles of Tramadol Hydrochloride combined with Acetaminophen, especially in diverse patient populations with acute and chronic pain. Notably:

1. Enhanced Safety Profile Evaluations: Recent Phase IV post-marketing surveillance studies have targeted adverse event profiling, emphasizing liver toxicity risks associated with Acetaminophen and dependency concerns linked to Tramadol [1].
2. Extended Indication Trials: Investigations include its use in managing osteoarthritis, postoperative pain, and cancer-related pain, with results indicating comparable or superior efficacy relative to other NSAID or opioid alternatives [2].
3. Formulation Innovations: Several ongoing trials evaluate sustained-release formulations aiming to improve compliance and reduce peak-trough fluctuations, potentially reducing abuse liability and side effects [3].
4. Pharmacogenomic Studies: Research into genetic markers influencing Tramadol metabolism is ongoing, seeking to personalize pain therapy and mitigate adverse reactions [4].

Regulatory and Approval Status

While the United States FDA approved the combination for short-term pain management, recent safety concerns regarding opioid dependence and Acetaminophen-induced hepatotoxicity — particularly at higher doses — have prompted regulatory bodies like the European Medicines Agency (EMA) to reinforce prescribing guidelines. Several countries have introduced warnings about long-term use and maximum dose limitations, impacting market accessibility and clinical practices [5].

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Market Dynamics and Trends

Market Size and Revenue

The global analgesics market, valued at approximately USD 12 billion in 2022, is projected to reach USD 15.8 billion by 2030, growing at a CAGR of about 4.2% [6]. Tramadol Hydrochloride and Acetaminophen combination products account for roughly 14% of this market, driven by their widespread use in primary care settings and low-cost formulations.

Key Market Players

Major pharmaceutical companies, including Johnson & Johnson, Mylan, and Teva, dominate the formulation manufacturing landscape. Generic versions are prevalent, contributing to price competitiveness and access, particularly in emerging markets.

Geographical Trends

North America leads market revenues due to higher prescription rates, advanced healthcare infrastructure, and predominant opioid-based pain management practices. Europe follows, with increased regulatory scrutiny influencing prescriber behavior and formulary decisions. Asia-Pacific represents a growing segment driven by expanding healthcare access, with markets like India and China showing increased adoption, despite regulatory hurdles regarding opioid usage.

Regulatory and Societal Factors

Recent opioid crises in the US have compelled policymakers and healthcare providers to reevaluate the role of tramadol-based products. For example, the CDC's guidelines recommend cautious prescribing to mitigate addiction risks [7]. Concurrently, societal pressures advocate for non-opioid alternatives, fostering growth in combination formulations with perceived lower abuse potential.

Competitive Landscape

The presence of numerous generics, coupled with advancements in non-opioid analgesics—such as NSAID alternatives and nerve-targeted therapies—pose competitive challenges. Additionally, the rise of digital health tools for pain management and pharmacovigilance influences market positioning and product adoption strategies.

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Market Projections

Short-term Outlook (Next 3–5 Years)

The market for Tramadol Hydrochloride and Acetaminophen is expected to experience modest growth, primarily driven by:

• Increased adoption in countries with expanding healthcare infrastructure.
• Development of abuse-deterrent formulations to navigate regulatory restrictions.
• Continued focus on combination therapies that reduce opioid dosage and mitigate dependency risks.

However, growth may be tempered by regulatory constraints, particularly in markets enforcing stringent opioid prescribing laws, and by the growing emphasis on non-opioid pain management.

Long-term Trends (Next 10 Years)

Projection models suggest that the combination’s market share may decline relative to emerging non-opioid therapies, such as monoclonal antibodies targeting nerve growth factors or novel NSAIDs with improved safety profiles. Nevertheless, in regions where regulatory restrictions are less stringent and healthcare costs remain a priority, Tramadol-AC formulations could sustain a significant niche.

The increasing integration of pharmacogenomics into clinical practice could also enable more personalized therapy, potentially revitalizing interest in tailored tramadol-based approaches and expanding indications, including chronic pain management with minimized adverse outcomes.

Impact of Regulatory Changes

Legislative actions restricting opioid use, especially in North America and parts of Europe, are anticipated to influence prescribing behaviors substantially. Manufacturers might focus on reformulating products to meet new standards—such as abuse-deterrent formulations—or pivot towards non-opioid therapies.

Innovation and Development Drivers

Future growth hinges on innovation:

• Development of extended-release, abuse-deterrent formulations.
• Incorporation of digital health monitoring for adherence and adverse event detection.
• Combining tramadol with adjunct therapies to expand indications and safety profiles.

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Key Takeaways

• Regulatory landscape significantly influences market dynamics, with increasing restrictions on opioid prescriptions prompting shifts toward safer formulations and alternative therapies.
• Clinical trials are intensively focused on safety, with recent emphasis on toxicity profiles, pharmacogenomics, and novel delivery systems to optimize benefit-risk balance.
• Market growth remains steady but faces headwinds from regulatory limits and competition from emerging non-opioid analgesics.
• Emerging markets present significant growth potential due to expanding healthcare access, though regulatory hurdles around opioid use must be addressed.
• Innovation in formulations—especially abuse-deterrent, sustained-release, and personalized medicines—is key for sustaining relevance and market share.

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FAQs

1. What are the primary safety concerns associated with Tramadol Hydrochloride and Acetaminophen?
The main concerns include hepatotoxicity linked to Acetaminophen overdose and dependency or abuse potential related to Tramadol, particularly in long-term use. Pharmacogenomic variability also affects Tramadol metabolism, influencing adverse effects.

2. How are regulatory bodies affecting the use of Tramadol-AC combination products?
Regulators aim to curb misuse by implementing prescribing restrictions, maximum dose limitations, and safety warnings. Some countries classifying tramadol as a controlled substance have reduced its availability, impacting market access.

3. Are new formulations being developed to improve safety and efficacy?
Yes, sustained-release and abuse-deterrent formulations are under development to reduce overdose risks and improve adherence, with some already introduced in select markets.

4. What market segments are driving growth for Tramadol-AC?
Primary segments include post-operative pain, osteoarthritis, and cancer pain management, especially in regions with limited access to newer, more expensive analgesics.

5. What is the outlook for Tramadol Hydrochloride and Acetaminophen in the next decade?
While global shifts toward non-opioid alternatives may reduce its overall market share, strategic reformulation, personalized medicine approaches, and expanding markets in emerging economies promise sustained relevance for specific patient populations.

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References

1. Pharmacovigilance reports on Tramadol safety
2. Clinical trial data on analgesic efficacy
3. Formulation development studies
4. Pharmacogenomic research articles
5. Regulatory agency guidelines
6. Market research reports, Global Analgesics Market
7. CDC opioid prescribing guidelines