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 That study was repeated prospectively (unpublished) and confirmed that Dutch patients do not feel their pain is undertreated.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.
NCT00236483 ↗	A Comparison of the Effectiveness and Safety of ULTRACET® (Tramadol Hydrochloride/Acetaminophen) Versus ULTRAM® (Tramadol Hydrochloride) Versus Placebo in Patients With Pain After Oral Surgery	Completed	PriCara, Unit of Ortho-McNeil, Inc.	Phase 4	2002-11-01	The purpose of this study is to explore the pain-relieving effects and safety of two analgesic treatment regimens as compared to placebo in patients experiencing pain after oral surgery. Tramadol hydrochloride/acetaminophen is approved to treat acute pain. This study will evaluate the effectiveness and safety of tramadol hydrochloride/acetaminophen compared with tramadol hydrochloride alone compared with placebo as a pain medication in the treatment of pain following oral surgery.
NCT00236483 ↗	A Comparison of the Effectiveness and Safety of ULTRACET® (Tramadol Hydrochloride/Acetaminophen) Versus ULTRAM® (Tramadol Hydrochloride) Versus Placebo in Patients With Pain After Oral Surgery	Completed	Johnson & Johnson Pharmaceutical Research & Development, L.L.C.	Phase 4	2002-11-01	The purpose of this study is to explore the pain-relieving effects and safety of two analgesic treatment regimens as compared to placebo in patients experiencing pain after oral surgery. Tramadol hydrochloride/acetaminophen is approved to treat acute pain. This study will evaluate the effectiveness and safety of tramadol hydrochloride/acetaminophen compared with tramadol hydrochloride alone compared with placebo as a pain medication in the treatment of pain following oral surgery.
NCT00236535 ↗	A Study of the Efficacy and Safety of Tramadol HCl/Acetaminophen, Hydrocodone Bitartrate/Acetaminophen and Placebo in Patients With Pain From an Ankle Sprain With a Partial Torn Ligament	Completed	PriCara, Unit of Ortho-McNeil, Inc.	Phase 3	2003-12-01	The purpose of this study is to explore the pain-relieving effects and safety of two analgesic treatment regimens as compared to placebo in patients experiencing acute musculoskeletal pain. Patients who are experiencing at least moderate acute musculoskeletal pain from an ankle sprain severe enough to require prescription pain relief medication will be randomized to receive either tramadol HCl/acetaminophen, hydrocodone bitartrate/acetaminophen or placebo.

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
Turkey	5
Italy	5
Korea, Republic of	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	2
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	75
Industry	39
U.S. Fed	6

Last updated: July 25, 2026

Acetaminophen + Tramadol Hydrochloride Clinical Trials Update, Market Analysis, and 2025–2035 Projections

Executive summary

• The combined analgesic acetaminophen and tramadol hydrochloride product line is a mature, generic-dominated segment in the US and most high-income markets. Competitive pressure is structurally high because multiple abbreviated new drug pathways exist and patent coverage is narrow relative to the long commercial history of tramadol-containing fixed-dose combinations.
• Clinical-trial activity is typically sparse for already-established fixed-dose combinations because sponsors often pursue incremental reformulations (dose, abuse-deterrent, opioid-risk mitigation) or new combination regimens rather than re-running pivotal efficacy programs.
• Near-term growth drivers are pricing normalization after generic entry, periodic label/REMS-driven risk controls, and shifts between brand vs. generic mix. Upside in revenue is likely modest and mostly comes from geography expansion, formulary penetration, and payer contracting rather than major therapeutic breakthroughs.
• Supply-side risk centers on opioid regulatory scrutiny and manufacturing continuity. Demand-side risk centers on ongoing opioid prescribing limitations and policy shifts that reduce conversion from moderate pain to opioid-containing regimens.

Scope note: This update is limited to the fixed-dose combination of acetaminophen + tramadol hydrochloride (commonly marketed as an immediate-release combination tablet). No other tramadol products (ER tramadol alone, combination with other analgesics, or branded variants) are included.

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What clinical trials exist for acetaminophen and tramadol hydrochloride fixed-dose combinations?

Clinical development for acetaminophen/tramadol fixed-dose combinations typically focuses on:

• bioequivalence and formulation comparability studies after generic approvals
• abuse-deterrent or tamper-resistant approaches (when pursued by sponsors)
• bridging studies for label updates, dosing intervals, or patient-subgroup analyses
• occasional post-marketing commitments related to safety surveillance

Trial patterns that matter commercially

• Efficacy relabeling is rare: most sponsors of generics avoid costly new outcome trials and instead rely on equivalence. That means trial pipelines tend to have “regulatory bridging” rather than new Phase 2/3 efficacy.
• Safety surveillance is ongoing: tramadol carries seizure risk (dose-related), serotonergic toxicity risk when combined with interacting agents, and dependence/abuse risk. Post-marketing studies and pharmacovigilance tend to dominate the clinical evidence flow.

What to look for in a “real” pipeline signal

• New Phase 3 pain programs that specify endpoints such as WOMAC/Brief Pain Inventory or functional outcomes.
• Dedicated studies in opioid-naïve populations or settings aligned with stewardship targets.
• Studies tied to abuse-deterrent claims (or requirements) with validated performance metrics.

(No concrete, verifiable trial registry dataset is provided in this request. Without named trials, registry IDs, sites, dates, and sponsors, a detailed “clinical trials update” would be incomplete and cannot be produced as hard data.)

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Which regulatory milestones affect acetaminophen and tramadol hydrochloride market access?

Regulatory impact is mostly indirect for established combination products because market access depends on generic approvals and product-level labeling, not novel regulatory pathways.

US access drivers

• FDA generic approvals via ANDA: most competition enters via abbreviated pathways supported by bioequivalence.
• Labeling constraints tied to opioid risk management: tramadol is subject to evolving opioid stewardship expectations, including REMS-related communications even when specific REMS programs differ by product.
• Controlled substance compliance: tramadol is regulated as a controlled opioid in the US; distribution and pharmacy-level controls can affect uptake and persistence in certain channels.

Global access drivers

• Different acetaminophen safety thresholds: hepatotoxicity labeling and maximum daily limits can differ by country, affecting formulary recommendations.
• National opioid policies: policies can reduce opioid-containing analgesic utilization, especially for chronic non-cancer pain.

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What is the Orange Book status of acetaminophen + tramadol hydrochloride combinations?

A complete Orange Book status analysis requires listing each relevant NDA/ANDA record, strength, dosage form, listed patents (drug substance, drug product, and method-of-use), and the relevant expiration and exclusivity data. That hard dataset is not included in the prompt, so a complete Orange Book status cannot be produced.

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When does acetaminophen + tramadol hydrochloride lose exclusivity?

For combination products where generics dominate, “loss of exclusivity” is typically already achieved for most strengths unless a specific brand product has later-introduced exclusivity (new formulation, new dosage, new method-of-use, or new manufacturing process).

A credible timeline requires:

• exact product identifiers (NDA and strength)
• the latest listed exclusivity expiration date(s)
• any patent term adjustments and pediatric exclusivity tie-ins

No such identifying data is provided. A hard exclusivity timeline cannot be generated from the prompt alone.

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What patents protect acetaminophen and tramadol hydrochloride, and how strong is the patent estate?

A patent estate assessment requires:

• the Orange Book patent list and associated patent numbers
• claims scope for fixed-dose combination formulations and method-of-use
• maintenance status and terminal disclaimers
• Paragraph IV litigation and settlements by ANDA filer

Because the prompt does not provide product IDs or any patent list, a claim-by-claim protection map cannot be completed without fabricating data.

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What generic entry risks exist for acetaminophen + tramadol hydrochloride?

For this drug class, generic entry risk is generally low in the sense that multiple generics likely exist, but ongoing risk occurs through:

• additional ANDA entrants for remaining strengths/dosage forms that still have limited competitors
• switching of manufacturers and product discontinuations that can temporarily reduce supply and increase prices
• policy-driven substitution from one opioid product to another, affecting relative demand

A precise risk assessment needs current market share by product, documented supply constraints, and the latest ANDA pipeline. Those inputs are not provided.

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How does acetaminophen + tramadol hydrochloride compare with alternatives for moderate pain?

Commercial substitution usually occurs along these axes:

• Opioid alternatives
  • immediate-release combination products with different opioid components
  • tramadol alone (often less preferred when fixed-dose combination is the incumbent formulary choice)
• Non-opioid analgesics
  • NSAIDs and acetaminophen-only regimens
  • topical agents depending on indication mix
• Stewardship alignment
  • payer preference for non-opioid first-line pathways in chronic pain
  • coverage rules that require prior non-opioid trials for opioid claims

Key implication: even if the acetaminophen/tramadol combination remains clinically effective, demand can erode via policy and payer pathways rather than via new clinical evidence.

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Market analysis: revenue pools, demand drivers, and competitive landscape

A full market analysis needs data such as:

• current global and US sales
• segment breakdown by strength, channel (retail vs mail), and geography
• brand vs generic mix
• unit volumes and average selling prices
• export and tender volumes by country

No numerical market dataset is provided, so a quantified market model cannot be produced as hard data.

Qualitative market forces that are highly likely to shape projections

• Pricing pressure: generic competition compresses margins. Revenue growth depends on volume replacement and supply-driven pricing events.
• Policy and prescribing trends: opioid stewardship reduces total “opioid days,” which can reduce tramadol-containing combination utilization in chronic pain settings.
• Safety and hepatotoxicity awareness: acetaminophen limit counseling and product labeling affect switching behavior and adherence.
• Manufacturing continuity: short supply events can create short-lived price spikes and channel preference for available SKUs.

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2025–2035 projections: what is the most likely revenue trajectory?

A defensible forecast requires baseline revenue, CAGR history, and elasticity parameters. Those are not in the prompt, so quantified projections cannot be produced without guessing.

Directional projection framework (non-quantified)

• Base case: modest unit growth or flat units with declining ASP, resulting in low single-digit revenue growth or decline depending on supply and pricing.
• Downside case: faster substitution away from opioids reduces units; revenue contracts.
• Upside case: payer contracting or formulary reopening in acute-care or post-procedural pain increases short-course volume; revenue stabilizes or grows modestly.

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Clinical development and litigation: what patent cases affect market timing?

Paragraph IV litigation, ITC actions, and settlement agreements can shift generic launch timing and pricing in the year of entry. A litigation impact analysis requires:

• ANDA filer names
• Orange Book patent lists
• case numbers and decision dates
• settlement dates and agreed launch triggers

No litigation dataset is included. A hard litigation summary cannot be produced.

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Manufacturing and IP barriers: what could slow supply for acetaminophen/tramadol?

Main barriers that typically matter:

• regulatory compliance and facility inspections
• controlled substance handling and distribution controls
• stability and bioavailability constraints for combination tablets
• formulation and process changes that trigger CMC re-qualification

Quantification requires facility-level and inspection history data which is not provided.

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Key Takeaways

• Acetaminophen + tramadol hydrochloride fixed-dose combinations are a mature, competitive space where clinical-trial “updates” are usually dominated by regulatory bridging rather than new Phase 3 efficacy programs.
• Market dynamics are driven more by policy, generic pricing, and supply continuity than by new therapeutic breakthroughs.
• Quantified clinical and market projections cannot be produced from the prompt alone without product identifiers, trial registry inputs, and baseline sales or market share data.

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FAQs

1. Are there ongoing Phase 3 trials for acetaminophen and tramadol hydrochloride fixed-dose combinations?
2. Does tramadol plus acetaminophen face REMS or opioid policy changes that affect prescribing?
3. Which countries have the strictest acetaminophen safety labeling that could reduce combination use?
4. How does generic entry typically impact acetaminophen/tramadol ASP and market share after launch?
5. Do abuse-deterrent formulations exist for tramadol-containing combination products, and do they change formulary uptake?

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References

1. FDA Orange Book. (n.d.). Drugs@FDA and Orange Book. U.S. Food and Drug Administration.
2. ClinicalTrials.gov. (n.d.). Acetaminophen tramadol hydrochloride trials. National Library of Medicine.
3. FDA. (n.d.). Drug Safety Communications and opioid-related labeling updates. U.S. Food and Drug Administration.