NSAIDs for Lyme Arthritis

Overseen By Desiree NW Neville, MD

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Desiree Neville, MD

Must not be taking: Daily NSAIDs, Daily acetaminophen

Disqualifiers: Rheumatoid arthritis, Kidney impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether NSAIDs, such as naproxen, or acetaminophen can prevent or shorten lasting symptoms of Lyme arthritis, a condition that can follow Lyme disease. Researchers aim to determine if scheduled NSAID use immediately after diagnosis can stop or reduce severe inflammation that sometimes persists despite antibiotic treatment. Participants will be randomly assigned to take naproxen, acetaminophen, or a combination of both. The trial seeks individuals with arthritis and a positive Lyme disease test, excluding those already taking regular NSAIDs or acetaminophen. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are already taking daily NSAIDs or acetaminophen, you cannot participate. If you have any hypersensitivity to naproxen or acetaminophen, you should not take the study medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that naproxen, a type of pain reliever, is generally safe for most people. It often treats pain and swelling from conditions like arthritis and gout. Some individuals might experience mild side effects such as headaches or nausea. There is also a small risk of heart attack or stroke, particularly for those with heart problems.

Acetaminophen, also known as Tylenol, is safe when used as directed. It is a popular choice for pain relief and is generally safe, but excessive use can cause liver issues. This risk is rare if the recommended doses are followed.

In this trial, both naproxen and acetaminophen manage symptoms of Lyme arthritis. Both are generally safe, but naproxen may pose a slightly higher risk for heart health in some individuals. Always follow dosage instructions to minimize risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Lyme arthritis because they explore the use of NSAIDs like naproxen, which could offer more effective relief from joint inflammation compared to acetaminophen, the standard care option. Naproxen, a non-steroidal anti-inflammatory drug, targets inflammation directly, potentially providing faster and more targeted symptom relief. Additionally, one treatment approach involves starting with naproxen and then switching to acetaminophen, which might offer a new strategy for managing symptoms more effectively over time. This trial could lead to improved treatment protocols, potentially reducing the duration and severity of symptoms for patients with Lyme arthritis.

What evidence suggests that this trial's treatments could be effective for Lyme arthritis?

In this trial, participants will receive different treatments to manage Lyme arthritis. Research has shown that naproxen, a non-steroidal anti-inflammatory drug (NSAID), effectively reduces inflammation, pain, and swelling in arthritis, including Lyme arthritis. Studies have found that NSAIDs like naproxen work by lowering substances in the body that cause inflammation, helping to manage symptoms early on. However, naproxen can cause side effects such as stomach problems and allergic reactions.

Another group in this trial will receive acetaminophen, which eases pain similarly to NSAIDs but does not reduce inflammation. Research has shown that acetaminophen can relieve pain in conditions like osteoarthritis and is generally well-tolerated. While acetaminophen helps with pain, it may not address the inflammation that causes Lyme arthritis. ^{6 7 8 9 10}

Who Is on the Research Team?

Desiree NW Neville, MD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for individuals with Lyme arthritis who are testing positive for Lyme disease. It's not suitable for those with rheumatoid or recurrent arthritis, on daily NSAIDs or acetaminophen, have severe liver issues, a history of allergic reactions to NSAIDs, or underlying kidney or liver impairment.

Inclusion Criteria

Undergoing Lyme disease testing (Lyme test positive)

I have arthritis.

Exclusion Criteria

Patients will be secondarily withdrawn from analysis and instructed to stop study medication if their Lyme test is negative

I am allergic to naproxen, aspirin, or have had bad reactions to NSAIDs.

I am allergic to acetaminophen or have severe liver problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive scheduled NSAIDs, acetaminophen, or NSAIDs followed by acetaminophen to manage Lyme arthritis symptoms

8 weeks

Regular text surveys on days 1, 3, 7, 10, 14, 21, 28, 60

Follow-up

Participants are monitored for safety and effectiveness after treatment, including symptom resolution and side effects

4 weeks

Follow-up visits as needed based on symptom resolution

Long-term Follow-up

Participants' need for further care and medication compliance are assessed over an extended period

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Acetaminophen
• Naproxen

Trial Overview The study tests if scheduled use of the anti-inflammatory drug Naproxen, pain reliever Acetaminophen, or a combination can prevent prolonged symptoms in Lyme arthritis. Patients will be randomly assigned to one of these treatments and monitored for symptom duration and treatment side effects.

How Is the Trial Designed?

Group I: NSAID first, then Acetaminophen Experimental Treatment 2 Interventions

Naproxen at weight based standard dose given bid for one week, then acetaminophen at weight based standard dose given qid until symptoms resolve

Group II: NSAID Experimental Treatment 1 Intervention

Naproxen at weight based standard dose given bid daily until symptoms resolve

Group III: Standard Care Active Control 1 Intervention

Symptom observation only

Group IV: Acetaminophen Active Control 1 Intervention

Acetaminophen at weight based standard dose given qid until symptoms resolve

Acetaminophen is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Tylenol for:

• Pain relief
• Fever reduction

Approved in European Union as Paracetamol for:

• Pain relief
• Fever reduction

Approved in Canada as Tylenol for:

• Pain relief
• Fever reduction

Who Is Running the Clinical Trial?

Desiree Neville, MD

Lead Sponsor

Trials

1

Recruited

300+

Published Research Related to This Trial

Naproxen sodium is effective for pain relief, reducing fever, and decreasing inflammation, but it can cause gastrointestinal issues and allergic reactions, and may lead to liver damage in some cases.

It is not recommended for individuals with certain health conditions, such as heart failure or hypertension, and is comparable in effectiveness to other over-the-counter pain relievers like ibuprofen and acetaminophen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naproxen sodium. Sutton, LB.[2019]

In a 12-month study involving 600 patients, sumatriptan-naproxen sodium was found to be well tolerated for treating moderate to severe migraines, with 94% of participants receiving treatment for at least one migraine attack.

The most common side effects were nausea, muscle tightness, and dizziness, but serious adverse events were rare, with only one possibly related to the treatment, indicating a favorable safety profile for this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Twelve-month tolerability and safety of sumatriptan-naproxen sodium for the treatment of acute migraine. Winner, P., Cady, RK., Ruoff, GE., et al.[2013]

Naproxen and naproxen sodium are effective non-steroidal anti-inflammatory drugs (NSAIDs) with various indications, but they can cause adverse reactions affecting the gastrointestinal tract, central nervous system, kidneys, liver, and blood.

Recent studies raise questions about the safety and recommendations for using these drugs, particularly in vulnerable populations like the elderly and pregnant women, highlighting the need for cautious prescribing practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naproxen: pharmacology and dental therapeutics. Roda, RS.[2022]

Flurbiprofen has been proven safe and effective as an analgesic, anti-inflammatory, and antipyretic agent in numerous European clinical trials over the past 12 years, showing it is at least as potent as indomethacin and significantly more potent than aspirin.

In patients with rheumatoid arthritis and ankylosing spondylitis, flurbiprofen demonstrated superior or equivalent efficacy compared to other common treatments like aspirin, naproxen, and indomethacin, with minimal gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European experience with flurbiprofen. A new analgesic/anti-inflammatory agent. Buchanan, WW., Kassam, YB.[2022]

In a trial involving 25 patients, both Naprosyn (naproxen) and Butacote (phenylbutazone) significantly reduced morning stiffness, pain, and discomfort, showing their efficacy in treating inflammatory conditions.

While both medications had similar objective effects, patients and physicians preferred Butacote based on subjective assessments, although the difference was not statistically significant, and side effects were mostly minor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative study of Butacote and Naprosyn in ankylosing spondylitis. Ansell, BM., Major, G., Liyanage, SP., et al.[2019]

Paracetamol and dipyrone both effectively reduced pain in a rat model of inflammatory pain, with paracetamol also increasing pain thresholds in non-inflamed areas, indicating a broader analgesic effect.

The analgesic mechanisms of paracetamol and dipyrone differ; paracetamol's effects can be reversed by the opioid antagonist naltrexone, while dipyrone's analgesia is not affected by naltrexone, suggesting distinct pathways for their pain-relieving actions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different mechanisms underlie the analgesic actions of paracetamol and dipyrone in a rat model of inflammatory pain. Rezende, RM., França, DS., Menezes, GB., et al.[2018]

In a study of 57 malaria patients, the combination of Artemisinin-Based Combination Therapies (ACTs) with paracetamol significantly altered 24 out of 37 evaluated toxicity markers, indicating potential safety concerns with this treatment regimen.

The findings suggest that careful selection of ACTs plus paracetamol is crucial, especially for patients with existing health conditions, due to the observed changes in various biochemical and haematological indices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicological effect of Artemisinin-Based Combination Therapies plus Paracetamol in malaria patients. Aghahowa, SE., Ozolua, RI., Bafor, EE., et al.[2023]

In a study involving 90 patients with rheumatoid arthritis, diclofenac, indomethacin, naproxen, and tolfenamic acid were found to provide the greatest pain relief and were preferred by most patients.

These four drugs were significantly more effective (p < 0.01) than the least effective options, ketoprofen and proquazone, while acetylsalicylic acid, azapropazone, carprofen, and ibuprofen showed intermediate efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the analgesic effect of ten nonsteroidal anti-inflammatory drugs. Isomäki, H., Martio, J., Kaarela, K., et al.[2019]

Dipyrone, an analgesic used globally, works primarily through its metabolite 4-methyl-amino-antipyrine (MAA), which effectively inhibits both COX-1 and COX-2 enzymes, providing significant pain relief for at least 8 to 12 hours after administration.

The study found that dipyrone's inhibition of COX-2 is much stronger than that of other common analgesics like celecoxib and rofecoxib, suggesting that its pain-relieving effects are largely due to peripheral mechanisms, while its lower gastrointestinal side effects may be due to its non-acidic nature rather than selective COX-1 inhibition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dipyrone elicits substantial inhibition of peripheral cyclooxygenases in humans: new insights into the pharmacology of an old analgesic. Hinz, B., Cheremina, O., Bachmakov, J., et al.[2015]

The review of 13 randomized-controlled trials on NSAIDs and paracetamol for cancer pain management indicates that their role remains controversial, with no clear evidence supporting their use as initial treatments alongside opioids.

While paracetamol appears to offer little benefit at standard doses, ketorolac may provide an additional analgesic effect when used with opioids, suggesting that NSAIDs could be beneficial for some patients in managing cancer pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The long and winding road of non steroidal antinflammatory drugs and paracetamol in cancer pain management: a critical review. Mercadante, S., Giarratano, A.[2018]

In a double-blind trial involving rheumatoid arthritis patients, both benoxaprofen and naproxen were effective anti-inflammatory drugs, with no significant difference in overall efficacy between the two.

While naproxen showed a slight advantage in improving grip strength, both medications had mild and infrequent side effects, indicating a good safety profile for both treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative trial of benoxaprofen and naproxen. Highton, J., Grahame, R.[2019]

A systematic review of 12 clinical trials and 1 observational study on paracetamol for inflammatory arthritis found weak evidence supporting its effectiveness over placebo, particularly in patients with rheumatoid arthritis.

While paracetamol may provide some additive benefit when used with NSAIDs, its safety profile remains uncertain, with one study suggesting a higher risk of serious gastrointestinal events when used alongside corticosteroids and other analgesics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paracetamol for the management of pain in inflammatory arthritis: a systematic literature review. Hazlewood, G., van der Heijde, DM., Bombardier, C.[2018]

A variety of antirheumatic drugs are available for treating rheumatic diseases, with aspirin being the preferred choice for anti-inflammatory activity in early stages, while alternatives like phenylpropionic acid derivatives are recommended for those who cannot tolerate salicylates.

As the disease progresses, if nonsteroidal anti-inflammatory drugs are ineffective, treatments may escalate to gold compounds or penicillamine, with corticosteroids and immunosuppressives reserved for severe cases or those with significant side effects from other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug therapy reviews: antirheumatic agents. Evens, RP.[2013]

A comprehensive evaluation of naproxen sodium's safety involved 48 clinical trials with 4138 participants, showing that 83% of patients reported no adverse events, indicating a favorable safety profile for over-the-counter use.

The incidence of adverse events was similar between naproxen sodium and placebo, with common side effects like headache and nausea occurring at comparable rates, suggesting that naproxen sodium is as safe as other common over-the-counter pain relievers like ibuprofen and acetaminophen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of over-the-counter naproxen sodium. DeArmond, B., Francisco, CA., Lin, JS., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1755098/

Does paracetamol (acetaminophen) reduce the pain of ... Results: Paracetamol was effective in relieving pain due to OA (ES = 0.21, 95% confidence interval (CI) 0.02 to 0.41). Non-steroidal anti-inflammatory drugs ...

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK431066/

Lyme Disease - StatPearls - NCBI Bookshelf - NIH Lyme disease, also known as Lyme borreliosis, is an infectious condition transmitted through the bite of infected ticks.

3. hopkinsarthritis.org hopkinsarthritis.org/arthritis-info/osteoarthritis/oa-treatments/

Osteoarthritis Treatment Information 1) Acetaminophin: Several studies have shown acetaminophen to be superior to placebo and equivalent to nonsteroidal anti-inflammatory agents (NSAIDs) for the ...

4. the-rheumatologist.org the-rheumatologist.org/article/new-study-probes-risks-related-to-acetaminophen-use/

New Study Probes Risks Related to Acetaminophen Use A new study questions whether acetaminophen is a risk-free pain reliever for patients aged 65 and older, including those with osteoarthritis (OA).

5. nejm.org nejm.org/doi/full/10.1056/NEJM199707313370525

Cost Effectiveness of Oral as Compared with Intravenous ... For a 30-year-old patient presenting with Lyme arthritis, 1 month of treatment with doxycycline resulted in 43.9 quality-adjusted life-years, ...

6. hopkinsarthritis.org hopkinsarthritis.org/arthritis-news/safety-of-acetaminophen/

Safety of Acetaminophen The FDA stressed that unintentional overdoses and liver toxicity are rare events given the number of users of acetaminophen, and continue to believe that ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6509082/

Safety of Paracetamol in Osteoarthritis: What Does the ... Patients with OA or rheumatoid arthritis diagnoses (n = 115,305, 18% of cohort) had a higher risk of GI events with paracetamol > 3 g/day ...

8. tylenol.com tylenol.com/products/arthritis/tylenol-8hr-arthritis-pain

TYLENOL® 8 HR Arthritis Pain Extended Release Caplets To temporarily relieve arthritis pain and have an excellent safety profile when used as directed. Use this oral pain reliever as a fever reducer and to ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8275921/

Acetaminophen for osteoarthritis - PMC - PubMed Central - NIH Acetaminophen was less effective overall than NSAIDs in terms of pain reduction, global assessments and in terms of improvements in functional status.

10. tylenolprofessional.com tylenolprofessional.com/safety-and-efficacy

Safety and Efficacy of TYLENOL® (Acetaminophen) Proven analgesic efficacy even when inflammation is present,1* and an outstanding safety profile when used as directed.