Exercise + Duloxetine for Knee Osteoarthritis

Overseen By Alan M Rathbun, PhD, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Maryland, Baltimore

Must not be taking: Duloxetine, Antipsychotics, Benzodiazepines, Opioids

Disqualifiers: Cognitive impairment, Bipolar, Substance abuse, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding the medication duloxetine (an antidepressant) to aerobic exercise can improve knee osteoarthritis symptoms and depression in adults. Participants will begin with a low dose of duloxetine, which may increase as needed, and will follow a walking exercise plan. The trial seeks individuals with knee osteoarthritis and depression who aren't currently engaging in regular aerobic exercise and can join a supervised exercise program. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to potentially benefit from an innovative approach.

Will I have to stop taking my current medications?

The trial requires that you stop taking duloxetine, antipsychotics, benzodiazepines, or opioid pain medications before participating.

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

Research has shown that combining duloxetine with aerobic exercise can safely help manage knee osteoarthritis and depression. Duloxetine already treats pain and depression, providing confidence in its safety. Studies have found that people generally tolerate duloxetine well, especially when starting with a low dose and gradually increasing it.

Aerobic exercise is not only safe for individuals with knee osteoarthritis but also beneficial. It does not worsen the condition and can improve overall health.

Overall, using duloxetine and exercise together appears safe based on past research. Some side effects might occur, but they are usually manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining aerobic exercise with Duloxetine for knee osteoarthritis because it offers a dual approach to managing the condition. Unlike standard treatments that often focus solely on pain relief through medications like NSAIDs or corticosteroids, this approach aims to enhance both physical activity and mood, potentially leading to better overall outcomes. Duloxetine is an antidepressant that targets pain by acting on neurotransmitters in the brain, which is different from traditional pain relievers. Pairing this with a structured exercise plan could improve joint function and quality of life more effectively than medication alone.

What evidence suggests that this treatment might be an effective treatment for knee osteoarthritis?

Research has shown that combining aerobic exercise with the medication duloxetine may help people with knee osteoarthritis and depression. In this trial, participants will receive both aerobic exercise and duloxetine. Duloxetine effectively manages both pain and mood for those with knee osteoarthritis and is the only antidepressant known to also relieve pain in this condition. Aerobic exercise alone can reduce pain and improve activity levels. Together, these treatments might provide more relief than using either exercise or duloxetine alone. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

This trial is for English-speaking adults over 40 with knee osteoarthritis and depression, who can do aerobic exercise but aren't currently exercising twice a week or more. They shouldn't be planning knee surgery within six months, have cognitive issues, unstable heart conditions, severe hypertension, certain leg diseases, or be pregnant.

Inclusion Criteria

I am 40 years old or older.

English speaking

I have been diagnosed with major depressive disorder.

Exclusion Criteria

I cannot safely do supervised exercise due to my current health issues.

Substance abuse disorder or suicidal ideation within the previous year

Pregnant or lactating women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of aerobic exercise and duloxetine for the treatment of symptomatic knee osteoarthritis and comorbid depression

24 weeks

Weekly exercise sessions, medication titration visits as needed

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Aerobic exercise
• Duloxetine

Trial Overview The study tests adding the drug Duloxetine to an aerobic exercise program for treating knee osteoarthritis and depression in adults. Everyone gets both treatments; first checking if it's feasible then doing a pilot test to see how well it works.

How Is the Trial Designed?

Group I: Aerobic exercise plus Duloxetine Experimental Treatment 2 Interventions

Participants will have a starting duloxetine dosage of 30 mg/day and be titrated up to a daily optimal dosage of 60 mg/day as tolerated during the first 12-weeks of the study. Twelve weeks after the receipt of their prescription, participants will be evaluated for the need to increase medication dosage to 90 mg/day. After duloxetine initiation, participants will be provided an exercise prescription that includes a progressive walking program aiming to achieve 50 minutes of moderate-intensity physical activity, three times per week, over 24 weeks.

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

Approved in United States as Aerobic Exercise for:

• Rehabilitation after stroke
• Improvement of physical function
• Enhancement of cognitive function
• Reduction of depression

Approved in European Union as Aerobic Exercise for:

• Cardiovascular rehabilitation
• Improvement of physical function
• Enhancement of cognitive function

Approved in Canada as Aerobic Exercise for:

• Rehabilitation after stroke
• Improvement of physical function
• Enhancement of cognitive function

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

Duloxetine significantly reduced knee pain in Japanese patients with osteoarthritis compared to placebo, with an average pain score improvement of -2.57 versus -1.80 over 14 weeks, indicating its efficacy in managing pain.

The treatment was well-tolerated, with common side effects like somnolence and dry mouth, but it did not lead to any significant changes in knee joint mobility or structural abnormalities on X-ray, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled Phase III trial of duloxetine in Japanese patients with knee pain due to osteoarthritis. Uchio, Y., Enomoto, H., Alev, L., et al.[2022]

In a review of 16 studies involving 5111 patients treated with duloxetine for chronic pain conditions, significant mean weight loss was observed compared to placebo during the acute phase of treatment.

Long-term results showed that while patients with diabetic peripheral neuropathic pain (DPNP) experienced weight loss, those with fibromyalgia and chronic low back pain (CLBP) had a slight weight increase, indicating varying effects of duloxetine based on the specific pain condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weight change with long-term duloxetine use in chronic painful conditions: an analysis of 16 clinical studies. Gaynor, P., McCarberg, B., Zheng, W., et al.[2015]

In a study involving 48 male Wistar rats with induced osteoarthritis, treadmill exercise was found to be more effective than swimming in reducing pro-inflammatory cytokines and enhancing anti-inflammatory responses, suggesting a beneficial impact on joint inflammation.

Treadmill exercise not only improved the inflammatory profile but also resulted in better histological outcomes, including a higher number of chondrocytes, indicating potential for improved joint health in osteoarthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectiveness of treadmill and swimming exercise in an animal model of osteoarthritis. da Silva, LA., Thirupathi, A., Colares, MC., et al.[2023]

Duloxetine significantly reduces knee osteoarthritis pain and improves physical function, as shown in a systematic review of 6 studies with 2059 patients, indicating its efficacy as a treatment option.

Despite its effectiveness, duloxetine did not show a significant difference in serious adverse events compared to placebo, suggesting it may have a similar safety profile, but further well-controlled studies are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Updated Systematic Review and Meta-analysis of Duloxetine for Knee Osteoarthritis Pain. Chen, B., Duan, J., Wen, S., et al.[2023]

In a 12-month study involving 93 patients with early knee osteoarthritis, neuromuscular exercise (NEMEX) showed significant improvements in knee symptoms compared to pharmacological treatment (PHARMA), with 47% of NEMEX participants reporting clinically relevant symptom relief.

However, there was no significant difference in the ability to perform activities of daily living (ADL) between the NEMEX and PHARMA groups, indicating that while NEMEX may help with symptoms, it does not necessarily translate to improved daily functioning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One year effectiveness of neuromuscular exercise compared with instruction in analgesic use on knee function in patients with early knee osteoarthritis: the EXERPHARMA randomized trial. Holsgaard-Larsen, A., Christensen, R., Clausen, B., et al.[2018]

Exercise is an effective intervention for reducing pain and improving function in individuals with knee osteoarthritis, and it also provides pain relief for those with hip osteoarthritis, based on a review of multiple studies.

Despite the positive outcomes, there is a lack of clarity regarding the optimal frequency, dose, and duration of exercise for managing osteoarthritis, highlighting the need for more standardized research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing Hip and Knee Osteoarthritis with Exercise: What is the Best Prescription? Iversen, MD.[2021]

In a long-term study involving 93 Japanese patients with chronic knee pain due to osteoarthritis, duloxetine was found to be well tolerated, with most patients experiencing only mild adverse effects like constipation and dry mouth.

Duloxetine treatment led to sustained improvements in pain and quality of life over 48 weeks, with no significant deterioration in knee function or radiographic changes, indicating its efficacy for managing chronic pain in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of duloxetine in Japanese patients with chronic knee pain due to osteoarthritis: an open-label, long-term, Phase III extension study. Uchio, Y., Enomoto, H., Ishida, M., et al.[2022]

Exercise therapy is effective in reducing pain and activity limitations in patients with knee osteoarthritis, and it is likely beneficial for hip osteoarthritis as well, highlighting its role as a non-invasive treatment option.

Combining exercise therapy with weight loss can further alleviate symptoms in overweight osteoarthritis patients, and new targeted exercise modalities are being developed to address specific activity limitations and joint instability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Exercise therapy in hip or knee osteoarthritis]. Dekker, J., Peter, W., van der Leeden, M., et al.[2011]

In a long-term study of duloxetine for major depressive disorder involving 177 patients, the treatment maintained efficacy with a mean Hamilton Depression Rating scale score below 7, indicating sustained improvement in depression symptoms over an average of 305 days.

Only 7% of patients experienced clinically significant worsening of depression leading to discontinuation, and while 11.9% discontinued due to adverse events, most were not unique to the long-term phase, suggesting duloxetine is generally well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term tolerability and effectiveness of duloxetine in the treatment of major depressive disorder. Dunner, DL., Wilson, M., Fava, M., et al.[2015]

Duloxetine has been shown to provide significant pain relief in chronic pain conditions such as fibromyalgia, osteoarthritis, chronic low back pain, and diabetic peripheral neuropathic pain, with at least 50% pain intensity reduction observed in many patients after 2-12 weeks of treatment.

The response to duloxetine treatment is bimodal, meaning patients either experience substantial pain relief or very little, indicating that average responses may not accurately reflect individual patient experiences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duloxetine use in chronic painful conditions--individual patient data responder analysis. Moore, RA., Cai, N., Skljarevski, V., et al.[2022]

Adding duloxetine to the usual care for knee osteoarthritis (OA) patients with moderate pain is cost-effective, providing significant health benefits (31 additional quality-adjusted life years per 1,000 subjects) at a reasonable cost of $39,300 per quality-adjusted life year.

Implementing a depression screening strategy before prescribing duloxetine also proves beneficial, yielding 17 additional quality-adjusted life years per 1,000 subjects at a cost of $17,000 per quality-adjusted life year, making it a viable option for improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does Screening for Depressive Symptoms Help Optimize Duloxetine Use in Knee Osteoarthritis Patients With Moderate Pain? A Cost-Effectiveness Analysis. Lenhard, NK., Sullivan, JK., Ross, EL., et al.[2023]

Duloxetine significantly reduces pain intensity and improves functional outcomes in osteoarthritis patients, as shown in a meta-analysis of five randomized controlled trials involving 2059 patients.

While duloxetine is effective, it is associated with higher rates of treatment-emergent adverse events and discontinuation compared to placebo, although severe adverse events were not significantly different between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The short-term effect and safety of duloxetine in osteoarthritis: A systematic review and meta-analysis. Gao, SH., Huo, JB., Pan, QM., et al.[2022]

Therapeutic exercises are effective for managing osteoarthritis (OA), improving muscle strength, joint stability, and reducing pain, with moderate effect sizes for aerobic (0.52) and strengthening exercises (0.32) in knee OA.

Individualized exercise programs are essential for OA patients, as there is no significant difference in efficacy between group and individual sessions, highlighting the need for collaboration among healthcare providers for optimal patient education and treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise Programmes for Osteoarthritis with Different Localization. Lambova, S.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38130375/

Duloxetine plus exercise for knee osteoarthritis and depression To assess the feasibility of a 24-week, center-based, aerobic exercise program plus duloxetine to treat symptomatic knee osteoarthritis (OA) and major ...

2. oarsijournal.com oarsijournal.com/article/S1063-4584(23)00691-X/pdf

A feasibility study of combined treatment using aerobic ... A hybrid or home-based exercise program plus duloxetine may be more feasible, and knee OA patients with depressive symptoms who are at risk for major depres-.

3. ard.bmj.com ard.bmj.com/content/82/Suppl_1/100.1

OP0151 DULOXETINE PLUS EXERCISE FOR KNEE ... Duloxetine is indicated to treat neuropathic pain and depression among knee OA patients and could serve as a therapeutic complement to exercise.

4. ncbi.ncbi.grantome.com ncbi.ncbi.grantome.com/grant/NIH/K01-AG064041-02

A Feasibility and Pilot Study of Combined Treatment ... Duloxetine is the only antidepressant medication indicated for pain management in knee OA patients that has demonstrated efficacy and tolerability when treating ...

5. withpower.com withpower.com/trial/phase-3-depression-3-2021-162d6

Exercise + Duloxetine for Knee Osteoarthritis Exercise therapy is effective in reducing pain and activity limitations in patients with knee osteoarthritis, and it is likely beneficial for hip ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10733673/

Duloxetine plus exercise for knee osteoarthritis and depression To assess the feasibility of a 24-week, center-based, aerobic exercise program plus duloxetine to treat symptomatic knee osteoarthritis (OA) and

7. reumatismo.org reumatismo.org/reuma/article/view/1466

The preventive and therapeutic role of physical activity in ... Adapted physical activity, even at high intensity, does not appear to trigger or exacerbate knee OA; on the contrary, it may prevent obesity or lower limb ...