Exercise + Duloxetine for Knee Osteoarthritis

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Maryland, Baltimore

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

Disqualifiers: Cognitive impairment, Bipolar, Substance abuse, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests a treatment combining duloxetine and aerobic exercise for adults with knee osteoarthritis and depression. Duloxetine helps manage pain and mood, making it easier for patients to stick to their exercise routine. Duloxetine, an anti-depressant medication, has been recently approved for managing knee osteoarthritis and has shown effectiveness in reducing pain and improving function in patients with osteoarthritis.

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.

What data supports the effectiveness of the drug duloxetine for knee osteoarthritis?

Research shows that duloxetine can help reduce pain in people with knee osteoarthritis, as it has been effective in treating pain from various chronic conditions, including osteoarthritis. ^{1 2 3 4 5}

Is the combination of exercise and duloxetine safe for humans?

Duloxetine has been studied for safety in various conditions, including knee osteoarthritis and major depressive disorder. In these studies, some people stopped using it due to side effects like weight gain, but most found it tolerable. Exercise is generally safe for most people, but it's always best to consult with a healthcare provider before starting any new treatment. ^{2 3 6 7 8}

How does the treatment of exercise combined with the drug duloxetine differ from other treatments for knee osteoarthritis?

This treatment is unique because it combines aerobic exercise, which helps improve joint function and reduce pain, with duloxetine, a medication that can help manage pain and improve mood, offering a dual approach to managing knee osteoarthritis symptoms. ^{9 10 11 12 13}

Research Team

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• Aerobic exercise (Behavioural Intervention)
• Duloxetine (Serotonin-Norepinephrine Reuptake Inhibitor)

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.

Participant Groups

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 Canada for the following indications:

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+

Dr. Mohan Suntha

University of Maryland, Baltimore

Chief Executive Officer since 2019

MD from Jefferson Medical College, MBA from Wharton School of Business, BA from Brown University

Dr. Taofeek K. Owonikoko

University of Maryland, Baltimore

Chief Medical Officer

MD, PhD

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Dr. Richard J. Hodes

National Institute on Aging (NIA)

Chief Executive Officer since 1993

MD from Harvard Medical School

Dr. Marie Bernard

National Institute on Aging (NIA)

Chief Medical Officer

MD from Harvard Medical School

Findings from Research

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 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]

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]

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]

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]

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]

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 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]

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 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]

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]

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 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]

References

1. United States 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. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

An Updated Systematic Review and Meta-analysis of Duloxetine for Knee Osteoarthritis Pain. [2023]

3. New Zealand 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. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Duloxetine use in chronic painful conditions--individual patient data responder analysis. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

The short-term effect and safety of duloxetine in osteoarthritis: A systematic review and meta-analysis. [2022]

6. New Zealand 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. [2022]

7. India pubmed.ncbi.nlm.nih.gov

Weight change with long-term duloxetine use in chronic painful conditions: an analysis of 16 clinical studies. [2015]

8. United States pubmed.ncbi.nlm.nih.gov

Long-term tolerability and effectiveness of duloxetine in the treatment of major depressive disorder. [2015]

9. Netherlands pubmed.ncbi.nlm.nih.gov

[Exercise therapy in hip or knee osteoarthritis]. [2011]

10. England 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. [2018]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Exercise Programmes for Osteoarthritis with Different Localization. [2018]

12. England pubmed.ncbi.nlm.nih.gov

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

13. Switzerland pubmed.ncbi.nlm.nih.gov

The effectiveness of treadmill and swimming exercise in an animal model of osteoarthritis. [2023]