Chronic Knee Pain, Chronic Pain, Knee Osteoarthritis (Knee OA)
Conditions
Brief summary
The goal of this clinical trial is to examine the effects of duloxetine on walking ability and physical activity in patients with knee osteoarthritis. Researchers will compare duloxetine to a placebo (a look-alike substance that contains no drug) to see if duloxetine works to improve walking ability in patients with knee osteoarthritis. At study visits, participants will complete surveys, perform physical function tasks, undergo non-invasive brain imaging, and undergo sensory testing.
Detailed description
Using a double-blind, cross-over, 16-week randomized clinical trial of duloxetine versus placebo, this study will investigate whether duloxetine improves walking ability and physical activity in knee osteoarthritis patients (N=85). Aerobic exercise such as walking is important in preventing joint deterioration and is a first-line treatment for knee osteoarthritis, despite being painful. Indeed, many patients are limited in their ability to walk due to pain. Prior literature and preliminary data from our group indicate that central nervous system (CNS) pain processing contributes to pain-related walking impairment. While acetaminophen, nonsteroidal anti-inflammatories, opioids, and surgery are often used in knee osteoarthritis, side effects and health risks limit their use in many patient subgroups. In patients with CNS changes, these treatments may be less effective. In patients with nociplastic pain related to CNS sensitization, knee replacement is associated with worse post-operative pain and functional outcomes. Potentially targeting CNS sensitization, duloxetine is the only CNS-acting medication FDA-approved for knee osteoarthritis pain, and given that patient-reported physical function improves with duloxetine, its use may slow joint degeneration and delay the need for knee replacement by improving walking ability. However, no clinical trials have investigated whether duloxetine improves objectively measured physical function. This study will address this gap and lead to future large-scale studies examining knee osteoarthritis endophenotypes, related to CNS pain processing and other pathophysiology, which may aid in identifying patients who respond better to duloxetine versus other existing therapies. Techniques used in the setting of this randomized clinical trial include patient-reported outcomes, physical performance tests, actigraphy, noninvasive brain imaging, and quantitative sensory testing.
Interventions
DRUGDuloxetine
Duloxetine is an FDA-approved treatment for osteoarthritis. The drug will be prescribed for subjects with knee osteoarthritis pain to improve pain during mobility. The treatment consists of 30 mg of encapsulated duloxetine by mouth once daily for one week followed by 60 mg of encapsulated duloxetine by mouth once daily for 4 weeks. Then, patients will taper back down to 30 mg of encapsulated duloxetine by mouth once daily for one week.
DRUGPlacebo
The placebo is a capsule that has been filled with an inactive filler, microcrystalline cellulose (Avicel). It will match in look to the overencapsulated duloxetine capsules but not contain the duloxetine itself. Participants will take 1 week of the placebo pill identical in appearance to encapsulated duloxetine 30 mg followed by 4 weeks of the placebo pill identical in appearance to encapsulated duloxetine 60 mg. Then, patients will take one week of the placebo pill identical in appearance to encapsulated duloxetine 30 mg.
Sponsors
Benedict Alter
National Institute of Neurological Disorders and Stroke (NINDS)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Knee pain for greater than 6 months. * Moderate-to-severe knee pain (\>3/10) due to osteoarthritis, as defined by American College of Rheumatology and EULAR diagnostic criteria (Zhang 2010, Altman 1986) on \>50% of days in the past month. * KL grade 2-4 (Kellgren and Lawrence 1957) indicating significant degenerative changes on knee X-ray. This will be determined on evaluation of weight-bearing clinical X-rays on review of medical records. In the infrequent situation that the patient does not have an X-ray on review of their medical records, then the patient will obtain weight-bearing knee X-rays as part of the Screening Visit. * Age: 45-80 years old * Gender: Males and females will be recruited. * Language: only English-speaking subjects will be included.
Exclusion criteria
* Inflammatory arthritis (e.g. rheumatoid arthritis). * More intense pain due to another chronic pain syndrome (e.g. fibromyalgia, hip osteoarthritis) * Significant pain or weakness in the lower extremities due to a neurological condition (e.g. lumbar radiculopathy, paresis due to stroke) * New, ongoing acute pain * Recent use of duloxetine defined as any use within the last 3 months * Current use of antidepressants or tramadol * Current routine use of more than 30 mg oral morphine equivalents per day (use of \<=30 mg OME does not exclude the participant). * New treatment that may help knee osteoarthritis (including medication, exercise, behavioral, or complementary and integrative treatments) started in the last month. Stable use of treatments for greater than 1 month does not exclude the participant. * Unwillingness to maintain current knee osteoarthritis treatments for the duration of the study. This means that eligible participants must plan for the following: medications and dietary supplements should not change substantially in frequency or dose; behavioral therapy, exercise therapy, and complementary and integrative therapies should be consistent; and there should be no interventional treatments planned for lower extremity musculoskeletal conditions (e.g. joint steroid injections, knee radiofrequency ablation, knee replacement surgery). * Recent knee intra-articular injection of steroid or other agent (greater than 1 month does not exclude the participant) * Recent knee radiofrequency ablation (greater than 3 months does not exclude the participant) * Recent knee arthroscopic surgery (greater than 3 months does not exclude the participant) * History of knee replacement or open knee surgery on the index knee, defined as the more painful knee on average over the last month. * Inability to walk or climb stairs without significant assistance (e.g. a one-person assist, use a wheelchair; use of a cane does not exclude the participant). * Inability to participate in study procedures (e.g. cognitive impairment limiting ability to understand directions, inability to understand and read English) * Uncontrolled or unstable medical disorder preventing participation in study procedures * History of brain surgery * Tattoos on sensory testing sites * Pregnancy * History of severe renal impairment defined by GFR \< 30 ml/min or, if renal function testing is not available on EMR review, patient-reported history of acute or chronic kidney disease of any severity * History of chronic liver disease or cirrhosis * History of angle-closure glaucoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Distance walked in the 6-minute walking test | 6 minutes per measurement; measured several times from enrollment to last study visit for up to 16 weeks. | Distance walked during 6 minute walking task |
Countries
United States
Contacts
CONTACTBenedict Alter, MD, PhD
CONTACTEmma Racunas, BS
PRINCIPAL_INVESTIGATORBenedict Alter, MD, PhD
University of Pittsburgh
Outcome results
None listed