Duloxetine Significantly Reduced Osteoarthritis Knee Pain In New Study

Main Category: Bones / Orthopedics
Also Included In: Pain / Anesthetics;  Clinical Trials / Drug Trials;  Pharma Industry / Biotech Industry
Article Date: 17 Feb 2009 - 1:00 PDT

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In a new study, duloxetine hydrochloride (Cymbalta®), administered at 60 mg to 120 mg taken once daily, reduced pain severity significantly, compared with placebo, in patients with osteoarthritis pain of the knee. Data from the 13-week randomized, double-blind, placebo-controlled clinical trial 1 were presented at the annual meeting of the American Academy of Pain Medicine (AAPM) in Honolulu, Hawaii.

Duloxetine-treated patients showed greater reductions from baseline on the primary endpoint, the 24-hour average pain score on the Brief Pain Inventory (BPI), compared with placebo-treated patients. In the study, 65 percent of duloxetine-treated patients experienced a clinically significant (at least 30 percent) improvement in pain, compared with 44 percent of placebo-treated patients.

The duloxetine-treated patients also showed improved physical function, compared with placebo, as measured by the Western Ontario and McMaster Osteoarthritis Index (WOMAC). In this study, patients on duloxetine did not show statistically significant improvements on the WOMAC pain and stiffness subscales compared with placebo.

"With an aging population, the number of people with osteoarthritis of the knee is expected to rise," said Jacques P. Brown, M.D., of the Rheumatology and Bone Diseases Research Group in Quebec City, Canada. "This condition can have a real impact on a person's life, limiting functionality and ability to perform day-to-day activities."

The most common adverse events in the study (occurred at a rate of ≥5 percent and at least twice the rate of placebo) included nausea, constipation and excessive sweating (hyperhidrosis). Adverse events were similar to those seen in previous duloxetine studies.

Osteoarthritis is the most common form of arthritis and the most frequent cause of joint disease, which affects more than 5 percent of all adults worldwide.2 Almost 80 percent of patients with osteoarthritis have some degree of limitation of movement and 25 percent cannot perform their major daily activities of life.3 In addition to pain, other symptoms of osteoarthritis include aching, stiffness and limited range of motion of the joint.4

In Europe, duloxetine is approved for the treatment of DPNP, major depressive disorder (MDD) and generalised anxiety disorder (GAD).

Duloxetine is approved in various countries outside of Europe for the management of DPNP, for the treatment of MDD, for the treatment of GAD and for the management of fibromyalgia.

Additional Study Highlights

-- Compared with patients receiving placebo, patients receiving duloxetine experienced additional improvements associated with osteoarthritis pain of the knee, including:

-- Decreased interference from pain in general activity and normal work, as measured by the BPI Pain Interference (BPI-I) scales.

-- Duloxetine-treated patients did not show statistically significant improvements compared with placebo according to BPI-I measures of mood, walking ability, relations with other people, sleep, enjoyment of life and average interference.

-- Weekly mean of the 24-hour average pain severity and worst pain severity.

-- PGI-Improvement (PGI-I).

-- Duloxetine-treated patients showed statistically significant improvements compared with placebo as measured by PGI-I at each office visit, but not at study endpoint.

-- CGI-Severity.

-- A total of 31 patients in the study discontinued due to adverse events seven in the placebo-treated group and 24 in the duloxetine-treated group.

Methods

In this 13-week double-blind trial, patients were at least 40 years of age without a current diagnosis of major depressive disorder; no confounding painful conditions, diagnosis of inflammatory arthritis or autoimmune disorders; and no invasive therapy of the knee in the past three months, knee arthroscopy within the past year or joint replacement of the index knee at anytime. Patients were randomized to duloxetine (n=128) or placebo (n=128) and stratified by whether or not they used nonsteroidal anti-inflammatory drugs. At week seven, patients who showed suboptimal response to the 60 mg (33 patients) dose had their dose increased to 120 mg. The primary efficacy endpoint of the study was the Brief Pain Inventory (BPI) 24-hour average pain rating, which was analyzed using a mixed-model repeated measures (MMRM) approach. Secondary outcomes included the BPI-Severity and Interference items, weekly mean of the 24-hour worst pain and average pain scores, response rates on BPI average pain and weekly 24-hour average pain, the Patient Global Impressions of Improvement, the Western Ontario and McMaster Universities Index (WOMAC) total and subscales, Clinical Global Impressions of Severity, health survey Short Form-36 (SF-36) and EuroQoL Questionnaire 5 Dimension.

About Duloxetine

While duloxetine's mechanism of action in humans is not fully known, it is believed to affect both serotonin and norepinephrine/noradrenaline-mediated nerve signaling in the brain and the spinal cord. Based on pre-clinical studies, duloxetine is a reuptake inhibitor of serotonin and norepinephrine/noradrenaline. Scientists believe its effect on mood and pain perception is due to increasing the activity of serotonin and norepinephrine in the central nervous system.

Duloxetine is approved for the treatment of major depressive disorder and diabetic peripheral neuropathic pain in many countries and is also approved in some countries for the treatment of stress urinary incontinence and generalized anxiety disorder and the management of fibromyalgia. Duloxetine is approved only for adults 18 and over. There is a possibility of an increased risk of suicidal thoughts or behavior in children and young adults treated with antidepressants. Patients should call their doctor right away if they experience worsening depression symptoms, unusual changes in behavior or thoughts of suicide, especially at the beginning of treatment or after a change in dose.

Patients taking duloxetine may experience dizziness or fainting upon standing. The most common side effects of duloxetine include:

-- For depression: Dry mouth, nausea, diarrhea, headache, insomnia

-- For diabetic peripheral neuropathic pain: Nausea, fatigue, dizziness, headache, somnolence (sleepiness)

-- For generalized anxiety disorder: Dry mouth, nausea, fatigue, dizziness, headache, somnolence (sleepiness)

-- For stress urinary incontinence: Constipation, dry mouth, nausea, fatigue

-- For fibromyalgia: Constipation, dry mouth, nausea, diarrhea, fatigue, decreased appetite, dizziness, headache, somnolence (sleepiness), insomnia

This is not a complete list of side effects.

Duloxetine is contraindicated in patients who are allergic to it, who have liver disease resulting in hepatic impairment, who are taking a monoamine oxidase inhibitor (MAOI), fluvoxamine, ciprofloxacin or enoxacine or who have severe kidney disease. The initiation of treatment with duloxetine also is contraindicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis.

Eli Lilly and Company and Boehringer Ingelheim

In November 2002, Eli Lilly and Company and Boehringer Ingelheim signed a long-term agreement to jointly develop and commercialize duloxetine hydrochloride. This partnership covers neuroscience indications in most countries outside of the United States and Japan, with few exceptions.

About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers through medicines and information for some of the world`s most urgent medical needs.

About Boehringer Ingelheim

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 135 affiliates in 47 countries and almost 38,900 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine. In 2007, Boehringer Ingelheim posted net sales of 10.9 billion euro while spending one fifth of net sales in its largest business segment Prescription Medicines on research and development. For more information please visit http://www.boehringer-ingelheim.com.

Duloxetine for major depressive episodes, diabetic peripheral neuropathic pain, and generalized anxiety disorder is marketed by Lilly and Boehringer Ingelheim in all countries included in the partnership under the brand name Cymbalta®, except for Greece, Italy and Spain. In Greece, Italy and Spain Lilly markets the product as Cymbalta® and Boehringer Ingelheim markets the product as Xeristar®. In addition, in Germany, Lilly and Boehringer Ingelheim market duloxetine for diabetic peripheral neuropathic pain as Ariclaim®. In the United States, Cymbalta® is marketed by Lilly and Quintiles. In Japan, duloxetine is co-developed and co-marketed by Lilly and Shionogi & Co., Ltd.

Duloxetine for stress urinary incontinence is marketed by Lilly under the brand name Yentreve®.

This press release contains forward-looking statements about the potential of Cymbalta for chronic pain including the management of osteoarthritis pain of the knee and reflects Lilly's current beliefs. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. There is no guarantee that the product will continue to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

References:

1 Chappell, A, et al. Duloxetine 60 to 120 mg Once Daily Versus Placebo in the Treatment of Patients with Osteoarthritis Knee Pain. Poster presented at the American Academy of Pain Medicine Annual Meeting. 29 January 2009.

2 PHG Foundation. Osteoarthritis. Genomics and Population Health. Available on: http://www.phgfoundation.org/news/893/, accessed on 19 January 2009

3 The World Health Organisation, 50 Facts: Muskoskeletal Disorders. WHO. Available on: http://www.who.int/whr/1997/media_centre/50facts/en/, accessed on 19 January 2009

4 Types of Arthritis Pain. The National Pain Foundation. Available on: http://www.nationalpainfoundation.org/MyTreatment/articles /Arthritis_Types.asp, accessed on 19 January 2009.

Boehringer Ingelheim
http://www.boehringer-ingelheim.com