Equivocal Message on Duloxetine for Pain from Panel

An FDA advisory committee has voted narrowly — 8 to 6 — to recommend that the agency expand the indication for the antidepressant duloxetine (Cymbalta) to treat chronic musculoskeletal pain.

In two votes earlier in the afternoon, members of the Anesthetic and Life Support Drugs Advisory Committee telegraphed the final equivocal message when they voted — with equally slim margins — that the drug eased pain better than placebo in patients with lower back pain, but wasn’t effective against arthritis pain.

Drugmaker Eli Lilly is seeking an indication for treatment of chronic pain. During the meeting, FDA officials said that such a broad indication was no longer under consideration and the agency would instead consider approving the drug to treat musculoskeletal pain, because the company’s trials tested the drug only as a treatment for two types of musculoskeletal pain — lower back pain and osteoarthritis.

But “musculoskeletal pain” is still a broad designation and can be applied to 30 to 40 million people each year, according to the estimate of several panelists. If the FDA chooses to approve the new indication, it could significantly increase prescriptions of the drug.

“This will be an explosion of use in this drug seeing as most of the people sitting here my age have chronic arthritis and knee pain,” said panelist Thomas Boyer, MD, of the University of Arizona.

An 8 to 6 vote is considered a “null” vote, and provides no clear indication of what the FDA will do. The FDA is not required to follow the advice of its committees, but it often does.

The panel’s vote on duloxetine’s efficacy in back pain was, if anything, even more equivocal than the final vote — 8 to 5 that the drug works, with one member abstaining.

To support its application, Eli Lilly had submitted three trials testing various doses of duloxetine against placebo in 1,041 chronic low-back pain patients. The primary efficacy endpoint for all the trials was the change from baseline to week 13 in pain intensity, which was measured by the 11-point Brief Pain Inventory and patient diaries.

In all three back pain trials, duloxetine — given at between 60 mg and 120 mg — demonstrated greater pain reduction than placebo (P<0.05 for all).

However, the benefit isn’t that impressive, said panelist John Markman, MD, director of the Neuromedicine Pain Management Center at the University of Rochester Medical Center in Rochester, N.Y. He estimated that for every 10 patients treated with duloxetine, just one would experience a 30% reduction in pain.

“The problem we have with chronic pain is that nothing has that large of a treatment effect,” said Daniel Clauw, MD, of the University of Michigan, who spoke on behalf of Eli Lilly. “At least with duloxetine, you were able to see a treatment effect in all studies.”

However, the panel was less confident about the arthritis indication and voted 4 to 9, with one member abstaining, that the company provided convincing proof that the drug eased the pain of patients with arthritis.

The drugmaker submitted two trials comparing duloxetine with placebo in 487 osteoarthritis patients. The study had the same endpoints as the back pain trials, but this time, only one of the trials showed duloxetine eases arthritis pain better than placebo.

Although concerns were raised prior to the meeting about the drug’s side effects — notably hepatoxicity — the panel seemed to agree the side effects, including the risk for liver damage, were acceptable. The committee voted 9 to 4 that the benefits of duloxetine outweighed the risks.

“The safety profile is reasonable,” said panel chairman Jeffery Kirsch, MD, of the Oregon Health & Science University.

“It won’t be any more toxic, and perhaps less toxic that the [medication] I currently use,” said panelist Jack Rosenberg, MD, of the University of Michigan.

Duloxetine use also appears to be associated with an increased risk of Stevens-Johnson syndrome, a skin disease that usually results from a drug reaction, as well as another form of the disease called toxic epidermal necrolysis.

Other adverse events reported in the trials included nausea, sleep disturbances, dizziness, dry mouth, somnolence, constipation, and fatigue. Most of the events were dose-dependant.

The drug also carries a boxed warning for suicidality in children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders, although that issue was hardly discussed at Thursday’s meeting.

Duloxetine, a serotonin-norepinephrine reuptake inhibitor, was originally approved to treat depression, and its indications were subsequently extended to include fibromyalgia, anxiety, and pain associated with diabetic neuropathy.

Prescriptions for the drug increased from five million in 2005 to more than 14 million in 2009, a threefold increase, according to an FDA reviewer, Rajdeep Gill, PharmD. The majority of prescriptions are for depression, but at least 14% are already for off-label use in pain treatment, she said.

If approved, duloxetine would be the first non-NSAID, nonopioid analgesic broadly indicated for the treatment of chronic pain.

Earlier this year, the agency took Lilly to task for making false and misleading claims in Cymbalta marketing materials, overstating drug’s use against pain and minimizing its risks. During Thursday’s meeting, Kirsch said he was “perturbed” over how the company has been marketing Cymbalta as a pain reliever for depressed patients, when the drug isn’t approved for that exact indication.

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