An FDA advisory committee will meet today to review whether the antidepressant Cymbalta should be used as a treatment for chronic pain, despite risks that include liver damage and skin disease.
Drugmaker Eli Lilly is seeking an indication for use in treatment of chronic pain, including pain related to arthritis and chronic low back pain.
In briefing documents posted on Tuesday, FDA reviewers said four
studies found Cymbalta worked better than the placebo at easing pain, but they questioned one crucial aspect of Eli Lilly's study design, and pointed to a number of major safety concerns associated with Cymbalta.
Earlier this year, the agency took Lilly to task for making false and misleading claims in Cymbalta marketing materials, overstating efficacy of the drug against pain and minimizing its risks.
If the FDA approves Lilly's current application, it would "likely result in a substantial increase in the prescribing of the product in the general population given the large number of Americans suffering from these types of chronic pain conditions," wrote Dr. Bob Rappaport, director of the FDA's Division of Anesthesia and Analgesia Products in the briefing documents.
Many physicians say the decision likely won't change their prescribing habits, but an approval could expand insurance coverage.
"Insurance reimbursement of an antidepressant for pain will help patients who couldn't get access to the meds due to restrictive formularies and so may expand coverage that way," said Dr. Joan M. Von Feldt, a pain specialist at the University of Pennsylvania, in an e- mail.
Von Feldt added that many doctors are pleased to have non-narcotic options for chronic pain treatment, especially with the troubling trend of prescription opioid addiction.
Some, however, don't see the need for the alternative.
Dr. Nortin Hadler, an arthritis specialist at the University of North Carolina Chapel Hill, called the potential approval "a marketing ploy."
"The marketing of Cymbalta as an analgesic is an example of data torturing," he said. "I do not prescribe it for [pain]."
Dr. Randy Wexler, a primary care physician at Ohio State University, agreed.
"I do not prescribe this unless a patient comes to me already on it," Wexler said. "There are other, and in my opinion safer, medications which are also generic that can be used."
Few seemed concerned about the potential side effects.
"Any medication with the potential to treat pain has potential side effects," said Dr. John Messmer of Pennsylvania State University, "but the risks of hepatotoxicity and Stevens-Johnson syndrome are so low as to be not worthy of mention."
Von Feldt added that all medications have side effects, and "some patients may have more susceptibilities to some side effects than to others."
Cymbalta, 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 another FDA reviewer, Rajdeep Gill. The majority of prescriptions are for depression, but at least 14 percent are already for off-label use in pain treatment, he said.
"Approving the use of Cymbalta ... for chronic pain may increase the patient exposure and physician prescribing to an area that is already not uncommon," wrote Gill.
If approved, Cymbalta would be the first non-NSAID, nonopioid analgesic broadly indicated for the treatment of chronic pain.
Lilly previously filed an application for a chronic pain indication for Cymbalta in May 2008, but withdrew it the following November after the FDA disapproved of efficacy results. Results of an ongoing osteoarthritis trial were not available at that time.
Because it is a "nontraditional" analgesic where the mechanism of action is not well-defined, the agency may need greater evidence to support a chronic pain indication than it would for opioids and NSAIDS, wrote Rappaport.
The advisory committee will examine five new clinical trials from Eli Lilly: three testing various doses of Cymbalta versus placebo in 1,041 chronic low-back pain patients, and two comparing Cymbalta with placebo in 487 osteoarthritis patients.
All five trials were multicenter, randomized, double-blind trials with a treatment duration of at least 12 weeks. 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 four of the five trials, Cymbalta -- given at between 60 mg and 120 mg -- demonstrated greater pain reduction compared with placebo.
However, FDA reviewers criticized the trial design because it assumed that patients dropped out of the trials at random, which was likely not the case.
"In analgesic trials, early discontinuations should be considered treatment failures; therefore, an improvement in a subject's pain score prior to dropping out due to an adverse event should not be credited in the analysis," the FDA reviewers wrote.
Patients in the Cymbalta trials were more likely to discontinue treatment because of adverse events, including nausea, sleep disturbances, dizziness, dry mouth, somnolence, constipation, and fatigue. Most of the events were dose-dependent.
Cymbalta 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. The FDA reviewers recommended that, if it is given the chronic pain indications, it should carry warning labels about the increased skin disease risks.
The FDA also has concerns about its risk of serious liver toxicity, already included in the drug's labeling.
No deaths were reported during the trials.
The safety findings aren't new or unexpected and are very similar to Cymbalta's current safety label, the FDA reviewers said.
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.
"[Cymbalta] is not universally tolerated nor free of safety risks," wrote Eli Lilly staff in the company's briefing documents posted on the FDA's website. However, the safety profile is "well-characterized" and not any different for chronic pain patients than it is for other patients who are already using the drug.
"Additionally, [it] is a centrally acting analgesic with a mechanism of action different from that of NSAIDs and opioids," Eli Lilly reviewers wrote. "As such, it constitutes a promising new modality for treatment of chronic pain."
The FDA is not required to follow the advice of its advisory committees, although it often does.