FDA Approves Extended-Release Lyrica

By Pat Anson, Editor

The U.S. Food and Drug Administration has approved a new extended-release version of Lyrica for the treatment of neuropathic pain. Lyrica CR is designed to be taken once a day, instead of the two or three doses recommended for Lyrica’s original formulation.

“Lyrica CR was developed to offer patients an effective treatment option with the convenience of once-daily dosing,” said James Rusnak, MD, Chief Development Officer in Pfizer’s Global Product Development. “It provides an important option for patients and health care providers managing these often debilitating pain conditions.”

Pfizer said the effectiveness of Lyrica CR was established in a clinical trial of over 800 patients with neuropathic pain. Patients who took Lyrica CR had a 74% reduction in pain, compared to about 55% who took a placebo. The most common side effects of Lyrica CR were dizziness, somnolence, headache, fatigue, peripheral edema, nausea, blurred vision, dry mouth and weight gain.

Lyrica (pregabalin) is one of Pfizer’s top selling drugs, but the company will likely face strong competition from cheaper generic versions of pregabalin when its U.S. patent expires next year.

Pfizer is undoubtedly hoping that current Lyrica users will switch over to the new extended release version, which will have full patent protection for many years to come. The company did not release any information on the cost of the new drug, which is expected to be available in January.

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Unlike the original formulation of Lyrica, which is widely prescribed to treat fibromyalgia, Lyrica CR is only approved to treat nerve pain caused by diabetic peripheral neuropathy and postherpetic neuralgia caused by shingles. But that won’t stop doctors from prescribing it off-label to fibromyalgia and other chronic pain conditions.

Pregabalin Under Scrutiny

The extended release version of Lyrica comes at a time when pregabalin is drawing new scrutiny from researchers and doctors who believe the medication is over-prescribed and being abused. Pregabalin belongs to a class of nerve drug known as gabapentinoids, which are increasingly being prescribed as alternatives to opioid pain medication.

 “We believe… that gabapentinoids are being prescribed excessively — partly in response to the opioid epidemic,” Christopher Goodman, MD, and Allan Brett, MD, recently wrote in a commentary published in The New England Journal of Medicine. “We suspect that clinicians who are desperate for alternatives to opioids have lowered their threshold for prescribing gabapentinoids to patients with various types of acute, subacute, and chronic noncancer pain.”

As PNN has reported, the World Health Organization and the FDA are also investigating reports that pregabalin is being abused. Addicts have learned pregabalin enhances the effects of heroin and other opioids.

“Reports indicate that patients are self-administering higher than recommended doses to achieve euphoria, especially patients who have a history of substance abuse, particularly opioids, and psychiatric illness. While effects of excessively high doses are generally non-lethal, gabapentinoids such as pregabalin are increasingly being identified in post-mortem toxicology analyses,” the FDA said in a recent notice published in the Federal Register.

The warning label for Lyrica CR will caution users that the drug can be abused.

“Patients should not drink alcohol while taking Lyrica CR. Patients may have more dizziness and sleepiness if taking Lyrica CR with alcohol, narcotic pain medicines, or medicines for anxiety. Patients who have had a drug or alcohol problem may be more likely to misuse Lyrica CR,” the label warns.

Pregabalin is classified as Schedule V controlled substance in the U.S., which means it has a low potential for abuse.

New Drugs Could Relieve Neuropathy Pain

By Pat Anson, Editor

After more than a decade of study, researchers at Boston Children’s Hospital are close to developing a new class of non-narcotic drugs that relieve chronic nerve pain by targeting a protein that enhances pain and inflammation.

Their findings, reported in the journal Neuron, could lead to new treatments for diabetic peripheral neuropathy, post-herpetic neuralgia, and inflammatory diseases like rheumatoid arthritis. Current treatments provide meaningful pain relief in only about 15 percent of patients.

"Most pain medications that have been tested in the past decade have failed in Phase II human trials despite performing well in animal models," notes Clifford Woolf, MD, PhD, director of Boston Children's F.M. Kirby Neurobiology Center and a co-senior investigator on the study. "Here, we used human genetic findings to guide our search from the beginning."

Previous research by Woolf and his colleagues found that people with variants of the gene for GTP cyclohydrolase (GCH1) -- about 2 percent of the population -- are at markedly lower risk for chronic pain. GCH1 is needed to synthesize the protein tetrahydrobiopterin (BH4), and people with GCH1 variants produced less BH4 after a nerve injury. This suggested that BH4 regulates pain sensitivity.

To test their theory, researchers took a "reverse engineering" approach in genetic experiments on mice.  First they showed that mice with severed sensory nerves produce excess BH4, created by the injured nerve cells and by macrophages-- immune cells that infiltrate damaged nerves and inflamed tissue.

Mice that were genetically engineered to make excess BH4 had heightened pain sensitivity even when they were uninjured. Conversely, mice that were genetically unable to produce BH4 had lower pain hypersensitivity after a peripheral nerve injury.

"We then asked, if we could reduce production of BH4 using a drug, could we bring about reduction of pain?" said Alban Latremoliere, PhD, also of Boston Children's Kirby Center, who led the current study.

The answer was yes. The researchers blocked BH4 production using a specifically designed drug that targets sepiapterin reductase (SPR), a key enzyme that makes BH4. The drug reduced the pain hypersensitivity induced by nerve injury and without any detectable side effects.

Because BH4 plays an important role in the brain and blood vessels, the goal of any treatment would be to dial down excessive BH4 production, but not eliminate it entirely. Latremoliere showed that blocking SPR still allowed minimal BH4 production through a separate pathway and reduced pain without causing neural or cardiovascular side effects.

"Our findings suggest that SPR inhibition is a viable approach to reducing clinical pain hypersensitivity," says Woolf. "They also show that human genetics can lead us to novel disease pathways that we can probe mechanistically in animal models, leading us to the most suitable targets for human drug development."