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 Drug Discovered for Neuropathic Pain

By Pat Anson, Editor

Researchers at The University of Texas have discovered a potent non-opioid pain reliever that acts on a previously unknown pain pathway. They say the synthetic compound, known as UKH-1114, is as effective at relieving neuropathic pain in laboratory mice as gabapentin, but lasts much longer.

Now scientists need to find out if drug is safe, effective and nonaddictive in humans -- a process that could take years.

"This opens the door to having a new treatment for neuropathic pain that is not an opioid," said Stephen Martin, a chemistry professor at The University of Texas at Austin. "And that has huge implications."

UKH-1114 binds to a receptor on cells in the central nervous system called the sigma 2 receptor. Although it was discovered 25 years ago, scientists did not know what sigma 2 did until now.

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Theodore Price, an associate professor of neuroscience at The University of Texas at Dallas, tested UKH-1114 on mice with nerve damage and found that it alleviated pain as well as gabapentin did, but was effective much longer -- lasting for a couple of days, compared to 4 to 6 hours. Price’s research was the first to demonstrate that the sigma 2 receptor may be a target for treating neuropathic pain.

"We started out just working on fundamental chemistry in the lab," said James Sahn, a research scientist at The University of Texas at Austin. "But now we see the possibility that our discoveries could improve the quality of people's lives. That is very satisfying."

Sahn and his colleagues have filed patent applications on the new compound. Their findings have been published in the journal ACS Chemical Neuroscience. An earlier paper on the sigma 2 receptor was published in the journal Proceedings of the National Academy of Sciences.

Chronic neuropathic pain is caused when nerves in the central nervous system are damaged by chemotherapy, shingles, diabetes or injuries to the brain or spinal cord. About 8% of adults worldwide suffer from some form of neuropathy.

Diabetic peripheral neuropathy causes nerves to send out abnormal signals. Patients can feel stinging or burning pain, as well as loss of feeling, in their toes, feet, legs, hands and arms. Nearly 26 million Americans have diabetes and about half have neuropathy, according to the American Diabetes Association. 

Many patients say drugs commonly used to treat neuropathic pain, such as gabapentin (Neurontin) and pregabalin (Lyrica), either don’t work or have unpleasant side effects such as dizziness, fatigue and diminished cognitive ability. Some doctors also feel the drugs are being overprescribed as alternatives to opioid pain medication.  

Lyrica and Neurontin Face More Scrutiny

By Pat Anson, Editor

The safety and effectiveness of Lyrica (pregabalin) and Neurontin (gabapentin) – two non-opioid drugs widely used to treat chronic pain – are drawing new scrutiny from researchers and doctors who believe the medications are over-prescribed.

In a study published in PLOS Medicine, Canadian researchers say there is little evidence that gabapentinoids – a class of nerve medication that includes Neurontin and Lyrica – are effective in treating chronic low back pain. In their review of 8 clinical studies, the researchers also found the drugs have a “significant risk of adverse effects.”

Lyrica and Neurontin are commonly prescribed for fibromyalgia and neuropathic pain, but the researchers say the drugs are increasingly prescribed for chronic back pain, even though there is “no clear rationale” for it.

"Despite their widespread use, our systematic review with meta-analysis found that there are very few randomized controlled trials that have attempted to assess the benefit of using gabapentin or pregabalin in patients of chronic low back pain," wrote lead author Harsha Shanthanna, MD, an assistant professor at McMaster University in Hamilton, Ontario.

"They necessitate prolonged use and are associated with adverse effects and increased costs. Recent guidelines from the National Health Service (NHS), England, expressed concerns on their off-label use, in addition to the risk of misuse.”

Shanthanna and his colleagues found that gabapentin showed “minimal improvement” in back pain compared to a placebo and pregabalin was “inferior” compared to other analgesics. There were no deaths or hospitalizations reported in any of the studies, but both drugs were associated with increased risk of dizziness, fatigue, visual disturbances, and diminished mental activity.

Lyrica and Neurontin are both made by Pfizer and are two of the company’s top selling drugs, generating billions of dollars in sales annually. Lyrica is approved by the FDA to treat diabetic nerve pain, fibromyalgia, post-herpetic neuralgia caused by shingles, and spinal cord injuries. It is also prescribed off-label to treat other chronic pain conditions, including lower back pain.

Neurontin is only approved by the FDA to treat epilepsy and neuropathic pain caused by shingles, but is widely prescribed off label to treat depression, ADHD, migraine, fibromyalgia and bipolar disorder. According to one estimate, over 90% of Neurontin sales are for off-label uses. Pfizer has paid $945 million in fines to resolve criminal and civil charges that it marketed Neurontin off-label to treat conditions it was not approved for.

Sales of pregabalin and gabapentin have risen steadily in recent years, in part because of CDC prescribing guidelines that recommend the two drugs as alternatives to opioid pain medication. About 64 million prescriptions were written for gabapentin in the U.S. last year, a 49% increase since 2011.

“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.

“Patients who are in pain deserve empathy, understanding, time, and attention. We believe some of them may benefit from a therapeutic trial of gabapentin or pregabalin for off-label indications, and we support robust efforts to limit opioid prescribing. Nevertheless, clinicians shouldn’t assume that gabapentinoids are an effective approach for most pain syndromes or a routinely appropriate substitute for opioids.”

FDA Seeks Public Comment on Abuse of Lyrica

The U.S. Food and Drug Administration announced last week that it was seeking public comment on reports that pregabalin is being abused. The FDA action was in response to a formal notification from the World Health Organization (WHO) that it may place international restrictions on pregabalin to reduce the risk of abuse and diversion. The FDA has until September 30 to respond to WHO.

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 notice published in the Federal Register.

Pregabalin is already classified as Schedule V controlled substance in the U.S. under the Controlled Substances Act, which means the DEA considers it to have a low potential for abuse.

The idea that Lyrica and Neurontin are being abused is surprising to many patients and doctors, but there are growing signs the drugs are being used recreationally.

Both Lyrica and Neurontin have been linked to heroin overdoses in England and Wales, where prescriptions for both drugs have soared in recent years.  Addicts have apparently found the medications enhance the effects of heroin and other opioids.

A small study of urine samples from patients being treated at U.S. pain clinics and addiction treatment centers found that one in five patients were taking gabapentin without a prescription.

Gabapentin and pregabalin are also being abused by prison inmates, according to Jeffrey Keller, MD, chief medical officer of Centurion, a private corrections company. 

“Gabapentin is the single biggest problem drug of abuse in many correctional systems,” Keller recently wrote in Corrections.com. “There is little difference (in my opinion) between Lyrica and gabapentin in both use for neuropathic pain or for abuse potential.”

Pfizer did not respond to a request for comment.

Insurance Claims Climb for Lyme Disease

By Pat Anson, Editor

Private insurance claims with a diagnosis of Lyme disease have soared in the U.S. over the past decade, according to a new report by FAIR Health, a nonprofit that tracks healthcare costs and insurance trends.

Lyme disease is a bacterial illness spread by ticks. It can also lead to other chronic pain conditions such as joint and back pain, chronic fatigue, fibromyalgia and neuropathy.

Fair Health analyzed a database of 23 billion private insurance claims from 2007 to 2016, and found that claims with a diagnosis of Lyme disease increased by 185 percent in rural areas and 40 percent in urban areas.

A recent CDC study also found the number of Lyme disease cases increasing, with nearly 40,000 confirmed and probable cases in 2015.

"Lyme disease is growing as a public health concern,” said FAIR Health President Robin Gelburd

Although Lyme disease historically has been concentrated in the Northeast and upper Midwest, the FAIR Health study suggests that it is spreading geographically. In 2007, insurance claims with diagnoses of Lyme disease were highest in New Jersey, Rhode Island, Connecticut, Massachusetts and New York.

By 2016, the top states were Rhode Island, New Jersey, Connecticut, North Carolina and New York -- with the emergence of North Carolina suggesting significant expansion to a new region.

Summer is the peak season for Lyme disease, with insurance claims more common in rural than in urban settings, according to the FAIR Health report. In the winter and early spring (December through April), claims involving Lyme disease were reported more often in urban than rural settings.

Age is also a differing factor in rural and urban environments. In rural settings, claims with Lyme disease diagnoses were more common for middle-aged and older people. Patients aged 41 years and older accounted for nearly two-thirds of the rural diagnoses. In urban populations, younger individuals with Lyme disease accounted for a higher percentage of claims.

Lyme disease is usually treated with antibiotics, but some patients experience complications that lead to Lyme disease syndrome (PTLDS), with long-term symptoms such as fatigue, muscle and joint pain and cognitive issues. Autoimmune diseases have also been associated with chronic Lyme disease.

Left untreated, Lyme disease can lead to serious chronic conditions, as Sarah Elizabeth Hirschle shared with us recently.

For patients with a Lyme disease diagnosis, FAIR Health reported the most common subsequent diagnoses were:

  • Joint pain (dorsalgia, low back pain, hip and knee pain)
  • Chronic fatigue  
  • Soft tissue disorders (myalgia, neuralgia, fibromyalgia)
  • Hypothyroidism
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Early symptoms of Lyme disease include fever, chills, headaches, fatigue, muscle and joint aches, and swollen lymph nodes. A delayed rash often appears at the site of the tick bite. The rash grows in size and sometimes resembles a bulls-eye.

To see some tips from the CDC on how to avoid tick bites, click here.

How Chronic Pain Changes Nerve Signals

By Pat Anson, Editor

Swedish researchers have developed a surprising new theory about what causes chronic nerve pain and why it is so difficult to treat.  

It has long been assumed that some sensory neurons only transmit pleasant tactile sensations, while others specialize in transmitting pain. But scientists at Karolinska Institutet have discovered that neurons that normally allow us to feel a caress or soft touch can switch roles and start signaling pain after nerve damage.

The researchers identified a small RNA molecule (microRNA) in neuron cells that regulates how touch is perceived. Levels of the molecule drop after neurons are damaged, which raises levels of a specific ion channel that makes the nerves sensitive to pain.

"Our study shows that touch-sensitive nerves switch function and start producing pain, which can explain how hypersensitivity arises," says Professor Patrik Ernfors at Karolinska Institutet's Department of Medical Biochemistry and Biophysics.

"What's interesting about our study is that we can show that the RNA molecule controls the regulation of 80 per cent of the genes that are known to be involved in nerve pain. My hope, therefore, is that microRNA-based drugs will one day be a possibility."

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The research was primarily conducted on mice but also verified in tests on human tissue, where low microRNA levels could be linked to high levels of the ion channel and vice versa, suggesting that the mechanism is the same in humans. Researchers believe the study findings, published in the journal Science, could lead to more effective pain treatments   

"It's vital that we understand the mechanisms that lead to chronic nerve pain so that we can discover new methods of treatment," says Ernfors. "The pharmaceutical companies have concentrated heavily on substances that target ion channels and receptors in pain neurons, but our results show that they might have been focusing on the wrong type of neuron."

Neuropathy and chronic nerve pain are common conditions, but the drugs available to treat them have limited efficacy. One widely used medication that blocks ion channels -- gabapentin (Neurontin) – is only effective in about half of the patients who take it, according to Ernfors.

West Virginia Admits Pain Patients Suffering

By Pat Anson, Editor

As Ohio, New Jersey and other states move to put further limits on opioid prescribing, West Virginia is acknowledging that its own efforts may have gone too far.

This week the West Virginia House of Delegates unanimously passed a bill that would create a commission to review state regulations on opioid pain medication and report back to the legislature on ways to make them “less cumbersome.”

Senate Bill 339 calls the abuse of pain medication in West Virginia “a nearly insurmountable plague,” but recognizes that efforts aimed at curbing abuse and overprescribing have “resulted in unforeseen outcomes often causing patients seeking pain treatment to suffer from a lack of treatment options.”

“Effective early care is paramount in managing chronic pain. To that end, prescribers should have the flexibility to effectively treat patients who present with chronic pain. However, there must be a balance between proper treatment for chronic pain and the abuse of the opioids found most effective in its treatment,” the bill states.

The legislation calls for the Dean of the School of Public Health at West Virginia University to serve as chair of the commission, which is to be known as the Coalition for Responsible Chronic Pain Management. Other members of the panel will include a board certified pain specialist, three physicians, a pharmacist, a chiropractor and a pain patient. 

The coalition will meet quarterly to review regulations on physicians and pain clinics, and will advise the legislature on ways to “further enhance the provider patient relationship in the effective treatment and management of chronic pain.”

Because the bill was amended in the House, it now returns to the West Virginia Senate for approval.

In many ways, West Virginia was ground zero for the nation’s overdose epidemic, and was one of the first states to crackdown on pill mills and the overprescribing of pain medication. Fewer opioids are now being prescribed, but West Virginia still leads the nation with the highest overdose death rate in the country.

At least 844 people died of drug overdoses in the state in 2016, a record number, compared to 731 in 2015. As in other parts of the country, addicts in West Virginia have increasingly turned to heroin and illicit fentanyl, which are more potent, dangerous and easier to obtain than prescription painkillers. Over a third of the overdose deaths in West Virginia last year were linked to fentanyl. Most of the deaths involved multiple drugs.   

Ohio Tightens Opioid Regulations

In neighboring Ohio, Gov. John Kasich last week announced new plans to limit opioid prescriptions to just seven days of supply for adults and five days for minors. Doses are also being limited to no more than 30 mg of a morphine equivalent dose (MED) per day.

The new regulations, which are expected to take effect this summer, are more than just guidelines – they are a legal requirement for prescribers. Although only intended for acute pain patients, many chronic pain patients are worried they will lose access to opioid medication.

"Doctors are already feeling this pressure not to prescribe pain medications," Amy Monahan-Curtis told NBC News. "What I am hearing is people are already being turned away. They are not getting medications. They are not even being seen. "

Ohio has been down this path before. In 2012, it began a series of actions to restrict access to pain medication. By 2016, the number of opioid prescriptions in Ohio had fallen 20 percent, or 162 million doses.

As in West Virginia, however, the number of drug overdoses continues to soar. Ohio led the nation with over 3,000 drug overdoses in 2015, with many of those deaths linked to illicit fentanyl and heroin. The situation is so bad that some county coroners are storing bodies in temporary cold storage facilities because they’ve run out of room at the morgue.

Next month new regulations will go into effect in New Jersey that will limit initial opioid prescriptions to just five days of supply. Only after four days have passed can a patient get an additional 25 day supply.

That law is primarily intended for acute pain patients, but many chronic pain patients are worried they’ll be forced to make weekly trips to the doctor and pharmacy for their prescriptions, or not be able to get them at all.

“You can imagine my alarm and fear when I was told yesterday that I will likely have to have the dosage of my medications reduced soon,” said Robert Clayton, a New Jersey man who suffers from chronic back and neck pain.

“This is LUNACY. As a nurse who treats individuals with chronic pain and addiction issues, I can tell you these new laws are going to have catastrophic results. Most of the people abusing opiates and dying are the addicts who abuse heroin and other prescription drugs like benzodiazepines, not the chronic pain patients like myself and the other unfortunate souls who have a genuine need for these drugs through no fault of our own.”

According to a recent survey of over 3,100 pain patients by PNN and the International Pain Foundation, one in five pain patients are hoarding opioid medications because they fear losing access to them.

Few Drugs Effective in Treating Neuropathy Pain

By Pat Anson, Editor

Cymbalta and some other anti-depressants are moderately effective at relieving diabetic nerve pain, according to a new report by the Agency for Healthcare Research and Quality (AHRQ).

But researchers found little or no evidence that opioids, Lyrica, Neurontin and other widely prescribed medications are helpful in treating neuropathy pain.

Nearly 26 million Americans have diabetes and about half have some form of neuropathy, according to the American Diabetes Association. 

Diabetic peripheral neuropathy causes nerves to send out abnormal signals. Patients can feel stinging or burning pain, as well as loss of feeling, in their toes, feet, legs, hands and arms.

"Providing pain relief for neuropathy is crucial to managing this complicated disease," said lead author Julie Waldfogel, PharmD, of The Johns Hopkins Hospital in Baltimore.

"Unfortunately, more research is still needed, as the current treatments have substantial risk of side effects, and few studies have been done on the long-term effects of these drugs."

In a systematic review of over 100 clinical studies published in the journal Neurology, AHRQ researchers found moderate evidence that the SNRI antidepressants duloxetine (Cymbalta) and venlaxine (Effexor) were effective in reducing neuropathic pain. Nausea, dizziness and somnolence were common side effects of the drugs.

The evidence was weaker for anti-seizure medication such as pregabalin (Lyrica) and oxcarbazepine (Trileptal). Common side effects from those drugs are weight gain, dizziness, headache and nausea.

While pregabalin works in the same way as gabapentin (Neurontin) -- both are often used to treat nerve pain -- the reviewers found gabapentin was not more effective than placebo. The seizure drug valproate and capsaicin cream were also found to be ineffective.

Oxycodone was not effective in treating neuropathy pain, and the evidence was weak for two other opioids, tramadol and tapentadol.

The U.S. Food and Drug Administration has approved only three medications -- duloxetine, pregabalin and tapentadol -- for diabetic nerve pain. However, many others drugs are prescribed “off label” for the disease.

"We hope our findings are helpful to doctors and people with diabetes who are searching for the most effective way to control pain from neuropathy," said Waldfogel. "Unfortunately, there was not enough evidence available to determine if these treatments had an impact on quality of life.”

Researchers noted that all of the studies were short-term, many for less than three months, and even the most effective drugs had relatively high rates of side effects. They say longer-term studies are needed so that adverse effects and the continued effectiveness of the drugs can be assessed.