Lyrica Not Effective for Treating Traumatic Nerve Pain

By Pat Anson, Editor

Pregabalin is not effective in relieving chronic pain caused by traumatic nerve injury, but it may be useful as an analgesic in treating pain after surgery, according to a new study published in the Journal of Neurology.

The placebo-controlled study followed 539 patients in North America, Europe, Africa and Asia for three months. About half had nerve pain after surgery, while the rest had nerve pain after an accident or trauma.

Researchers found that pregabalin was not an effective pain reliever for the patients with traumatic nerve injuries, but the drug did provide better pain relief than placebo for the surgery patients.

"While these finding show that pregabalin is not effective in controlling the long-term pain for traumatic injury, it may provide relief for patients (that) experience post-surgical pain," said lead author John Markman, MD, director of the Translational Pain Research Program in the University of Rochester Department of Neurosurgery.

"The possibility that there was pain relief for those patients who had a hernia repair, or breast surgery for cancer, or a joint replacement lays the groundwork for future studies in these post-surgical syndromes where there is so much need for non-opioid treatments."

Pregabalin, which is sold by Pfizer under the brand name Lyrica, is FDA-approved for the treatment of chronic pain associated with shingles, spinal cord injury, fibromyalgia, and diabetic peripheral neuropathy.

It is also commonly prescribed as an "off label" treatment for other types of chronic pain and as an alternative to opioid medication.

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A major challenge for doctors is that biological changes in nerves and other tissues while healing from surgery or trauma vary from one patient to the next. There is also no diagnostic method that allows doctors to identify which patients will respond to a particular type of pain treatment.

"Given the rising rates of surgery and shrinking reliance on opioids, it is critical that we understand how to study new drugs that work differently in patients like the ones included in this study," Markman added.

While critics often say there is little or no evidence to support the long-term use of opioids, the same is true for other types of pain medication, including pregabalin. Nevertheless, in its guideline for opioids, the Centers for Disease Control and Prevention recommends pregabalin and its chemical cousin gabapentin as alternatives for treating chronic pain – without even mentioning their side effects or potential for abuse.

Pregabalin and gabapentin belong to a class of nerve medication called gabapentinoids, which were originally developed to treat epilepsy, not pain. In recent, deaths involving gabapentinoids have increased in the UK, Australia and Canada, where some addicts have learned the drugs can heighten the euphoric effect of heroin and other opioids.

The use of pregabalin and gabapentin has tripled in the U.S. over the past decade, but health officials have only recently started looking into their misuse and abuse. While gabapentin has a warning label cautioning users who take the drug with opioids, there is no similar warning for pregabalin.

Studies Warn of Pregabalin Deaths

By Pat Anson, Editor

Two new studies – one in Canada and one in Australia – should give pause to patients who use opioids and pregabalin (Lyrica), an anticonvulsant medication increasingly prescribed for fibromyalgia, neuropathy and other chronic pain conditions. Both studies found a number of overdose deaths that involve – but were not necessarily caused -- by pregabalin.

The Canadian study, published in the Annals of Internal Medicine, looked at over 1,400 patients in Ontario on opioid medication from 1997 to 2016 who died from opioid-related causes. Another group of over 5,000 surviving opioid patients was used as a control group.

Researchers found that patients who were co-prescribed opioids and pregabalin had a significantly higher risk of an overdose.

The risk of death was over two times higher for patients receiving opioids and a high dose of pregabalin (over 300mg) compared to those who took opioids alone.

Patients on a low or moderate dose of pregabalin also had a heightened risk, although not as large.

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Researchers say pregabalin has a sedative effect and may interact with opioids in ways that increase respiratory depression. Few doctors and patients are aware of the risk, even though over half of Ontario residents who begin pregabalin therapy are also prescribed an opioid.

"There is an important drug interaction between opioids and pregabalin that can lead to increased risk of fatal overdose, particularly at high doses of pregabalin," lead author Tara Gomes, PhD, of the Institute for Clinical Evaluative Sciences (ICES) and St. Michael's Hospital in Toronto, told MedPage Today.

"Clinicians should consider carefully whether to prescribe opioids and pregabalin together. If they decide that both medications are clinically appropriate, they should start with low doses and monitor their patients closely."

Lyrica (pregabalin) and Neurontin (gabapentin) are both made by Pfizer and belong to a class of anticonvulsant nerve medication called gabapentinoids. Sales of gabapentinoids have tripled in recent years, in part because of CDC prescribing guidelines that recommend the drugs as alternatives to opioid medication.  

U.S. health officials have only recently started looking into the misuse and abuse of gabapentinoids, which are increasingly used by addicts to enhance the euphoric effects of heroin and other illicit opioids. While gabapentin  has a warning label cautioning users who take the drug with opioids, there is no similar warning for pregabalin.

“Although current product monographs for gabapentin contain warnings about serious adverse events when this agent is combined with opioids, those for pregabalin do not. The importance of our finding warrants a revision of the pregabalin product monographs,” wrote Gomes.

Pregabalin Abuse in Australia

Health officials in Australia are also concerned about the growing use of pregabalin.  Researchers at the NSW Poisons Information Centre say poisoning cases involving pregabalin rose from zero in 2005 to 376 cases in 2016.

“Our study shows a clear correlation between the rapid and continuous rise of pregabalin dispensing and an increase in intentional poisonings and deaths associated with pregabalin,” said lead author Dr. Rose Cairns, a specialist at the NSW Poisons Information Centre.

According to the Australian Journal of Pharmacy (AJP), there have been 88 recorded deaths associated with pregabalin in recent years. Most of the deaths involved young, unemployed males who had a history of substance abuse, particularly with opioids, benzodiazepines, alcohol and illicit drugs.

“We believe that Australian doctors may not be aware of the abuse potential of pregabalin,” Cairns said. “Most patients who are prescribed this medication are in the older population but the group who are at high risk of overdosing are much younger. These people are likely to have been prescribed pregabalin despite having a history of substance abuse.”

According to researchers, up to two-thirds of people who intentionally misused pregabalin had a prior documented substance abuse history. “Prescribers need to consider this growing body of evidence that pregabalin has abuse potential before prescribing, especially to patients with substance abuse history,” said Cairns.

Pfizer did not respond to a request for comment on the Canadian and Australian studies.

New Treatments on Horizon for Chronic Pain

By Steve Weakley

Patients and doctors have long complained that there are few new treatments for chronic pain. And those that do come along are often reformulations of old medications or have unwelcome side effects.

Two developments this week suggest that trend may be changing. A new drug application has been submitted to the Food and Drug Administration for an “opioid of the future” that is less addictive, and research has uncovered a new way to treat neuropathic pain long term with a single injection.

In experiments on laboratory mice, researchers at the University of California at San Diego discovered a new method to block the root cause of pain with the injection of a naturally occurring protein, apolipoprotein A-I binding protein (AIBP). 

AIBP “turns off” a receptor called TLR4 that sits on the surface of nerve cells and searches for signs of infection or tissue damage.  Researchers say turning off the receptor prevents and even reverses inflammation and other cellular processes that create the sensation of pain.

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A single spinal injection of AIBP relieved neuropathic pain associated with chemotherapy in the mice for two months with no side effects, according to findings published in the journal Cell.

“What’s so special about our new approach, inhibiting the TLR4 receptor with AIBP, is that it actually modifies the pain processing systems themselves," says study co-author Tony Yaksh, PhD, a professor and vice chair for research in the Department of Anesthesiology at UCSD School of Medicine.

"So, if you think of neuropathic pain as a disease, then we see this as truly disease-modifying. We’re blocking the underlying mechanism that causes pain, not just masking the symptoms.”

Neuropathic pain is a common side effect of chemotherapy treatments for cancer. Chemotherapy not only inhibits the growth of cancer cells, it can permanently damage nerve cells and make people sensitive to even the slightest touch. Opioids and other medications such as gabapentin (Neurontin) are commonly prescribed for neuropathy, but both have unwelcome side effects.

“If it comes down to a choice between living with chronic pain or getting a spinal injection once every few months, we think most people would take the injection," said co-author Yury Miller, MD, a professor in the UCSD Department of Medicine. “As it stands now, AIBP could be developed as therapy for unremitting severe pain that only responds to high dose morphine. AIBP would remove the need for opioids, and reduce the potential for drug abuse.

"We're not saying we shouldn't use opiates to treat chronic pain, or in particular cancer pain—that would be a tragedy.” Yaksh said. "But it would also be a greater tragedy if we didn't support work to find a substitute for systemic opiates.”

“Opioid of the Future”

While AIBP is still in its experimental phase and could be years away from being available for treatment, Nektar Therapeutics’ so-called “opioid of the future” is one step closer to market.  Nektar has completed over a dozen clinical trials on NKTR-181 and applied to the FDA for approval of the drug as a treatment for chronic low back pain.

PNN has previously reported on NKTR-181, a new type of opioid that shows promise in relieving moderate to severe pain with less risk of abuse and addiction of traditional opioids like oxycodone or hydrocodone.

Because of its slow rate of entry into the central nervous system, NKTR-181 significantly reduces the “high” or euphoric effect that recreational drug users crave. Many pain sufferers don't feel that high when taking opioid medication, they just get pain relief.

In trials, NKTR-181 showed a 65% reduction in low back pain vs. placebo in tablets taken twice a day. Safety studies found recreational drug users had significantly less “drug liking” of NKTR-181 -- even at high doses -- when compared to oxycodone. Participants also had less daytime sleepiness and fewer withdrawal symptoms.

nektar therapeutics

nektar therapeutics

If it receives FDA approval, Nektar hopes to launch the drug commercially as early as next year. The company has yet to announce a partnership with a larger pharmaceutical company to help produce and commercialize NKTR-181 -- which is when the no-name "opioid of the future" will get a makeover with a branded name to make it more marketable.

Growing Abuse of Gabapentin

By Christine Vestal, Stateline

Doctors who are cutting back on prescribing opioids increasingly are opting for gabapentin, a safer, non-narcotic drug recommended by the Centers for Disease Control and Prevention.

By doing so, they may be putting their opioid-using patients at even greater risk.

Recently, gabapentin has started showing up in a substantial number of overdose deaths in hard-hit Appalachian states. The neuropathic (nerve-related) pain reliever was involved in more than a third of Kentucky overdose deaths last year.

Drug users say gabapentin pills, known as “johnnies” or “gabbies,” which often sell for less than a dollar each, enhance the euphoric effects of heroin and when taken alone in high doses can produce a marijuana-like high.

Medical researchers stress that more study is needed to determine the role gabapentin may have played in recent overdose deaths. However, a study of heroin users in England and Wales published last fall concluded that combining opioids and gabapentin “potentially increases the risk of acute overdose death” by hampering breathing and reversing users’ tolerance to heroin and other powerful opioids.

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Kentucky last year classified gabapentin as a controlled substance, making it harder for doctors to prescribe it in copious quantities and for long durations. The new classification also allows police to arrest anyone who illicitly sells the drug, although the state’s drug control chief, Van Ingram, said that was not the intent of the new law.

In the last two years, Illinois, Ohio, Massachusetts, Minnesota, Tennessee, Virginia and Wyoming also have moved to control the flow of gabapentin by requiring doctors and pharmacists to check a prescription drug database before prescribing it to patients to make sure they aren’t already receiving gabapentin, or some other medication that interacts with it, from another physician.

In a statement to Stateline, Pfizer communications director Steven Danehy said, “Reports of misuse and abuse with this class of medicines are limited and typically involve patients with a prior history of substance abuse, including opioids.”

The drugmaker also pledged to “continue working with regulatory authorities and health officials to evaluate and monitor the safety of these medicines.”

Prescribed for Many Conditions

Approved by the FDA in 1993 for the treatment of epilepsy and the nerve pain associated with shingles, gabapentin is sold by Pfizer under the brand name Neurontin. A generic form of the drug has been available since 2004 and is now sold by several other companies as well.

Gabapentin is now one of the most popular prescription drugs in the United States, according to the New England Journal of Medicine. It was the 10th-most-prescribed medication in 2016. Its more expensive cousin, pregabalin, sold as Lyrica and also made by Pfizer, was the eighth best-selling.

Many doctors recommend gabapentin to patients for a long list of disorders, including hot flashes, migraines, restless leg syndrome, fibromyalgia, and neuropathic pain associated with diabetes and spinal injuries. Some doctors also prescribe it for anxiety and insomnia.

Now, research is underway to determine whether gabapentin may be effective as a treatment for alcoholism.

Already, it is widely used to ease the symptoms of drug and alcohol detoxification. And addiction specialists routinely use gabapentin to manage pain in people who are either addicted or at risk of addiction to opioids and other substances.

Alone, high doses of gabapentin have not been found to affect breathing. The vast majority of gabapentin deaths, about 4 in 5, also involved opioids, according to the journal Addiction.

People who stop taking the medication abruptly, however, can suffer withdrawal symptoms such as trembling, sweats and agitation.

In February, Food and Drug Administration director Scott Gottlieb said the agency was reviewing the misuse of gabapentin and, for now, had determined no action was necessary. Similarly, the CDC has not issued a warning about gabapentin, nor has the Drug Enforcement Administration.

(Editor's note: the CDC opioid guidelines recommend gabapentin without any mention of the risk of abuse or overdose associated with the drug, or of possible side effects such as weight gain, anxiety and mood disorders.)

Early Signs of Abuse

In Kentucky, Ingram said it has been clear to police and pharmacists for the last three or four years that gabapentin was becoming an increasingly popular street drug. “People were seeking early refills, claiming they lost their prescriptions and openly conducting transactions in parking lots outside of drug stores,” he said.

But since it wasn’t a controlled substance, nothing was done about it. That’s likely to start changing with the new law, he said.

“Misuse of gabapentin is just one more collateral effect of the opioid epidemic,” said Caleb Alexander, an epidemiologist at Johns Hopkins University who has been studying the heroin and prescription drug epidemic. When one drug becomes less available, drug users historically seek out alternatives, he said. “What is most surprising is the sheer magnitude of its use.”

The share of Appalachian drug users who reported using gabapentin to get high increased nearly 30-fold from 2008 to 2014, according to a 2015 study in the American Journal of Psychiatry.

Paul Earley, an addiction doctor practicing in Georgia and a board member of the American Society of Addiction Medicine, said, “We knew that a small subset of our addiction patients would abuse gabapentin.” But he said it wasn’t until 2016, when Ohio sounded an alarm about the drug’s association with overdose deaths, that addiction doctors started taking the problem more seriously.

“For years, we considered gabapentin to be ‘good for what ails you,’” Earley said. “But I’m much more cautious than I used to be. If there’s anything we’ve learned from the opioid epidemic, it’s that we need to rethink how we prescribe drugs we once assumed were safe.”

This is story is republished with permission by Stateline, an initiative of The Pew Charitable Trusts.

Light Therapy Used to Treat Neuropathic Pain

By Pat Anson, Editor

For someone with peripheral neuropathy, even the slightest touch can cause burning, stinging or shooting pain, usually in the hands or feet.

The pain is caused when the peripheral nervous system is damaged by diabetes, shingles, chemotherapy or some other medical condition. About 8% of adults worldwide suffer from some form of neuropathy. Medications prescribed to dull the pain – such as opioids, anti-depressants or gabapentin (Neurontin) -- often prove to be ineffective, don’t last long or have unwanted side effects.

Scientists in Italy have now discovered an experimental way to treat neuropathy that provides pain relief for weeks at a time without the use of medication. In experiments on laboratory mice, researchers at the European Molecular Biology Laboratory (EMBL) in Rome identified a specific set of nerve cells in mouse skin that play a significant role in neuropathic pain.

NATURE COMMUNICATIONs

NATURE COMMUNICATIONs

When injected with a light-sensitive chemical and then exposed to infrared light, the nerve cells pull away from the skin’s surface and stop sending pain signals. The pain-relieving effects of the light therapy appear to last for weeks.

The accompanying image shows the skin of a mouse, with the nerve cells that are responsible for sensitivity to touch highlighted in green. The neurons are primarily located around hair follicles.

The EMBL's research, first reported in the journal Nature Communications, is still in its early stages. But scientists say human skin tissue is similar to that of mice, indicating that light therapy might be effective in managing neuropathic pain in humans.

"In the end, our aim is to solve the problem of pain in both humans and animals," says Paul Heppenstall, PhD, EMBL group leader. "Of course, a lot of work needs to be done before we can do a similar study in people with neuropathic pain. That's why we're now actively looking for partners and are open for new collaborations to develop this method further, with the hope of one day using it in the clinic."

Heppenstall says light therapy works on the treated nerve cells the same way spicy food or capsaicin patches can cause nerve fibers to retract.  

"It's like eating a strong curry, which burns the nerve endings in your mouth and desensitizes them for some time," says Heppenstall. "The nice thing about our technique is that we can specifically target the small subgroup of neurons causing neuropathic pain."

There are many different types of nerve cells in skin, which respond to different sensations like vibration, cold, heat or normal pain. Researchers say those cells are not affected by the light treatment. The skin is only desensitized to a gentle touch, breeze, or tickling.

Previous attempts to develop drugs to treat neuropathic pain have mostly focused on targeting single molecules.

"We think however, that there's not one single molecule responsible, there are many," Heppenstall explains. "You might be able to succeed in blocking one or a couple, but others would take over the same function eventually. With our new illumination method, we avoid this problem altogether."

The neuropathic pain in mice was assessed with a simple touch. The mice would normally quickly withdraw their paw when it was gently touched, but after light therapy they exhibited normal reflexive response to touch. The effect of the therapy lasted for a few weeks, until the nerve endings grew back and the gentle touch caused pain again.

Opioid Hysteria Has Gone Too Far

By Lisa Kehrberg, MD, Guest Columnist

I’m a 43-year-old physician who retired due to illness at the age of 39. I have a rare genetic disease called acute intermittent porphyria (AIP), an extremely painful and disabling condition.

Due to an enzyme deficiency, AIP causes toxins to buildup in the liver. The symptoms of porphyria are primarily neurological with the most notable being abdominal pain -- a burning sensation that is almost unbearable. The pain is similar to what I’d imagine it would feel like to have a blowtorch placed against my stomach and back.

Acute porphyria also causes peripheral neuropathy in the hands and feet. Along with the pain comes severe nausea, vomiting, headaches, fatigue, muscle weakness, motor neuropathy, and fluctuations in blood pressure and pulse. About 10 percent of AIP patients have a severe form of the disease referred to as “high excreter, recurrent attacks.”

Unfortunately, I am in that 10 percent.

Initially, I only had monthly attacks lasting 3-5 days, starting in my teenage years. Somehow, I managed to complete my education and training and became a physician despite that.

I was not finally diagnosed with AIP until the age of 39, when I suffered a life-threatening porphyria attack. It was almost too late for me at that point, as the attack was so severe that I was no longer able to work or do much at all. There is a one percent mortality rate during each AIP attack and I’ve had hundreds of them, so I’ve been lucky.

My older brother died unexpectedly at the age of 39. Genetic testing of autopsy samples later determined he had the same AIP gene mutation as I have. He died prior to my diagnosis and his gene mutation was discovered as I lay in a hospital bed being told my diagnosis.

LISA KEHRBERG, MD

LISA KEHRBERG, MD

At first, I felt such strong relief that my life was saved and sadness for my brother. But as the months passed, and I became sicker and more in pain, I started feeling a bit jealous of my brother. He was able to at least die with some dignity and is no longer suffering.

The pain that I experience is severe and the only thing effective enough to bring it down to tolerable levels is opioid medication. I’ve tried everything possible. Pain is a subjective experience and only the person experiencing it can know the severity and what helps to improve it.

I have difficulty understanding the response from some in the medical community, government, media and general public, who are so focused on “opioid addiction” that they are unable to see patients like me and empathize with us.

The media’s response has been extremely damaging. It seems people do not understand that addiction is a separate issue from pain management. Why is it that every time prescription pain medication is discussed, it's only in reference to addiction and the opioid epidemic? What about people like me who live with a life-threatening and severely painful disease? Not many reporters seem interested in that side of the story.

I have watched now as countless pain patients have taken their own lives due to discontinuation of their pain medication, often without any warning or consent. Physicians are not the problem in this. Physicians want to help patients. Physicians are being misled, brainwashed and even punished into thinking that prescription opioids usually lead to addiction.

Fortunately for patients like me, palliative care is a growing field and I’m so appreciative of my palliative care physician. I’m frightened for the future, not only for myself, but really for everyone. Pain affects everybody at some point in their lives. Whether it’s you, a family member or a friend -- pain will be there.

Everybody should be afraid of the direction where things are going. Even cancer patients at end of life are being denied appropriate pain treatments. Insurance companies are denying coverage for pain medications and getting away with it. I encourage everyone to please use common sense in this climate where the pendulum has swung too far in the wrong direction.

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Lisa Kehrberg, MD, is a retired family practice physician who specialized in pain management. You can read more about Lisa at the American Porphyria Foundation’s website.

Pain News Network invites other readers to share their stories with us. Send them to editor@painnewsnetwork.org.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Gluten-Free Diet May Relieve Neuropathy Pain

By Pat Anson, Editor

A small study by British researchers suggests that a strict gluten-free diet may help protect against the nerve pain caused by gluten sensitivity.

"These findings are exciting because it might mean that a relatively simple change in diet could help alleviate painful symptoms tied to gluten neuropathy," said lead author Panagiotis Zis, MD, a senior lecturer at the University of Sheffield. "While our study shows an association between a self-reported gluten-free diet and less pain, it does not show that one causes the other."

Gluten sensitivity has been associated with peripheral neuropathy -- a condition in which peripheral nerves become damaged, causing weakness, numbness and pain in the hands and feet. Diabetic neuropathy can also cause these symptoms, but when diabetes is ruled out and a person is sensitive to gluten – the pain and numbness might be caused by gluten neuropathy.

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The British study involved 60 mostly elderly people who had gluten neuropathy. They were asked about the intensity of their pain, mental health and whether they followed a strict gluten-free diet. About half of the participants had pain with their neuropathy.

People who were following a gluten-free diet were significantly more likely to be free of pain than those who did not. Over half of those without pain were on a gluten-free diet, while 21 percent who were gluten-free still experienced pain.

After adjusting for age, sex and mental health status, researchers found that people following the strict diet were 89 percent less likely to have pain.  

The study also found that people with painful gluten neuropathy scored significantly worse on their mental health assessment, which had a range of zero to 100 with 100 being best. Those with painful gluten neuropathy had an average score of 76, as opposed to the average score of 87 for those with painless gluten neuropathy.

"This study is promising because it shows that a gluten-free diet may help lower the risk of pain for people with gluten neuropathy," Zis said. "More research is needed to confirm these results and to determine whether the gluten-free diet led to the reduction in pain."

Further results of the study will be presented at the annual meeting of the American Academy of Neurology in April.

Gluten is a protein found in wheat, rye, barley, oats and other cereal grains. Gluten is found in many types of food, including bread, pasta, cereal, sauces and salad dressing.

When people with celiac disease eat gluten, it triggers an immune response that attacks the small intestine, causing pain and inflammation. About 1-2% of the population has celiac disease, but most cases go undiagnosed and untreated. Celiac disease is hereditary and runs in families.

People with non-celiac gluten sensitivity (NCGS) may also develop gastrointestinal symptoms, as well as headaches, chronic fatigue, fibromyalgia and allergies. Abdominal pain and irregular bowel movements are frequently reported with NCGS, which can make it difficult to distinguish from irritable bowel syndrome (IBS).

Research about the relationship between gluten and chronic pain conditions is rather slim, although there are many anecdotal reports that a gluten free diet reduces pain. In PNN columns, Donna Gregory Burch said going gluten-free helped reduce her fibromyalgia symptoms, while Lisa Ayres found that eliminating gluten quickly relieved her arthritis symptoms.