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."

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.

The 411 on Calmare Scrambler Therapy

By Michael Cooney, DC, Guest Columnist

As a chiropractor who treats various pain conditions caused by injury or disease, my biggest frustration is when our therapies do not achieve a successful patient outcome.

Often, “treatment-resistant” patients are forced to seek out more invasive procedures – surgeries, spinal cord stimulators, or powerful narcotics such as ketamine − where success has been uneven, but side effects can be significant.

I wasn’t comfortable recommending these “next level” neuropathic pain treatments for my patients. So my partner Dr. Robert Kelly and I spent two years looking for a non-invasive therapy that didn’t cause pain or come with added side effects.

Through a contact in Italy, we discovered Calmare scrambler therapy, which treats several types of drug and treatment-resistant pain, a big plus for our practice. After undergoing clinical training to use the machine and eventually testing it on patients, we saw results after just a few treatment sessions, in the majority of cases.

I’ll be honest, our aim in adding Calmare to our treatment offerings was designed to help our patients who were not responding to traditional pain therapies. No one was more surprised than I to experience the global interest in this alternative treatment option.

We have been performing Calmare Therapy since 2011, treating patients from coast-to-coast and as far away as Australia, the UK, South Africa and Brazil.

Today, we treat children, adults and seniors battling CRPS/RSD, fibromyalgia, neuropathy after chemotherapy treatment, and pain that develops after surgery or from diabetes. We have also treated many people with neuropathic pain after a shingles diagnosis.

How Scrambler Therapy “Talks” With the Brain

The brain’s reaction to pain can be compared to learning to play the piano or memorizing a poem. The more the body processes pain, the stronger the connections between pain nerves and the brain become.

When someone is injured, the brain sets up a process to heal the injury. For example, cells carry away dead tissue or it increases blood flow to the injured area. Eventually, the brain realizes the injury has healed, and cuts off the pain message.

But for some people, the brain never sends the all-important message: “There’s no more injury here. You can stop sending that pain signal.”

That’s where Calmare scrambler therapy comes in.

Using small electrodes (think EKG pads) judiciously placed in the region of the injury, the device sends a mild electric signal to the brain through the electrodes.

This message overrides the brain’s confused pain signal and corrects it to a “there’s no pain here” message.

We recommend a series of 10 daily scrambler treatments. But in many cases, the pain is lessened for the patient as soon as the first treatment.

The machine we use, the MC-5A Calmare device, has been tested in clinical trials at some of the most prestigious research institutions, including the Massey Cancer Institute at Virginia Commonwealth University, the Mayo Clinic, and the American Society of Clinical Oncology. Their studies reported significant reductions in pain associated with cancer treatment and other chronic pain conditions.

The Value of Alternative Medicine in Treating Neuropathy

The majority of patients we treat with scrambler therapy come to us frustrated and exhausted by the endless search for pain relief. They have often resorted to unproven surgeries, experimental procedures, or have used powerful pain medications that leave them mentally and physically debilitated by the drug’s side effects.

I encourage people with treatment-resistant neuropathy and their families to research and consider less invasive, alternative solutions to combat the effects of chronic pain. In some cases, the cost can be comparable to prescription medications and in-patient co-pays. The outcome can be life-changing.

Regardless of the pain therapy you choose, keep in mind there are treatments that do not involve narcotics, surgery or invasive procedures, which can result in more pain and discomfort.

Keep looking -- network with people who have your medical condition, conduct your own research, and reach out to doctors who understand the value of alternative therapy. Ask the provider to put you in touch with another patient who had the treatment. We enthusiastically offer this service through our Patient-2-Patient program.

There may very well be a solution out there to minimize your pain. But often, it’s up to you to discover it.

Michael J. Cooney has been a doctor of chiropractic for more than 30 years at Rutherford Allied Medical Group and Calmare Therapy NJ in Rutherford, New Jersey. He is one of six certified providers of Calmare in the U.S. Dr. Cooney can be emailed at calmarenj@gmail.com.

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.

Lyrica and Cymbalta Advised for Diabetic Neuropathy

By Pat Anson, Editor

New guidelines by the American Diabetes Association for the treatment of diabetic neuropathy strongly discourage the use of opioids to treat nerve pain, while recommending pregabalin (Lyrica) and duloxetine (Cymbalta).

Nearly 26 million people in the United States have diabetes and over half have some form of neuropathy, which often causes a painful stinging or burning sensation in the hands or feet.  Nerve pain is often the first symptom that prompts people to seek medical care before getting a diabetes diagnosis.

Researchers at the University of Michigan led a group of internationally recognized endocrinologists and neurologists, and teamed up with the American Diabetes Association (ADA) to craft a new position statement on the prevention, treatment and management of neuropathy. The ADA last released a statement on diabetic neuropathy in 2005.

"Our goal was to update the document so that it not only had the most up-to-date evidence, but also was easy to understand and relevant for primary care physicians," said lead author Rodica Pop-Busui, MD, a professor of internal medicine at Michigan Medicine Division of Metabolism, Endocrinology and Diabetes.

"Treatment of neuropathy pain is specifically relevant because, unfortunately, there has been much overprescribing of narcotics for neuropathic pain."

Although opioids like oxycodone and tramadol are effective in relieving nerve pain, they are not recommended by the ADA as a first, second or even a third-line treatment.

“Despite the demonstrated effectiveness of opioids in the treatment of neuropathic pain, there is a high risk of addiction, abuse, sedation, and other complications and psychosocial issues even with short-term opioid use. For these reasons, opioids are not recommended in the treatment of painful DSPN (distal symmetric polyneuropathy) before failure of other agents that do not have these associated concerns,” the guideline states.

Instead of opioids, the ADA recommends either pregabalin (Lyrica) or duloxetine (Cymbalta) as an initial treatment for neuropathic pain. Gabapentin (Neurontin) can also be considered.

PNN readers often complain of side effects from all three drugs – such as depression, fatigue, nausea, headache and weight gain -- yet the ADA statement only vaguely warns that their “adverse effects may be more severe in older patients.”

"Lyrica did help with my nerve pain but the side effects were intolerable and the withdrawal was absolute hell," said Laura.  "I gained 20 pounds in a month and was even more of a zombie than when I was on gabapentin. I had no personality, no interest in anything, and had completely lost motivation to do anything."

"I have been on Cymbalta a couple of years. It has helped overall with depression, anxiety and pain. I also can't miss a dose or try to quit cold turkey," wrote Rebecca Williams. "I become very dizzy, nauseated, night sweats, crazy dreams, electrical zaps in my head. I don't know how I would ever get off of it because the withdrawal symptoms are unbearable."

The ADA guidelines recommend that physicians try different therapies to prevent or slow the progression of diabetic neuropathy, most of which focus on controlling high blood sugar (glucose), which can cause irreversible damage to small nerve fibers. Insulin, regular exercise and a low-calorie, low-fat diet can help regulate glucose levels.

To see the ADA’s recommendations, click here.

Medication Could Reverse Peripheral Neuropathy

By Pat Anson, Editor

Blocking a sensory nerve signal with medication could prevent or even reverse symptoms of peripheral neuropathy, according to new research published in the Journal of Clinical Investigation. 

About 20 million Americans suffer from peripheral neuropathy, which often causes a painful stinging or burning sensation in the hands or feet.  

"Peripheral neuropathy is a major and largely untreated cause of human suffering," said lead author Nigel Calcutt, PhD, a professor of pathology at the University of California San Diego School of Medicine. "It has huge associated health care costs."

In studies on diabetic laboratory rats, Calcutt and his colleagues identified a molecular signaling pathway that, when blocked with the drug pirenzepine, promotes sensory neuron growth and prevents or reverses the nerve damage caused by peripheral neuropathy.

The discovery suggests that pirenzepine and other anti-muscarinic drugs – a class of nerve medication that is already used to treat Parkinson’s disease, motion sickness, irritable bowel syndrome and other conditions – could be used as a new treatment for peripheral neuropathy.

"This is encouraging because the safety profile of anti-muscarinic drugs is well-characterized, with more than 20 years of clinical application for a variety of indications in Europe," said senior study author Paul Fernyhough, PhD, a professor in the departments of pharmacology and therapeutics and physiology at the University of Manitoba in Canada. "The novel therapeutic application of anti-muscarinic antagonists suggested by our studies could potentially translate relatively rapidly to clinical use."

The first symptoms of peripheral neuropathy are usually a tingling or numbing sensation in the toes, feet, and hands caused by small fiber nerve damage. The symptoms progress, spread and become more painful, dramatically affecting quality of life.

Researchers say treating the disease in its early stages is key.

“Since small fiber degeneration develops early in the human disease and can be reliably quantified using a variety of minimal or noninvasive techniques that can be applied iteratively, future clinical trials of anti-muscarinic drugs might feasibly focus on reversal of these early indices of neuropathy,” they said.

“Further, as anti-muscarinic drugs were effective in augmenting collateral (nerve) sprouting in our in vitro assay, this new therapeutic approach may be most effective during the early stages of a dying-back neuropathy prior to overt and/or complete fiber loss.”

Nearly 26 million people in the United States have diabetes and about half have some form of neuropathy, according to the American Diabetes Association.  Small fiber neuropathy can also be caused by lupus, HIV, Lyme disease, celiac disease or chemotherapy.

Kratom Helps Relieve My Neuropathy Pain

By Robert Dinse, Guest Columnist

I suffer from diabetic peripheral neuropathy.  I can best describe the pain as something akin to being doused in gasoline and then having a match tossed on me.  Pretty much everything from the neck down at times is involved in severe burning pain.

Over time I've been placed on a number of combinations of anti-depressants and anti-seizure medications with various degrees of effectiveness. Presently I am on Lyrica and nortriptyline, an anti-depressant.  So far this seems to be the best compromise between sedation and pain.

I actually got slightly better pain control with amitriptyline, another anti-depressant, but nortriptyline helps my mood more and since Lyrica negatively impacts my mood but greatly reduces my pain, this seems to be the best compromise.

With this combination of drugs, my pain is reasonably controlled about six days of the week, but I have periods, usually lasting 3-6 hours, of breakthrough pain in which I'm on fire again.

Kratom provides relief during those times and it does so without getting me high, or noticeably affecting my mental state in any way.  This leaves me almost pain free and totally functional.

robert dinse

There are two other drugs I've found to be helpful for this breakthrough pain. The first is marijuana, which is legal in Washington State but leaves me pretty much non-functional. I cannot drive, nor effectively do my work on enough marijuana to give pain relief.  Marijuana also stimulates my appetite and as a diabetic I need to lose weight, not gain weight.

The other useful drug is tianeptine sodium, but for it to be effective I need about 140 mg, which is higher than the maximum recommended single dose. At that dosage I also build a rapid tolerance.  Not a problem if the pain flare up is short, but if it lasts more than two days, which on rare occasions it does, then tianeptine sodium becomes ineffective. 

Some people get withdrawal symptoms from tianeptine sodium. I am fortunate that I have not ever experienced that, but it's lack of effectiveness if I get a bad flare-up lasting more than two days is its chief drawback.

I do not seem to rapidly build tolerance to kratom, and I've yet to experience any loss of effectiveness.  It doesn't get me high.  I don't get withdrawal symptoms. For my needs it is ideal, yet the DEA wants to take this away.

I wish that doctors and DEA officials could experience neuropathic pain firsthand so they could understand the hell their fouled up policies are putting people through. We have tens of thousands of deaths every year due to alcohol and tobacco, and the 16 alleged kratom deaths in the last five years all involved a mixture of other drugs that were most likely responsible for those deaths.

It is very hard to overdose on kratom because you take too much and you puke it up.  I have experimentally determined the puke up threshold for me is about 12 capsules, and 10 capsules totally relieve my pain with no sense of intoxication or impairment.

I don't know how you could ask a pain reliever to be simultaneously anywhere near as effective or safe as kratom.  Too much aspirin and you bleed to death internally, too much Tylenol and you toast your liver, many other NSAIDS readily available over the counter are bad for your heart.

Problem is, as a natural product, it's not patentable and thus competes with other patentable but much more dangerous and less effective drugs.

Robert Dinse lives in Washington State with his family.

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.

Many Multiple Sclerosis Patients Misdiagnosed

By Pat Anson, Editor

Multiple Sclerosis (MS) is a chronic disease that attacks the body’s central nervous system, causing pain, numbness, difficulty walking, paralysis, loss of vision, and fatigue. Patients diagnosed with MS face enormous physical, emotional and financial challenges coping with a disease that cannot be cured.

Many also discover that they don’t actually have MS.

A new study published in the journal Neurology looks at 110 patients who were incorrectly diagnosed with MS when they actually suffered from more common and treatable conditions such as migraine and fibromyalgia.   

One third of the patients were misdiagnosed for a decade or longer, most took unnecessary and potentially harmful medication to treat a disease they didn't have, and some even participated in clinical trials for experimental MS therapies.

About a third suffered from “unnecessary morbidity” – morbid thoughts of death.

"Misdiagnosis of MS is common; patients may experience common MS symptoms, such as numbness and weakness with a variety of different conditions, many that are more common and less serious than multiple sclerosis," says the study's senior author Brian Weinshenker, MD, a neurologist at Mayo Clinic.

"With the advent of treatments for MS, many physicians feel pushed to reach an early diagnosis, and may be less strict than they should in requiring more specific symptoms or objective neurological findings before making a diagnosis of MS.”

Unlike other chronic illnesses, there is no specific biomarker or blood test for MS. The nerve damage caused by MS is also associated with a wide range of symptoms, many of which are also caused by other conditions such as Lyme disease, lupus, fibromyalgia, and Vitamin B12 deficiency.

Some diagnostic tests for MS, such as magnetic resonance imaging (MRI), can also be misinterpreted.

“Nonspecific MRI abnormalities that can mimic those of MS are very common in healthy individuals, and widespread use of MRI as a diagnostic tool increases the rate of misdiagnosis," said Weinshenker.

The 110 patients included in the study were identified by MS subspecialist neurologists at Mayo Clinic, University of Vermont, Washington University and Oregon Health & Science University.

Twenty two percent of the misdiagnosed patients actually had migraine; 15% had fibromyalgia; 12% had a nonspecific condition flagged by an abnormal MRI; 11% had a conversion or psychogenic disorder; and 6% had neuromyelitis optica spectrum disorder.

"This study suggests significant and long-term unnecessary risks for these patients," said lead author Andrew Solomon, MD, a neurologist at the University of Vermont College of Medicine. "While there may be different reasons for misdiagnoses by subspecialists and nonspecialists, this study suggests that we all make mistakes, and I think we can all do better.”

A previous survey of MS specialists found that more than 95% had seen at least one patient in the past year that was misdiagnosed with MS by another provider.

Some treatments for MS carry serious side effects. One drug, taken by 13 percent of the misdiagnosed patients in the current study, can cause a potentially fatal brain infection. Other patients suffered from the discomfort and inconvenience of daily injections; others experienced side effects from medications or lacked treatment for the conditions they actually had.

There are also enormous financial costs involved. The cost of medications to treat MS in the United States now exceeds $50,000 a year.

"Premature diagnosis of MS should be avoided," says Weinshenker. "When in doubt, physicians often can defer a diagnosis if it is not clear that there is a serious neurological problem or if a patient is stable. Physicians should request a second opinion when they are unsure but concerned that it might be harmful to delay a definitive diagnosis of MS."

Weinshenker and Solomon hope their study will encourage better education of clinicians on the proper use of MS diagnostic criteria and to further studies on how to recognize patients incorrectly diagnosed with MS.

Study Finds Link Between Chronic Pain and Anxiety

By Pat Anson, Editor

A new study helps explain why so many chronic pain patients also suffer from anxiety or depression.

Researchers at the University of Vermont discovered that the body releases the same neurotransmitter in response to stress as it does to chronic neuropathic pain. The findings, published in the journal Biological Psychiatry, could lead to the development of a new and safer class of medication that could treat both pain and anxiety.

In studies on laboratory mice, researchers found that pain signals and the PACAP neurotransmitter (pituitary adenylate cyclase activating polypeptide) share the same pathway to the brain - the spino-parabrachiomygdaloid tract - which travels from the spinal cord to the amygdala, where the brain processes emotional behavior.

"Chronic pain and anxiety-related disorders frequently go hand-in-hand," says senior author Victor May, PhD, a professor of neurological sciences at the University of Vermont. "By targeting this regulator and pathway, we have opportunities to block both chronic pain and anxiety disorders."

May and his colleagues found that anxious behavior and pain hypersensitivity were significantly reduced when a PACAP receptor antagonist -- designed to block the release of the neurotransmitter -- was applied.

"This would be a completely different approach to using benzodiazepine and opioids - it's another tool in the arsenal to battle chronic pain and stress-related behavioral disorders," said May, who found in a previous study that PACAP was highly expressed in women exhibiting symptoms of post-traumatic stress disorder (PTSD).

May’s findings are important because anxiety and stress are currently treated with sedatives, benzodiazepines and other central nervous system (CNS) depressants. When taken with opioid pain medication, the combination of the drugs can lead to extreme sleepiness, respiratory depression, coma and death.

Yesterday, the U.S. Food and Drug Administration ordered new “black box” warning labels be put on all medications that contain opioids, benzodiazepines and CNS depressants, warning patients and physicians about the increased risk.

According to a 2015 study, over a third of the patients prescribed opioids for chronic musculoskeletal pain were given a sedative. And patients with a history of psychiatric and substance abuse disorders were even more likely to be co-prescribed opioids and sedatives.

‘Wakeup Call’ for Neurontin Abuse

By Pat Anson, Editor

A drug that is often prescribed as an alternative to opioid pain medication is increasingly being abused by patients, according to a small study that found one out of five patients taking the drug illicitly.

Gabapentin – which is sold by Pfizer under the brand name Neurontin -- is approved by the Food and Drug Administration to treat epilepsy and neuropathic pain caused by shingles.

It is also prescribed “off-label” for a variety of other conditions, including depression, migraine, fibromyalgia and bipolar disorder.

In a study of urine samples from 323 patients being treated at pain clinics and addiction treatment centers, 70 patients were found to be taking gabapentin without a prescription.

“The high rate of misuse of this medication is surprising and it is also a wakeup call for prescribers. Doctors don’t usually screen for gabapentin abuse when making sure patients are taking medications, such as opioids, as prescribed. These findings reveal that there is a growing risk of abuse and a need for more robust testing,” said Poluru Reddy, PhD, medical director of ARIA Diagnostics in Indianapolis, IN. Reddy presented his study at the annual meeting of the American Association for Clinical Chemistry in Philadelphia.

Researchers found that of those patients taking gabapentin illicitly, over half (56%) were taking it with an opioid, about a quarter (27%) with an opioid and muscle relaxant or anxiety medication, and the rest with other substances. The urine samples came primarily from pain clinics in Indiana, Arizona, and Massachusetts.

“Little information exists regarding the significance of Gabapentin abuse among clinical patients. Until recently, it was considered to have little potential for abuse however this review has shown that a significant amount of patients are taking Gabapentin without physician consent. This could be due to the fact that recent studies have revealed that Gabapentin may potentiate the ‘high’ obtained from other central nervous system acting drugs,” wrote Reddy.

"Patient safety is Pfizer’s utmost priority.  We strongly support and recommend the need for appropriate prescribing and use of all our medicines," a spokesperson for Pfizer said in an email to Pain News Network.

Gabapentin is not scheduled as a controlled substance and when taken alone there is little potential for abuse. But when taken with other drugs, such as opioids, muscle relaxants, and anxiety medications like Valium and Xanax, researchers say gabapentin can have a euphoric effect.

Between 2008 and 2011 the number of emergency room visits for misuse or abuse of gabapentin increased by nearly five times, according to the Drug Abuse Warning Network. Side effects from gabapentin include weight gain, dizziness, ataxia, somnolence, nervousness and fatigue.

Increased Prescribing of Gabapentin

A report by IMS Health found that 57 million prescriptions for gabapentin were written in the U.S. in 2015, a 42% increase since 2011.

Gabapentin is one of several medications being promoted by the Centers for Disease Control and Prevention as a "safer"  alternative to opioids.  The American Pain Society recently recommended that gabapentin be considered for post-operative pain relief.

But the growth in gabapentin prescribing is drawing scrutiny in the UK, where the Advisory Council on the Misuse of Drugs (ACMD) recommended earlier this year that gabapentin and pregabalin (Lyrica) be reclassified as Class C controlled substances, which would make them harder to obtain.

“Both pregabalin and gabapentin are increasingly being reported as possessing a potential for misuse. When used in combination with other depressants, they can cause drowsiness, sedation, respiratory failure and death,” said Professor Les Iverson, ACMD chairman, in a letter to Home Office ministers.

“Pregabalin causes a ‘high’ or elevated mood in users; the side effects may include chest pain, wheezing, vision changes and less commonly, hallucinations. Gabapentin can produce feelings of relaxation, calmness and euphoria. Some users have reported that the ‘high’ from snorted gabapentin can be similar to taking a stimulant.”

Gabapentin is "one of the most abused and diverted drugs” in the U.S. prison system, according to Jeffrey Keller, MD,  the chief medical officer of Centurian, a private company that provides prison healthcare services.

“Inmates show up at my jails all the time with gabapentin on their current medication list,” Keller wrote in Corrections.com. “It produces euphoria, a marijuana-like high, sedation, and, at high enough doses, dissociative/psychedelic effects. It works so well that it is used in the drug community to mellow out methamphetamine tweaking and to cut heroin. Since drug abusers know about these illicit uses of gabapentin on the streets, once they get to jail they often view gabapentin as an obtainable ‘jail substitute’ for their preferred drugs.

“Unfortunately, the abuse potential of gabapentin is not recognized much outside of jails and prisons. Community prescribers are generally unaware that gabapentin can be misused and (in my experience) are often incredulous and even disbelieving when told about ‘the dark side’ of gabapentin.”

Gabapentin (Neurontin) has a checkered history. Originally developed as a nerve drug, Pfizer agreed to pay $430 million in fines to resolve criminal and civil charges for illegally marketing Neurontin to treat conditions it was not approved for. According to some estimates, over 90% of Neurontin sales are for off-label uses.

In 1999, a Pfizer executive was so mystified by Neurontin’s popularity he called it the “snake oil of the twentieth century.”  

An Opportunity to Make Ourselves Heard

By Richard “Red” Lawhern, Guest Columnist

Many kinds of chronic pain are represented by the readers of Pain News Network -- among them, several forms of peripheral neuropathic pain.  PNN readers might not be aware that a public meeting was recently held by the U.S. Food and Drug Administration on “Patient-Focused Drug Development for Neuropathic Pain Associated with Peripheral Neuropathy.” 

You can watch and listen to the June 10th meeting by clicking here.

The FDA maintains a public gateway for comments on the meeting and its goals.  I urge anyone who wishes to influence this issue to submit their comments. The public comment period ends August 10th. 

As of July 2nd, only 27 comments have been received! 

To get any notice at all, we need 2,700 -- or better yet, 27,000 comments -- not 27.  Silence will almost certainly be maliciously interpreted by the FDA to mean that pain patients are doing okay with presently available remedies, which all of us realize we most decidedly are not.

To make a comment, the FDA gateway may be reached by clicking here.

The following was the questionnaire filled out by meeting attendees.  Follow-up comments may be more effective if focused on these areas:

          Topic 1: Disease symptoms and daily impacts that matter most to patients.

1)  How would you describe your pain associated with peripheral neuropathy? What terms would
you use to describe the most bothersome aspects of pain? (Examples may include stabbing
sensations, electric shocks, burning or tingling, etc.)

2)  Are there specific activities that are important to you but that you cannot do at all or as fully as
you would like because of your neuropathic pain? (Examples may include sleeping
through the night, daily hygiene, participation in sports or social activities, intimacy with a
spouse or partner, etc.)

3)  How does your neuropathic pain affect your daily life on the best days? On the worst days?

4)  How has your neuropathic pain changed over time?

5)  What worries you most about your condition?

Topic 2: Patients’ perspectives on current approaches to treatment

1)  What are you currently doing to help treat your neuropathic pain associated with peripheral neuropathy? (Examples may include prescription medicines, over-the-counter products, and other therapies including non-drug therapies such as physical therapy). How has your treatment regimen changed over time, and why?

2)  How well does your current treatment regimen control your neuropathic pain? How well have these treatments worked for you as your condition has changed over time? Would you define your condition today as being well managed?

3)  What are the most significant downsides to your current treatments, and how do they affect your daily life? (Examples of downsides may include bothersome side effects, going to the hospital or clinic for treatment, time devoted to treatment, restrictions on driving, etc.)

4)  Assuming there is no complete cure for your neuropathic pain, what specific things would you look for in an ideal treatment for your neuropathic pain?  What would you consider to be a meaningful improvement in your condition (for example specific symptom improvements or functional improvements) that a treatment could provide?

5)  If you had the opportunity to consider participating in a clinical trial studying experimental treatments for neuropathic pain, what things would you consider when deciding whether or not to participate? (Examples may include how severe your neuropathic pain is, how well current treatments are working for you, your concern about risks, etc.)

Mine was one of the first comments submitted.  After summarizing my background as a chronic pain patient advocate, I offered several inputs.  Two seem particularly aligned with the concerns of PNN readers:

1)  Despite the legal restrictions still placed on medical marijuana, there is ample evidence in patient reports that several strains of this natural plant can be used effectively in pain management for a wide variety of chronic pain conditions, including peripheral neuropathy. Federal funding is needed to bring marijuana research out of the shadows and integrate it into mainstream medicine. If legislative changes are needed, then seek them soon.

2)  The most important near term outcome that this public meeting can reinforce is recognition that legally prescribed opioid medications play an indispensable role in present treatment of chronic neuropathic pain which is refractory to other therapies. In this context, the recently published CDC “voluntary” guidelines on prescription of opioids in adult chronic non-cancer pain need to be withdrawn immediately and rewritten to make this role clear -- for both peripheral neuropathic pain and many other chronic pain conditions.

In their present form, the CDC guidelines have become a de facto restrictive practice standard that is driving doctors out of pain management and thousands of patients into unmitigated agony. The basis for the guidelines is also scientifically weak and may have reflected professional or financial self-interest bias on the part of some participants in the “Core Expert Group” that supported the guidelines.

Insofar as I can determine, the working group did not include a SINGLE practicing board certified pain management specialist who is actively treating patients. Revisions of the guidelines need to reflect a much more patient-centered frame of reference, with explicit recognition that dose levels must be tailored to the individual patient and that effectiveness is highly variable between patients due to genetic factors which make some people poor metabolizers of this class of medication.

Richard “Red” Lawhern, PhD, became a patient advocate 20 years ago after his wife developed trigeminal neuralgia, a chronic facial pain disorder. He presently supports 20 groups on Facebook with a membership of over 15,000 patients and family members.

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.

How Neuroinflammation Causes Chronic Pain

Barby Ingle, Columnist

What is neuroinflammation and why does it cause severe burning pain even when there seems to be no injury?

Let me explain it as simply as I can. Say you sprain your ankle. Your ankle then hurts, swells, discolors, and the pain limits use. The swelling occurs because of “healing” chemicals that move into the affected area and work to repair any damage.

In a typical person, this process is successful and the healing chemicals trigger another set of chemicals to take the healing chemicals away. The swelling and discoloration go away and the person doesn’t have any additional issues healing from that trauma.

But sometimes the healing process doesn’t work correctly and the neuroinflammation becomes chronic, activating glial cells in our spine and brain. This poor healing process changes your spine and brain in ways that essentially leave your pain signals turned on.  

Glial cells are small nerve cell that fire off about every two minutes looking for any threats to the body. This is part of your fight or flight system. They are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for the brain's neurons. Glia is a Greek word meaning glue.

In the human brain, there is roughly one glia for every neuron, with a ratio of about two neurons for every three glia in the cerebral gray matter, according to the research article, “Equal Numbers of Neuronal and Nonneuronal Cells Make the Human Brain an Isometrically Scaled-Up Primate Brain.”

UNIVERSITY OF MANCHESTER

The four main functions of glial cells are to surround neurons and hold them in place; supply nutrients and oxygen to neurons; insulate one neuron from another; and to destroy pathogens and remove dead neurons. They also modulate neurotransmission, according to the “D-amino acids in the brain: d-serine in neurotransmission and neurodegeneration" research paper. Therefore, glia is a lot more than just the “glue” of the nervous system.

Why should we pay attention to glia activated neuroinflammation? There needs to be much more research into this area and ways to control glial activation. What else activates glia? What deactivates it?

At a medical conference in 2008, I learned how neuroinflammation primes the nervous system in chronic pain patients. Let’s say that someone slaps you unexpectedly. Your body reacts with a fight or flight response. Then down the road a few months, maybe a year, someone slaps you again. Now your fight or flight response is on guard. Instead of firing every two minutes or so, the glial are on full time. This is a signal to your healing process that something is wrong. Your body wants to be ready to protect you in case you are slapped again.

The second “slap” can be any kind of any trauma: a torn ligament, broken bone or even a paper cut. It can be just as big or even smaller than the first slap. The first slap causes the priming, the second one confirms the risk (even if there is none), and now the body’s protection system is “on” just in case.

Looking at my case, I had a tear in two of my knee ligaments in 2001 and underwent surgery. I bounced back in a very short time and continued on with my athletic activities as a head Division IA collegiate cheerleading and dance coach.

About a year later, I was in a minor auto accident and had a brachia plexus injury which devastated my life. The harder I fought it, the worse I got physically. Was it priming? Was I exposed to something that set off the neuroinflammation process?

Fortunately, years later I was able to deactivate my glia and go into remission because of infusion therapy. That helped me to understand the importance of controlling glia activation and neuroinflammation.

I hope by sharing my story it starts more conversations to get medical practices to catch up to the science that already exists. Is deactivating the glia a cure? No, but it does go a long way in assisting with chronic pain management.

It got me from wheels to walking. And now that I am walking, I will keep talking until more lives are changed for the better. 

Barby Ingle suffers from Reflex Sympathetic Dystrophy (RSD) and endometriosis. Barby is a chronic pain educator, patient advocate, and president of the International Pain Foundation. She is also a motivational speaker and best-selling author on pain topics.

More information about Barby can be found at her website.

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.

Lyrica Linked to Birth Defects

By Pat Anson, Editor

A drug widely prescribed to treat fibromyalgia, neuropathy and other chronic pain conditions increases the risk of major birth defects, according to a new study published in Neurology, the medical journal of the American Academy of Neurology.

Women taking pregabalin were six times more likely to have a pregnancy with a major defect than women who were not taking the drug, the study found. The birth defects included heart defects and structural problems with the central nervous system (CNS) or other organs. Birth defects due to chromosomal abnormalities were not included in the results.

Pregabalin is the generic name of Lyrica, which is approved by the FDA to treat diabetic nerve pain, fibromyalgia, epilepsy, post-herpetic neuralgia caused by shingles and spinal cord injury. It is also prescribed “off label” to treat a variety of other conditions. Lyrica is Pfizer’s top selling drug, generates over $5 billion in annual sales, and is currently approved for use in over 130 countries.

The international study involved nearly 700 pregnant women in seven different countries. Four of the 125 women who took pregabalin during pregnancy had children with central nervous system defects, or 3.2 percent. That compares to a birth defect rate of just 0.5% in the 570 women who did not take pregabalin.

Of the women taking pregabalin, 115 were taking it to treat neuropathic pain, 39 were taking it for psychiatric disorders, including depression and anxiety, five were taking it for epilepsy, and one for restless leg syndrome.

Most of the women started taking pregabalin before they became pregnant. All of them stopped taking the drug at an average of six weeks into their pregnancies.

A small number of women also took another anti-seizure drug during their pregnancy. Women in that group had a 6 percent chance of a major birth defect, compared to 2 percent of the women who did not take another anti-seizure medication.

“We can’t draw any definitive conclusions from this study, since many of the women were taking other drugs that could have played a role in the birth defects and because the study was small and the results need to be confirmed with larger studies, but these results do signal that there may be an increased risk for major birth defects after taking pregabalin during the first trimester of pregnancy,” said study author Ursula Winterfeld, PhD, of the Swiss Teratogen Information Service and Lausanne University Hospital in Lausanne, Switzerland.

“Pregabalin should be prescribed for women of child-bearing age only after making sure that the benefits of the drug outweigh the risks and after counseling them about using effective birth control. In cases where women have taken pregabalin during pregnancy, extra fetal monitoring may be warranted.”

A spokesman for Pfizer said the study was small and the findings could have been influenced by other factors.

"As the authors agree, the study has significant limitations and cannot be used to draw definitive conclusions," Steven Danehy said in an email to Pain News Network. "The study was small, did not account for other medical conditions or medications, and the women taking Lyrica had higher rates of smoking and diabetes, all of which can negatively affect pregnancy outcomes."  

Because women are more likely than men to have a chronic pain condition such as fibromyalgia, they are the biggest consumers of Lyrica.

The FDA warning label for Lyrica does not specifically warn pregnant women not to take the drug. But it does caution them to consult with a doctor if they are pregnant or plan to become pregnant.

“It is not known if Lyrica will harm your unborn baby. You and your healthcare provider will have to decide if you should take Lyrica while you are pregnant. If you become pregnant while taking Lyrica, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry,” the label says.

The label also cautions men to see a doctor if they plan to father a child while taking Lyrica. 

“Animal studies have shown that pregabalin, the active ingredient in Lyrica, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take Lyrica,” the warning label states.

What Does Your Pain Feel Like?

By Pat Anson, Editor

Does your chronic pain feel like you’ve been hit with a hammer, a bad sunburn that won’t go away, or ants crawling under your skin?

Those are some of the choices patients have in a new campaign launched in Ireland to change the way patients describepain to their physicians.   

Accurately assessing pain is difficult because pain is so subjective. For many years doctors have relied on various versions of the Wong Baker Pain Scale – a series of sad and smiling faces a patient chooses from to help their doctor understand how much pain they are in. The scale is so simple it was originally developed for children, but is now used around the world for adults.

The “Mypainfeelslike…” campaign aims to improve on that method by using more descriptive images and phrases to help doctors understand and diagnose their patient’s pain. The campaign focuses on neuropathic pain, but can be used for many other types of chronic pain. The initiative is sponsored by Grunenthal Group, a German pharmaceutical company.

Instead of an unhappy face, patients can choose from a dozen images, ranging from a burning flame to a rope tied in knots to a set of ice cubes. They also fill out a questionnaire and select different phrases to describe their pain, such as “a hot iron on my skin” or “a volcano erupting.”

Patients are also asked to fill out a questionnaire to select different phrases to describe their pain, such as “a hot iron on my skin” or “a volcano erupting.” And there's a list of multiple choice answers to describe how pain affects their ability to work, exercise and socialize.

It may take a few minutes to complete the questionnaire, but the idea is to get patients to “invest more time and accurateness in thinking about their symptoms, describing them more precisely, and preparing for doctors’ appointments.”

“Doing so forces us to reconsider our chronic pain, and the different ways that we feel it. This improves our self-awareness, allows us to better communicate our situation, and helps us get the most value out of the very short time that we usually have during doctors’ appointments,” the website says.

To take the questionnaire, click here.

According to a survey by Grunenthal, over half of Irish pain sufferers feel frustrated when trying to communicate their pain to a doctor. Over a quarter say they delay discussing their pain because they’re not sure how to do it.

“Living with chronic or nerve pain affects people’s well-being, their ability to be independent, their productivity and relationships, which can lead to feelings of depression," John Lindsay, chair of Chronic Pain Ireland told the Irish Independent.  “The ‘Mypainfeelslike…’ campaign will help raise awareness of the impact of chronic pain and give people living with this disease the tools to re-evaluate their pain management plans.”

Neuropathy More Damaging Than Previously Thought

By Pat Anson, Editor

A tingling, sometimes painful sensation in the hands and feet – the early stages of small fiber neuropathy -- may be more damaging to the peripheral nervous system than previously thought, according to new research published in JAMA Neurology.

A 3-year study by Johns Hopkins neurologists found that patients with small fiber neuropathy showed unexpected deterioration over the entire length of sensory nerve fibers, not just nerve fibers at the surface of the skin.

“I liken small fiber neuropathy to the canary in the coal mine,” says senior author Michael Polydefkis, MD, professor of neurology at the Johns Hopkins University School of Medicine and director of the Cutaneous Nerve Lab. “It signals the beginning of nerve deterioration that with time involves other types of nerve fibers and becomes more apparent and dramatically affects people’s quality of life. The results of this new study add urgency to the need for more screening of those with the condition and faster intervention.”

Nearly 26 million people in the United States have diabetes and about half have some form of neuropathy, according to the American Diabetes Association.  Small fiber neuropathy can also be caused by lupus, HIV, Lyme disease, celiac disease or alcoholism.

Diabetic peripheral neuropathy causes nerves to send out abnormal signals. Patients feel pain or loss of feeling in their toes, feet, legs, hands and arms. It may also include a persistent burning, tingling or prickling sensation. The condition can eventually lead to injuries, chronic foot ulcers and even amputations.

Polydefkis and his colleagues found that small fiber nerve damage occurs even in patients with prediabetes, and the early symptoms of burning pain may be less benign than most clinicians think. Routine nerve tests, like nerve conduction, often fail to identify nerve damage because they mostly assess injury to large diameter nerve fibers.

In an effort to measure nerve damage more accurately, Johns Hopkins researchers took small samples of skin — the size of a large freckle — from 52 patients diagnosed with small fiber neuropathy and from 10 healthy controls. Skin samples were taken from the ankle, the lower thigh near the knee and the upper thigh. Three years later, samples from the same area in the same patients were taken for comparison.

Microscopic analysis of the skin samples showed that patients with small fiber neuropathy initially had fewer nerve fibers on the ankle compared to the upper thigh, demonstrating the most nerve damage was further down the leg. But after three years, researchers found that longer nerve fibers were also lost from the lower and upper thighs, something that was not expected.

“We are all taught in medical school that the longest nerves degrade first, and we show that this isn’t always the case,” says lead author Mohammad Khoshnoodi, MD, assistant professor of neurology at Johns Hopkins,

Patients with prediabetes or diabetes had at least 50 percent fewer small nerve fibers in their ankles initially than those participants with an unknown cause for their small fiber neuropathy, indicating these patients started the study with more damage to their small nerve fibers.

The patients with prediabetes continued to have worsening damage to their small nerve fibers over the course of the study, losing about 10 percent of their nerve fiber density each year at all sites tested along the leg. Patients with diabetes also lost similar rates of nerve fibers along the three sites of the leg.

“I expected that people with diabetes would do worse, but I didn’t really expect people with prediabetes to experience a similar rate of degradation of their small nerve fibers,” says Polydefkis.

Researchers caution that their study was small, and that other factors such as high blood sugar, smoking, high blood pressure and high cholesterol, may also have contributed to the decline in nerve fibers.